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"abstract": "OBJECTIVE\nTo report 2 cases of nonoperable intracranial bleeding associated with apixaban managed by 3-factor prothrombin complex concentrate (PCC3).\n\n\nMETHODS\nCase 1 presented with a 1.3-cm left parieto-occipital hemorrhage and a thin subdural hematoma (SDH) on the left tentorium of the brain about 6 hours after his last dose of apixaban. Case 2 presented with a 4-mm left parafalcine SDH with time of most recent apixaban dose unknown. The patients received 24.9 to 25.5 U/kg of PCC3 with none to 1 U fresh frozen plasma (FFP) and demonstrated minimal or no progression in lesions measured by repeat computed tomography (CT) after treatment. One patient was discharged to a skilled nursing facility after 8 days; the other patient was discharged to home after 18 days.\n\n\nCONCLUSIONS\nApixaban has no specific antidote. Current bleeding management strategies are based on expert opinion. The risks and benefits for differing strategies are unclear, and little clinical experience for managing apixaban-associated intracranial bleeding has been reported to date. These cases describe the clinical use of PCC3 to manage parieto-occipital and subdural hemorrhage associated with apixaban in events not requiring surgical intervention.\n\n\nCONCLUSIONS\nIn these 2 cases, 25 U/kg PCC3, with none to one unit FFP, ceased apixaban-associated intracranial bleeding without apparent thrombogenic complications.",
"affiliations": "1 Department of Pharmacy, Texas Health Presbyterian Hospital Dallas, Dallas, TX, USA.;2 School of Pharmacy, University of California, San Francisco, CA, USA.;2 School of Pharmacy, University of California, San Francisco, CA, USA.;2 School of Pharmacy, University of California, San Francisco, CA, USA.;1 Department of Pharmacy, Texas Health Presbyterian Hospital Dallas, Dallas, TX, USA.;1 Department of Pharmacy, Texas Health Presbyterian Hospital Dallas, Dallas, TX, USA.;3 School of Pharmacy, Department of Clinical Pharmacy, University of California, San Francisco, CA, USA.",
"authors": "Faust|Andrew C|AC|;Tran|Dang M|DM|;Lo|Catherine|C|;Lai|Sophia|S|;Sheperd|Lyndsay|L|;Liu|Mary|M|;Denetclaw|Tina|T|",
"chemical_list": "D065427:Factor Xa Inhibitors; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban",
"country": "United States",
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"doi": "10.1177/0897190017697884",
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"issn_linking": "0897-1900",
"issue": "31(1)",
"journal": "Journal of pharmacy practice",
"keywords": "PCC3; apixaban; bleeding management; intracranial hemorrhage",
"medline_ta": "J Pharm Pract",
"mesh_terms": "D000369:Aged, 80 and over; D019468:Disease Management; D065427:Factor Xa Inhibitors; D006801:Humans; D020300:Intracranial Hemorrhages; D008297:Male; D011720:Pyrazoles; D011728:Pyridones",
"nlm_unique_id": "8900945",
"other_id": null,
"pages": "107-111",
"pmc": null,
"pmid": "29278991",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Managing Nonoperable Intracranial Bleeding Associated With Apixaban: A Series of 2 Cases.",
"title_normalized": "managing nonoperable intracranial bleeding associated with apixaban a series of 2 cases"
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"abstract": "Human herpesvirus 6 (HHV-6) is an ubiquitous virus that can reactivate in immunocompromised hosts, resulting in diverse clinical sequelae. We describe a case of fatal acute HHV-6 myocarditis in a patient who underwent allogeneic haemopoietic stem cell transplantation (HSCT). To our knowledge, this is the first reported case of biopsy proven HHV-6 myocarditis post-HSCT.",
"affiliations": "Department of Haematology, Westmead Hospital, Sydney, Australia.;Department of Haematology, Westmead Hospital, Sydney, Australia; The Westmead Millennium Institute for Medical Research, The University of Sydney, Sydney, Australia; Sydney Medical School, The University of Sydney, Sydney, Australia.;Coppe Healthcare Solutions, Waukesha, WI, USA.;Department of Haematology, Westmead Hospital, Sydney, Australia; The Westmead Millennium Institute for Medical Research, The University of Sydney, Sydney, Australia; Sydney Medical School, The University of Sydney, Sydney, Australia. Electronic address: emily.blyth@sydney.edu.au.",
"authors": "Brennan|Yvonne|Y|;Gottlieb|David J|DJ|;Baewer|David|D|;Blyth|Emily|E|",
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"journal": "Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology",
"keywords": "Haemopoietic stem cell transplantation; Human herpesvirus 6; Myocarditis",
"medline_ta": "J Clin Virol",
"mesh_terms": "D017809:Fatal Outcome; D015654:Herpesvirus 6, Human; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008853:Microscopy; D008875:Middle Aged; D009205:Myocarditis; D009206:Myocardium; D019349:Roseolovirus Infections; D033581:Stem Cell Transplantation; D014184:Transplantation, Homologous",
"nlm_unique_id": "9815671",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A fatal case of acute HHV-6 myocarditis following allogeneic haemopoietic stem cell transplantation.",
"title_normalized": "a fatal case of acute hhv 6 myocarditis following allogeneic haemopoietic stem cell transplantation"
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"abstract": "BACKGROUND\nBreast cancer metastasis to the gastrointestinal (GI) tract is rare and occurs more frequently in invasive lobular carcinoma. Patients may be asymptomatic or present with variable vague symptoms that may be mistakenly attributed to side effects of chemotherapy or other benign GI diseases. Treatment follows the principles of systemic disease and includes hormonal therapy, chemotherapy and signal transduction inhibitors, with surgical intervention indicated for complications such as obstruction, perforation and hemorrhage.\n\n\nMETHODS\nWe present the case of a female patient with a history of invasive lobular breast carcinoma who had undergone mastectomy and axillary dissection, followed by chemoradiotherapy. Over the next nine years, she developed ovarian and bone metastases for which appropriate treatment was provided. A right iliac fossa mass was discovered during routine clinic review, though she remained asymptomatic. Computed tomography scan showed ileocecal intussusception. Histopathological examination of the right hemicolectomy specimen following emergency surgery confirmed metastatic invasive lobular carcinoma to the GI tract.\n\n\nCONCLUSIONS\nGI tract metastasis may present 30 years after the primary breast cancer. Up to 20% of patients may be asymptomatic as shown by Montagna et al. When present, symptoms are commonly non-specific and vague. Histological diagnosis is challenging. GI metastasis typically appears as intramural infiltration of the bowel wall by small cells arranged in cords.\n\n\nCONCLUSIONS\nIt is important to maintain a suspicion for GI tract metastasis in breast cancer patients who present with abdominal mass or GI symptoms, as this aids in prompt institution of accurate and appropriate management.",
"affiliations": "Department of General Surgery, University Malaya Medical Centre, Lembah Pantai, 59100, Kuala Lumpur, Malaysia. Electronic address: joannemosiun@gmail.com.;Department of General Surgery, University Malaya Medical Centre, Lembah Pantai, 59100, Kuala Lumpur, Malaysia. Electronic address: syafiq.idris@ummc.edu.my.;Department of General Surgery, University Malaya Medical Centre, Lembah Pantai, 59100, Kuala Lumpur, Malaysia. Electronic address: lyteoh@um.edu.my.;Department of General Surgery, University Malaya Medical Centre, Lembah Pantai, 59100, Kuala Lumpur, Malaysia. Electronic address: msteh@um.edu.my.;Department of Pathology, University Malaya Medical Centre, Lembah Pantai, 59100, Kuala Lumpur, Malaysia. Electronic address: patricia@um.edu.my.;Department of General Surgery, University Malaya Medical Centre, Lembah Pantai, 59100, Kuala Lumpur, Malaysia. Electronic address: smhoong76@um.edu.my.",
"authors": "Mosiun|Joanne Aisha|JA|;Idris|Muhammad Syafiq Bin|MSB|;Teoh|Li Ying|LY|;Teh|Mei Sze|MS|;Chandran|Patricia Ann|PA|;See|Mee Hoong|MH|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ijscr.2019.10.003",
"fulltext": "\n==== Front\nInt J Surg Case RepInt J Surg Case RepInternational Journal of Surgery Case Reports2210-2612Elsevier S2210-2612(19)30547-410.1016/j.ijscr.2019.10.003ArticleGastrointestinal tract metastasis presenting as intussusception in invasive lobular carcinoma of the breast: A case report Mosiun Joanne Aisha joannemosiun@gmail.coma⁎Idris Muhammad Syafiq bin syafiq.idris@ummc.edu.myaTeoh Li Ying lyteoh@um.edu.myaTeh Mei Sze msteh@um.edu.myaChandran Patricia Ann patricia@um.edu.mybSee Mee Hoong smhoong76@um.edu.myaa Department of General Surgery, University Malaya Medical Centre, Lembah Pantai, 59100, Kuala Lumpur, Malaysiab Department of Pathology, University Malaya Medical Centre, Lembah Pantai, 59100, Kuala Lumpur, Malaysia⁎ Corresponding author. joannemosiun@gmail.com07 10 2019 2019 07 10 2019 64 109 112 9 9 2019 1 10 2019 © 2019 The Authors2019This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Highlights\n• Gastrointestinal (GI) tract metastasis in breast cancer is rare and occurs more commonly in invasive lobular carcinoma.\n\n• The interval between the index breast cancer and GI tract spread may be as long as 30 years.\n\n• 20% of patients with GI tract metastasis are asymptomatic, and detection may rely on physical examination and imaging.\n\n• Management follows the principles of treatment in systemic disease in breast cancer, with consideration for surgery in obstruction, perforation or bleeding.\n\n\n\nIntroduction\nBreast cancer metastasis to the gastrointestinal (GI) tract is rare and occurs more frequently in invasive lobular carcinoma. Patients may be asymptomatic or present with variable vague symptoms that may be mistakenly attributed to side effects of chemotherapy or other benign GI diseases. Treatment follows the principles of systemic disease and includes hormonal therapy, chemotherapy and signal transduction inhibitors, with surgical intervention indicated for complications such as obstruction, perforation and hemorrhage.\n\nPresentation of case\nWe present the case of a female patient with a history of invasive lobular breast carcinoma who had undergone mastectomy and axillary dissection, followed by chemoradiotherapy. Over the next nine years, she developed ovarian and bone metastases for which appropriate treatment was provided. A right iliac fossa mass was discovered during routine clinic review, though she remained asymptomatic. Computed tomography scan showed ileocecal intussusception. Histopathological examination of the right hemicolectomy specimen following emergency surgery confirmed metastatic invasive lobular carcinoma to the GI tract.\n\nDiscussion\nGI tract metastasis may present 30 years after the primary breast cancer. Up to 20% of patients may be asymptomatic as shown by Montagna et al. When present, symptoms are commonly non-specific and vague. Histological diagnosis is challenging. GI metastasis typically appears as intramural infiltration of the bowel wall by small cells arranged in cords.\n\nConclusion\nIt is important to maintain a suspicion for GI tract metastasis in breast cancer patients who present with abdominal mass or GI symptoms, as this aids in prompt institution of accurate and appropriate management.\n\nKeywords\nBreast cancerInvasive lobular carcinomaGastrointestinal metastasisIntussusceptionCase report\n==== Body\n1 Introduction\nGastrointestinal (GI) tract metastasis in breast cancer is rare, with autopsy studies reporting an incidence of 6–18% [1]. Compared to invasive ductal carcinoma, the lobular subtype has a predilection for distant spread to unusual sites such as the GI tract, peritoneum and adnexa [2]. Any part of the GI tract may be affected [3]. The most commonly involved sites are the stomach (6–18%), followed by the colon or rectum (8–12%). Metastasis to the small bowel seldom occurs [4].\n\nPatients with GI tract metastasis may remain asymptomatic, present with non-specific symptoms or manifest with intestinal obstruction, perforation or bleeding. GI tract metastasis may occasionally be the first indicator of an undiagnosed breast cancer [5]. Schwarz et al. has reported a median interval of 6 years (range 0.25–12.5 years) between the diagnosis of breast cancer and the development of GI tract secondary tumors [6]. However, a cancer-free interval of as long as 30 years has been reported by Benfiguig et al. [7].\n\nThe subtle presentation of GI tract metastasis may mimic other benign GI conditions. Thus, a high index of suspicion should be maintained to avoid delayed diagnosis and treatment. Management follows the principles of systemic disease and includes hormonal therapy, chemotherapy and signal transduction inhibitors. Palliative surgery is indicated in patients who present with complications of GI tract metastasis.\n\nThis work has been reported in line with the SCARE criteria [8].\n\n2 Presentation of case\nA 51-year-old female underwent right mastectomy and axillary dissection in 2008 for Stage 3 (T2N2M0) invasive lobular carcinoma of the right breast which was negative for estrogen (ER) and progesterone receptors (PR), and equivocal for human epidermal growth factor receptor 2 (HER2). Histopathological examination (HPE) of the mastectomy specimen showed clear margins with no lymphovascular invasion. She completed three cycles of 5-fluorouracil, epirubicin and cyclophosphamide (FEC), and three cycles of taxotere. This was followed by 15 fractions of radiotherapy to the right chest wall and supraclavicular fossa.\n\nTwo years later, the patient developed metastatic lobular carcinoma to the ovaries. She underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy. The metastatic tumor was positive for ER and PR, and equivocal for HER2. She was subjected to six cycles of chemotherapy comprising gemcitabine and cisplatin, after which tamoxifen was initiated. Seven years later, a left breast lump with palpable axillary and supraclavicular lymph nodes were found. Biopsy of the lump revealed invasive lobular carcinoma, ER and PR positive, and equivocal for HER2. Computed tomography (CT) detected bone metastasis. Daily oral letrozole led to resolution of both breast lump and lymph nodes. She was started on monthly intravenous zoledronic acid injections.\n\nSeven months later, the patient was found to have a right iliac fossa mass on abdominal examination. She denied having abdominal pain, vomiting, altered bowel habit or passage of bloody stools. There were no signs or symptoms or intestinal obstruction. A contrasted abdominal CT showed ileocecal intussusception (Fig. 1, Fig. 2).Fig. 1 Axial section of the abdominal CT scan demonstrating the target sign of intussusception, marked by a red arrowhead.\n\nFig. 1Fig. 2 Sagittal section of the abdominal CT scan showing an entrapped bowel segment within an edematous outer bowel loop, marked by a red arrow. The proximal small bowel was not dilated.\n\nFig. 2\n\nThe patient underwent emergency exploratory laparotomy. Intraoperatively, one litre of straw-colored ascitic fluid was drained from the peritoneal cavity. There were multiple peritoneal nodules as well as enlarged intraabdominal lymph nodes. Right hemicolectomy with the creation of double barrel stoma was performed (Fig. 3).Fig. 3 Sectioning of the right hemicolectomy specimen revealed telescoping of the distal ileum into the cecum through the ileocecal valve. The terminal ileum wall was thickened and fibrotic with whitish solid nodules. Multiple small polyps were seen in the cecum and part of the ascending colon mucosa.\n\nFig. 3\n\nMicroscopically, metastatic invasive lobular carcinoma with tumor cell infiltration into the full thickness of the terminal ileum, cecum and appendix was seen. Both proximal and distal surgical margins were involved and tumor deposits were seen in the sampled lymph nodes. There was weak ER positivity and focal staining for PR. HER2 was focally overexpressed. The tumor cells stained negative for E-cadherin (Fig. 4, Fig. 5).Fig. 4 Microscopic examination of the resected specimen at low power magnification (40×) showed diffuse infiltration of the submucosa and lamina propria right up to the mucosal layer in single file pattern.\n\nFig. 4Fig. 5 The tumor cells were round to oval in shape with nuclear pleomorphism and vesicular nuclei. There was HER2 overexpression in the cytoplasmic membrane of malignant cells.\n\nFig. 5\n\nPost-operative recovery was uneventful. The patient was continued on oral letrozole and intravenous zoledronic acid injections. She could not afford CDK4/6 inhibitor treatment due to financial constraints. Palliative paclitaxel was started three months later due to disease progression with malignant ascites.\n\n3 Discussion\nInvasive lobular carcinoma is a distinct subtype of invasive breast cancer that accounts for 5–15% of breast cancer cases [9]. Despite the higher prevalence of invasive ductal carcinoma, the lobular subset has been found to metastasize to the GI tract more frequently. In a study conducted by Borst et al. involving a series of 2605 patients, it was found that there was a statistical difference in the incidence of GI tract metastasis between invasive ductal and lobular carcinoma. The incidence of GI tract spread in invasive lobular carcinoma was 4.5% compared to 0.8% in invasive ductal carcinoma [10]. In patients with mixed ductal and lobular carcinoma, the likely cause of the metastatic disease is commonly the lobular component [1].\n\nThe reason for a higher rate of GI tract metastasis in invasive lobular carcinoma compared to ductal carcinoma has not been fully elucidated. However, there are postulations that it involves the loss of E-cadherins and the microenvironment of the GI tract. E-cadherins are cell-to-cell adhesion molecules that play a role in maintaining differentiation and preventing invasion. Invasive lobular carcinoma stains negative for E-cadherin. Consequently, this subtype of breast cancer is more dedifferentiated and invasive [11]. The microenvironment of the GI tract is thought to be conducive to the growth of secondary tumor cells as it provides the required building blocks for tumor proliferation, as well as possessing a microanatomy that favors entrapment of tumor cells [12].\n\nOur patient did not have any GI complaints and was only incidentally found to have an abdominal mass on examination. A case series of 40 patients by Montagna et al. showed that 80% of patients presented with GI symptoms, while the remaining 20% were asymptomatic [13]. This concurred with the findings of Switzer et al. in a case series of 21 patients which showed that 20% of patients were asymptomatic. Symptomatic patients presented with nausea (20%), abdominal pain (15%), small bowel obstruction (10%), dysphagia (5%), and GI bleed (5%) [14]. A review of 32 patients who sought treatment for GI tract breast cancer metastasis at the Mayo Clinic in Rochester from 2000 to 2013 showed that common presentations were nausea or vomiting (56%) and changes in stool (28%). Other complaints included weight loss, anemia, ascites, early satiety and dysphagia. Four patients (12%) were asymptomatic with metastases found incidentally on routine scanning [15].\n\nHistological diagnosis of GI tract metastasis in breast cancer can be challenging. GI tract metastasis of lobular carcinoma typically shows an intramural infiltration involving the serosal, muscular and submucosal layers with small cells invading the tissue in cords [16]. The tumor cells frequently have a signet-ring appearance [17]. A feature suggestive of metastatic spread is the lack of dysplasia or atypia in the adjacent colonic epithelium and the visualization of tumor cells infiltrating the nearby native preexisting glands. Immunohistochemical (IHC) markers are helpful in the diagnosis of metastatic lobular breast carcinomas. Cytokeratin 7 (CK 7), ER, PR and gross cystic disease fluid protein-15 (GCDFP-15) usually stain positive in secondary deposits of lobular carcinoma and negative in primary GI tumors. Cytokeratin (CK 20) and carcinoembryonic antigen (CEA) are usually positive in primary GI tumors and negative in metastatic lobular carcinoma to the GI tract [18]. The IHC staining of this patient’s hemicolectomy specimen showed that there was a weak positivity for ER and focal staining of PR. There was also overexpression of HER2. This pattern of IHC staining was favorable for the diagnosis of metastatic lobular breast carcinoma.\n\nThe treatment for metastatic breast cancer with GI tract involvement is systemic treatment with chemotherapy, endocrine therapy or signal transduction inhibitors. Palliative surgery is necessary in patients with complications such as intestinal obstruction, perforation or hemorrhage. Remissions are observed in 32–53% of patients [19]. Switzer et al. found that the five-year survival from diagnosis of GI tract metastasis was 29% [14].\n\n4 Conclusion\nIn conclusion, patients with a history of breast cancer who present with GI symptoms should be investigated for GI tract metastasis, regardless of how long ago the primary breast cancer diagnosis was made. Early investigation and establishment of the diagnosis are vital in ensuring prompt and adequate treatment.\n\nSources of funding\nNone to declare.\n\nEthical approval\nThis case report is exempt from ethical approval by our institution.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nAuthor contributions\nJoanne Aisha Mosiun: Conceptualization, Acquisition of data, Writing - original draft preparation.\n\nMuhammad Syafiq bin Idris: Surgical therapy for this patient, Visualization, Writing - Reviewing and Editing, Supervision.\n\nTeoh Li Ying: Writing - Reviewing and Editing, Supervision.\n\nTeh Mei Sze: Writing - Reviewing and Editing, Supervision.\n\nPatricia Ann Chandran: Visualization, Writing - Reviewing and Editing.\n\nSee Mee Hoong: Writing - Reviewing and Editing, Supervision, Validation.\n\nRegistration of research studies\nNone.\n\nGuarantor\nSee Mee Hoong.\n\nProvenance and peer review\nNot commissioned, externally peer-reviewed.\n\nDeclaration of Competing Interest\nNo potential conflicts of interest.\n==== Refs\nReferences\n1 Cervi G. Vettoreto N. Vinco A. Cervi E. Villanacci V. Grigolato P. Rectal localization of metastatic lobular breast cancer Dis. Colon Rectum 44 2001 453 455 11289296 \n2 Winston C.B. Hadar O. Teitcher J.B. Metastatic lobular carcinoma of the breast: patterns of spread in the chest, abdomen, and pelvis on CT Am. J. Roentgenol. 175 2000 795 800 10954469 \n3 Taal B.G. den Hartog Jager F.C. Steinmetz R. The spectrum of gastrointestinal metastases of breast carcinoma: I. Stomach Gastrointest. Endosc. 38 1992 130 135 1568608 \n4 Nazareno J. Taves D. Preiksaitis H.G. Metastatic breast cancer to the gastrointestinal tract: a case series and review of the literature World J. Gastroenterol. 12 2006 6219 6224 17036400 \n5 Van Halteren H.K. Peters H. Gerlag P.G.G. Large bowel mucosal metastases from breast cancer J. Clin. Oncol. 16 1998 3711 3713 9817292 \n6 Schwarz R. Klimstra D. Turnbull A. Metastatic breast cancer masquerading as gastrointestinal primary Am. J. Gastroenterol. 93 1998 111 114 9448188 \n7 Benfiguig A. Anciaux M.L. Eugene C.I. Benkemoun G. Etienne J.C. Gastric metastasis of breast cancer occurring after a cancer-free interval of 30 years Ann. Gastroenterol. Hepatol. (Paris) 28 1992 175 177 1444182 \n8 Agha R.A. Borrelli M.R. Farwana R. Koshy K. Fowler A. Orgill D.P. For the SCARE Group The SCARE 2018 statement: updating consensus Surgical CAse REport (SCARE) guidelines Int. J. Surg. 60 2018 132 136 30342279 \n9 Li C.I. Anderson B.O. Daling J.R. Moe R.E. Trends in incidence rates of invasive lobular and ductal breast carcinoma JAMA 289 2003 1421 1424 12636465 \n10 Borst M.J. Ingold J.A. Metastatic patterns of invasive lobular versus invasive ductal carcinoma of the breast Surgery 114 1993 637 642 8211676 \n11 Lehr H.A. Cytokeratin 8 immunostaining pattern and E-cadherin expression distinguish lobular from ductal breast carcinoma Am. J. Clin. Pathol. 114 2 2000 190 196 10941333 \n12 Arpino G. Infiltrating lobular carcinoma of the breast: tumor characteristics and clinical outcome Breast Cancer Res. 6 3 2004 149 156 \n13 Montagna E. Pirola S. Maisonneuv P. Roberto G.D. Cancello G. Palazzo A. Lobular metastatic breast cancer patients with gastrointestinal involvement: features and outcomes Clin. Breast Cancer 18 3 2017 401 405 \n14 Switzer N. Lim A. Du L. Al-Sairafi R. Tonkin K. Schiller D. Case series of 21 patients with extrahepatic metastatic lobular breast carcinoma to the gastrointestinal tract Cancer Treat. Commun. 3 2015 37 43 \n15 Wiisanen J.M. Kaur J.S. Gastrointestinal metastases from breast cancer, a comprehensive review Breast J. 21 5 2015 572 573 26215570 \n16 Van Trappen P. Serreyn R. Elewaut A.E. Abdominal pain with anorexia in patients with breast carcinoma Ann. Oncol. 9 11 1998 1243 1245 9862056 \n17 Signorelli C. Pomponi-Formiconi D. Nelli F. Single colon metastasis from breast cancer: a clinical case report Tumori 91 5 2005 424 427 16459641 \n18 Tot T. The role of cytokeratins 20 and 7 and estrogen receptor analysis in separation of metastatic lobular carcinoma of the breast and metastatic signet ring cell carcinoma of the gastrointestinal tract Acta Pathol. Microbiol. Immunol. Scand. 108 6 2000 467 472 \n19 Deogracias M. Jaime L. Camison I. Zamacola I. Murillo Guibert J. Suescun Garcia R. Rectal metastasis from lobular breast carcinoma 15 years after primary diagnosis Clin. Transl. Oncol. 12 2010 150 153 20156785\n\n",
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"issue": "64()",
"journal": "International journal of surgery case reports",
"keywords": "Breast cancer; Case report; Gastrointestinal metastasis; Intussusception; Invasive lobular carcinoma",
"medline_ta": "Int J Surg Case Rep",
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"title": "Gastrointestinal tract metastasis presenting as intussusception in invasive lobular carcinoma of the breast: A case report.",
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"abstract": "ABO incompatible kidney transplant recipients receive higher dose of immunosuppression. Previous data indicate that the incidence of malignancy is not higher in these patients. Compared to the general population, renal transplant recipients are at 4.4-fold higher risk of developing myeloma. We describe a case of posttransplant multiple myeloma in an ABO incompatible renal transplant recipient of a second graft.",
"affiliations": "Department of Nephrology, Apollo Hospitals, Chennai, Tamil Nadu, India.;Department of Nephrology, Apollo Hospitals, Chennai, Tamil Nadu, India.;Department of Hematology, Apollo Hospitals, Chennai, Tamil Nadu, India.",
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"fulltext": "\n==== Front\nIndian J NephrolIndian J NephrolIJNIndian Journal of Nephrology0971-40651998-3662Medknow Publications & Media Pvt Ltd India IJN-26-28010.4103/0971-4065.168143Case ReportEpstein-Barr virus-positive multiple myeloma following an ABO incompatible second renal transplantation Kirushnan B. Subbarao B. Prabhu P. 1Department of Nephrology, Apollo Hospitals, Chennai, Tamil Nadu, India1 Department of Hematology, Apollo Hospitals, Chennai, Tamil Nadu, IndiaAddress for correspondence: Dr. B. Kirushnan, Flat No. 11, Shanti Enclave, No. 71, Venkatakrishna Road, R. A. Puram, Chennai - 600 028, Tamil Nadu, India. E-mail: balajikirushnan@gmail.comJul-Aug 2016 26 4 280 283 Copyright: © 2016 Indian Journal of Nephrology2016This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.ABO incompatible kidney transplant recipients receive higher dose of immunosuppression. Previous data indicate that the incidence of malignancy is not higher in these patients. Compared to the general population, renal transplant recipients are at 4.4-fold higher risk of developing myeloma. We describe a case of posttransplant multiple myeloma in an ABO incompatible renal transplant recipient of a second graft.\n\nKey words\nABO incompatibleEpstein-Barr virusmultiple myelomaposttransplant lymphoproliferative diseaserenal transplantation\n==== Body\nIntroduction\nPosttransplant lymphoproliferative disorders represent a group of heterogeneous neoplasms. Epstein-Barr virus accounts for the cause of majority of these neoplasms. Adults are usually immune after the primary infection during childhood. ABO incompatible renal transplantation represent a state of heightened immunosuppression. 2nd renal transplant and immunosuppression used for desensitization in ABO incompatible renal transplant could be the reason for development of a hematological malignancy in our case.\n\nCase Report\nA 56-year-old patient underwent spousal renal transplantation in September 2011. No induction was given. On postoperative day 2, he had graft thrombosis due to a surgical cause, and graft nephrectomy was done.\n\nPatient's elder brother with A1 positive blood group was found suitable for renal transplantation. The following desensitization protocol was used in this patient for second renal transplantation [Figure 1]. One dose of rituximab 375 mg/m2 was given on day -30. Twenty-six days after rituximab injection, desensitization was carried out with three sessions of anti A antibody removal by an antigen specific immunoadsorption using Glycosorb A@ column. Immunosuppression with tacrolimus 0.75 mg/kg/day, mycophenolate mofetil 1000 mg/day, and prednisolone 10 mg/day was started on day -30. We did not measure tacrolimus levels prior to transplantation. Induction with basiliximab 20 mg was given on day 0 and day 4 of the surgery. Anti A antibody titer was 1:2 prior to transplantation (not shown in graph).\n\nFigure 1 Desensitization protocol used\n\nRenal transplantation was performed on November 22, 2011. HLA was a 3/6 match. Cross match by complement dependent cytotoxicity was 10%. He was discharged on postoperative day 5 with triple immunosuppresion of prednisolone 30 mg once daily, tacrolimus 0.1 mg/kg/day (3 mg twice daily), and mycophenolate mofetil 500 mg twice daily. Tacrolimus level was maintained between 6 and 10 ng/ml.\n\nOne year after the transplantation, he developed left frontal bone osteomyelitis due to methicillin resistant Staphylococcal aureus which was treated with linezolid for 21 days.\n\nTwo years later, he developed low back ache. Magnetic resonance imaging of the thoracolumbar spine was normal. However, he developed graft dysfunction with a creatinine of 2.3 mgdl with proteinuria and microscopic hematuria. Hemoglobin was 10 gdl, total count was 5100 cells with a normal differential count and normal platelet count. Anti A antibody titer was 1:2. Serum globulin was 7.6 gdl with serum total protein of 11.0 gdl. There was no hypercalcemia. Transplant kidney biopsy was suggestive of mild interstitial fibrosis and tubular atrophy with no features of cast nephropathy, light chain deposition disease or rejection. Immunofluorescence study revealed no deposits. Serum immunofixation electrophoresis was suggestive of kappa light chain monoclonal gammopathy. Free kappa levels were 12,660 mg/L and kappa lambda ratio was 25.59:1. Bone marrow aspiration showed 59% plasma cells and bone marrow biopsy revealed nodular plasma cell aggregates. Immunohistochemistry was suggestive of CD 138 plasma cells. Epstein-Bar virus (EBV) DNA was positive with titers of 12,567 copies/ml.\n\nHe was started on triple drug regimen of bortezomib 2 mg on day 1, 8, 14, and 28 of the month; dexamethasone 40 mg on day 1, 8, 14, and 28 of the month; and oral cyclophosphamide 500 mg on day 1, 8, 14, and 28 of the month.\n\nPatient was maintained on steroids as the sole immunosuppressant on other days. After 6 months of treatment, patient was well with no complaints. There was a marked reduction in total protein to 6.6 gdl, globulin levels to 2.1 gdl, and normalization of the kappa lambda ratio. Serum creatinine was 1.2 mgdl and there was no proteinuria or microscopic hematuria.\n\nDiscussion\nThe risk of malignancy after ABO incompatible renal transplantation is same as that of ABO compatible renal transplantation. Yamamoto et al. analyzed the risk of malignancy in these patients. ABO incompatible kidney transplant recipients were older than ABO compatible kidney transplant recipients and splenectomy was performed in all the ABO incompatible transplant recipients. In this study despite increased age and splenectomy, there was no difference in the incidence of malignancy between ABO incompatible kidney transplant recipients and ABO compatible kidney transplant recipients (4.8% and 4.2%).[1] Hall et al. showed that 7 of 318 ABO incompatible kidney transplant recipients experienced posttransplant cancer.[2]\n\nPost-transplant lymphoproliferative disorders (PTLD) are a group of heterogeneous neoplasms that are associated with EBV infection. Among the hematological malignancies occurring following transplantation, lymphomas are the most common followed by leukemia and multiple myeloma. Factors predisposing to this increased risk of malignancy include impaired immunity due to use of immunosuppressive drugs and primary infection or recrudescence of viral infections with oncogenic potential.[3]\n\nMost cases of PTLDs occur in the first post transplant year. The more intense the immunosuppression used the greater the risk of lymphomas and they occur early. Non-Hodgkin lymphoma accounts for 93% of the cases.[4] Post renal transplant multiple myeloma is a very rare neoplasm accounting for <4% of all PTLDs.[5] Other case series describe the incidence of the disease to be <1%.[6] However, compared to the general population, renal transplant recipients are at 4.4-fold higher risk of developing multiple myeloma and 10-year survival for posttransplant myeloma was 26% lower as compared to nonHodgkin's lymphoma.[7] The Indian scenario has been highlighted by Sakhuja et al. where 40 malignancies were diagnosed in 36 patients after transplantation. The incidence of posttransplant lymphoproliferative disease was 1.45% and only 7 patients had multiple myeloma accounting it to be 24.13% of all lymphomas.[8]\n\nThis case report illustrates a rare case in which posttransplant lymphoma presented as EBV-positive multiple myeloma after receiving aggressive immunosuppression for ABO incompatible kidney transplantation. We, however, did not measure Epstein-Barr serological status of both donor and recipient before transplantation as it is not a routine protocol.\n\nEBV infection produces self-limiting illness in young adults and persists as latent infection in B-cells. In vitro, EBV can transform B-lymphocytes into immortalized lymphoblastoid cell lines.[9] EBV-specific cytotoxic T-lymphocyte responses are impaired in patients who are treated with immunosuppressants and this in turn can lead to lymphoproliferative disorders.[10] Role of EBV infection in the genesis of multiple myeloma after transplantation has not been well elucidated. Given the later occurrence of multiple myeloma after transplantation as compared to other posttransplant lymphoproliferative disease, implication of an oncogenic viral infection following institution of aggressive immunosuppression regimens in the early posttransplant period remains highly speculative, despite the demonstration of EBV infection in a patient with multiple myeloma.[11]\n\nThe risk factors for the multiple myeloma were different in various studies. In a study from the French registry, Caillard et al. reported that posttransplantation myeloma was associated with older age, transplantation from deceased donor, and antithymocyte globulin treatment.[12] Cyclosporine and OKT3 induction regimen was used in a patient who developed post transplantation multiple myeloma after 3 years of transplantation.\n\nIn a study, plasmacytoma/multiple myeloma was described only in 5 out of 78 patients with PTLD.[13] About 75% of the multiple myeloma EBV-positive. EBV-negative post transplant myeloma has also be been reported. Association of multiple myeloma with hepatitis C virus infection has also been described. Multiple myeloma has been described as early as 2 months after transplantation, keeping aside donor transmitted myeloma or the basic disease recurrence. The average age of presentation described is between 2 and 3 years.\n\nApart from low backache, this patient did not have other features of multiple myeloma such as lytic bone lesions or fractures. The clinical presentation of myeloma in the study by Sakhuja et al. included backache (28.5%), severe anemia (28.5%), pathological fracture (57.1%), and graft dysfunction due to light chain deposition disease (14.3%).[8]\n\nBecause primary EBV infection is a risk factor for PTLD, it is essential to identify patients at risk by performing EBV serology before transplantation. In our center, this is not done as a routine. Patients at the highest risk of PTLD are EBV-seronegative recipients who received EBV-seropositive organs. Although the evidence for prophylaxis against EBV infection in patients with EBV Ig G-negative serology is not very clear, recipients who are EBV IgG-negative may benefit from prophylaxis with ganciclovir or acyclovir. Canadian transplant units recommend ganciclovir prophylaxis for donor positive and recipient negative EBV IgG children as they have not been previously exposed to the primary infection. Although ganciclovir is used for CMV prophylaxis which is used much more extensively and consistently in adults, there may be instances when the drug has to be used for EBV prophylaxis when not indicated for CMV prophylaxis. In a study published by Rocchi et al., a positive correlation between PTLD and number EBV infected cells in peripheral blood was made.[14] Acute EBV infection and infectious mononucleosis usually have 10–2000 copies/ml. In PTLD, the viral load is invariably above 5000 copies/ml.[15] Our patient had 12,567 copies/ml, strongly suggesting a positive correlation between EBV infection and PTLD.\n\nThus, we recommend routine pretransplant surveillance of all donors and recipients for EBV serology, especially in high risk groups such as second renal transplant who may benefit from prophylaxis to prevent PTLD. Second renal transplantation and heightened immunosuppression for ABO incompatibility could be the reason for the development of EBV-positive multiple myeloma after transplantation. There are no case reports of EBV-positive multiple myeloma after ABO incompatible renal transplant in the literature until date. Viral DNA demonstration in the plasma cells by in situ hybridization for Epstein-Barr coded RNA or immunohistochemistry to detect viral latent membrane protein-1 was not done due to financial constraints.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n\nAcknowledgment\nDr. Maya Menon – Department of Pathology.\n==== Refs\nReferences\n1 Yamamoto T Kawaguchi T Watarai Y Tujita M Hiramitsu T Nanmoku K Potent immunosuppression for ABO-incompatible renal transplantation may not be a risk factor for malignancy Transplant Proc 2012 44 210 3 22310616 \n2 Hall EC Engels EA Montgomery RA Segev DL Cancer risk after ABO incompatible living-donor kidney transplantation Transplantation 2013 96 476–79 23799426 \n3 London NJ Farmery SM Will EJ Davison AM Lodge JP Risk of neoplasia in renal transplant patients Lancet 1995 346 403 6 7623570 \n4 Penn I The changing pattern of posttransplant malignancies Transplant Proc 1991 23 1 Pt 2 1101 3 1899153 \n5 Sheil AG Flavel S Disney AP Mathew TH Hall BM Cancer incidence in renal transplant patients treated with azathioprine or cyclosporine Transplant Proc 1987 19 1 Pt 3 2214 6 3274496 \n6 Caillard S Agodoa LY Bohen EM Abbott KC Myeloma, Hodgkin disease, and lymphoid leukemia after renal transplantation: characteristics, risk factors and prognosis Transplantation 2006 81 888 95 16570013 \n7 Mahony JF Caterson RJ Coulshed S Stewart JH Sheil AG Twenty and 25 years survival after cadaveric renal transplantation Transplant Proc 1995 27 2154 5 Mahony JF, Caterson RJ, Coulshed S, Stewart JH, Sheil AG. Twenty and 25 years survival after cadaveric renal transplantation. Transplant Proc 1995;27:2154-5. 7792917 \n8 Sakhuja V Ramachandran R Kohli HS Jha V Gupta KL Rathi M Spectrum of lymphoproliferative disorders following renal transplantation in North India Indian J Nephrol 2013 23 287 91 23960346 \n9 Tierney RJ Steven N Young LS Rickinson AB Epstein-Barr virus latency in blood mononuclear cells: analysis of viral gene transcription during primary infection and in the carrier state J Virol 1994 68 7374 85 7933121 \n10 Crawford DH Sweny P Edwards JM Janossy G Hoffbrand AV Long-term T-cell-mediated immunity to Epstein-Barr virus in renal-allograft recipients receiving cyclosporin A Lancet 1981 1 10 2 6109048 \n11 Ancín I Sarrá J Peris J Romagosa V Domingo-Claros A Grañena A Demonstration of Epstein-Barr virus in a case of multiple myeloma after renal transplantation Haematologica 2000 85 773 4 10897139 \n12 Caillard S Lelong C Pessione F Moulin B French PTLD Working Group. Post-transplant lymphoproliferative disorders occurring after renal transplantation in adults: report of 230 cases from the French Registry Am J Transplant 2006 6 2735 42 17049061 \n13 Knight JS Tsodikov A Cibrik DM Ross CW Kaminski MS Blayney DW Lymphoma after solid organ transplantation: risk, response to therapy, and survival at a transplantation center J Clin Oncol 2009 27 3354 62 19451438 \n14 Rocchi G Felici A Ragona G Heinz A Quantitative evaluation of Epstein-Barr-virus-infected mononuclear peripheral blood leukocytes in infectious mononucleosis N Engl J Med 1977 296 132 4 187934 \n15 Rowe DT Qu L Reyes J Jabbour N Yunis E Putnam P Use of quantitative competitive PCR to measure Epstein-Barr virus genome load in the peripheral blood of pediatric transplant patients with lymphoproliferative disorders J Clin Microbiol 1997 35 1612 5 9163497\n\n",
"fulltext_license": "CC BY-NC-SA",
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"issue": "26(4)",
"journal": "Indian journal of nephrology",
"keywords": "ABO incompatible; Epstein-Barr virus; multiple myeloma; posttransplant lymphoproliferative disease; renal transplantation",
"medline_ta": "Indian J Nephrol",
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"title": "Epstein-Barr virus-positive multiple myeloma following an ABO incompatible second renal transplantation.",
"title_normalized": "epstein barr virus positive multiple myeloma following an abo incompatible second renal transplantation"
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"abstract": "Germline mutations in TP53, a tumor suppressor gene, are involved in the development of Li-Fraumeni syndrome, a rare disorder that predisposes carriers to multiple tumors. TP53 mutations have been associated with resistance to treatment and poor prognosis. A young female with the pathogenic germline TP53 mutation c.844C > T (p.R282W) was diagnosed with two metachronous breast tumors, one HER2-negative and the other HER2-positive. She was later diagnosed with synchronous glioblastoma, epidermal growth factor receptor-mutated lung adenocarcinoma, and HER2-negative breast cancer metastases. The patient was treated with local therapies, including brain surgery and radiotherapy, lung surgery, and a bilateral mastectomy, as well as with targeted systemic treatment. She proved to be highly sensitive to systemic therapy, and 13 years after the initial diagnosis of breast cancer and 6 years after the diagnosis of the two new primary tumors and recurrence of a prior cancer, she is alive with an excellent performance status. This surprising positive evolution may well be partly due to the pronged multidisciplinary approach to managing her disease and her extraordinary response to treatment: the lung adenocarcinoma showed excellent response to erlotinib; the breast cancer responded extremely well to eribulin and pegylated liposomal doxorubicin; and the glioblastoma has remained in response to surgery and radiotherapy. Despite harboring a TP53 mutation and having multiple tumors, this patient has shown an unexpectedly favorable evolution. The coordinated participation of a multidisciplinary team and the patient's own extraordinarily high sensitivity to systemic treatment played a major role in this evolution.",
"affiliations": "Medical Oncology Department, Badalona Applied Research Group in Oncology (B-ARGO Group), Catalan Institute of Oncology, Badalona, Spain.;Medical Oncology Department, Badalona Applied Research Group in Oncology (B-ARGO Group), Catalan Institute of Oncology, Badalona, Spain.;Medical Oncology Department, Badalona Applied Research Group in Oncology (B-ARGO Group), Catalan Institute of Oncology, Badalona, Spain.;Medical Oncology Department, Badalona Applied Research Group in Oncology (B-ARGO Group), Catalan Institute of Oncology, Badalona, Spain.;Medical Oncology Department, Badalona Applied Research Group in Oncology (B-ARGO Group), Catalan Institute of Oncology, Badalona, Spain.;Medical Oncology Department, Badalona Applied Research Group in Oncology (B-ARGO Group), Catalan Institute of Oncology, Badalona, Spain.;Genetic Counseling Department, Catalan Institute of Oncology, Badalona, Spain.;Radiotherapy Oncology Department, Catalan Institute of Oncology, Badalona, Spain.;Radiotherapy Oncology Department, Catalan Institute of Oncology, Badalona, Spain.;Medical Oncology Department, Badalona Applied Research Group in Oncology (B-ARGO Group), Catalan Institute of Oncology, Badalona, Spain.",
"authors": "Cirauqui|Beatriz|B|;Morán|Teresa|T|;Estival|Anna|A|;Quiroga|Vanesa|V|;Etxaniz|Olatz|O|;Balana|Carmen|C|;Navarro|Matilde|M|;Villà|Salvador|S|;Ballester|Rosa|R|;Margelí|Mireia|M|",
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"issn_linking": "1662-6575",
"issue": "13(1)",
"journal": "Case reports in oncology",
"keywords": "Breast cancer; Epidermal growth factor receptor-mutated adenocarcinoma; Glioblastoma; Li-Fraumeni syndrome; TP53",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "130-138",
"pmc": null,
"pmid": "32231534",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "22878818;15956649;12243922;25433984;25506014;30840781;11780887;23950206;12771997;23733779;17538175;16282176;28767137;1978757;9554443;18307025;2259385;17540308;23296650;16968874;21263025;21484931;27888811;24352766;30216591;20182618;29369176;22593439;24581301;23680148;25047674;15604253;25806266;15758009;20593219;10951339",
"title": "Breast Cancer Patient with Li-Fraumeni Syndrome: A Case Report Highlighting the Importance of Multidisciplinary Management.",
"title_normalized": "breast cancer patient with li fraumeni syndrome a case report highlighting the importance of multidisciplinary management"
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"companynumb": "ES-ASTELLAS-2020US009343",
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"abstract": "BACKGROUND\nMethadone is increasingly implicated in unintentional overdose deaths. Despite major interventions, rates continue to remain high. One primary intervention, Prescription Drug Monitoring Programs (PDMP) are limited in their ability to impact this epidemic due to federal law restricting Opioid Treatment Programs (OTPs) from sharing data to PDMPs, despite being a major source of Methadone dispensing.\n\n\nMETHODS\nThis retrospective, observational study analyzed all prescription-related deaths occurring in San Diego County during the year 2013 with a specific focus on methadone-related deaths. All patients designated by medical examiner to have died by unintentional prescription were then referenced in the California PDMP, the Controlled Substance Utilization Review and Evaluation System (CURES).\n\n\nRESULTS\nAs a whole, patients who died had a high number of average prescriptions, 21, and averaged 4.5 different providers, and three different pharmacies. Methadone-related deaths (MRD) accounted for 46 out of the 254 total patient deaths (18.1%). Methadone prescriptions were found in 14 patients with PDMP reports, 10 of who had methadone on toxicology report. Notably, 100% of methadone prescribed by primary care specialists. MRD patients were less likely to have toxicology reports matching PDMP data compared to other related drug deaths (20.6 vs. 61.2%, p<0.0001). Of the 46 methadone deaths, only 10 (29.4%) had prescriptions for methadone recorded in the database. Out of the 51 patients with only one drug recorded at death, methadone was most common (n=12; 23.5%). While all deaths had a notably high rate of chronic prescriptions at death (68.8% compared to 2% for all patients in CURES), there was no significant difference between MRD and other drug-related deaths (73.5 vs. 67.8%, p=0.68, respectively). MRD patients were less likely than other drug patients to have matching PDMP data without any illicit substance or alcohol (14.7 vs. 41.4%, p=0.003, respectively).\n\n\nCONCLUSIONS\nMethadone is a long-acting opioid that carries a higher risk profile than other opioids. In San Diego, the great majority of MRD had no data on methadone in the statewide PDMP database, bringing to question the restriction of OTP clinics from uploading information into the database. A risk-benefit analysis should be made to consider changing laws that would allow for OTP to input data into PDMP. OTP should make it standard of care to check PDMP data on their patients. Methadone prescribed for pain management should be limited to the most compliant patients.",
"affiliations": "Department of Emergency Medicine, Scripps Mercy Hospital, San Diego, CA, USA. Electronic address: roneet@cox.net.;University of Southern California Medical Center, Los Angeles, CA, USA.;Department of Emergency Medicine, Scripps Mercy Hospital, San Diego, CA, USA; University of Southern California Medical Center, Los Angeles, CA, USA; San Diego County Medical Examiner's Office, San Diego, CA, USA; Department of Emergency Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA.;Department of Emergency Medicine, Scripps Mercy Hospital, San Diego, CA, USA; University of Southern California Medical Center, Los Angeles, CA, USA; San Diego County Medical Examiner's Office, San Diego, CA, USA; Department of Emergency Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA.;San Diego County Medical Examiner's Office, San Diego, CA, USA.;Department of Emergency Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA.;Department of Emergency Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA.;Department of Emergency Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA.",
"authors": "Lev|Roneet|R|;Petro|Sean|S|;Lee|Ariella|A|;Lee|Oren|O|;Lucas|Jonathan|J|;Castillo|Edward M|EM|;Egnatios|Jeremy|J|;Vilke|Gary M|GM|",
"chemical_list": "D009294:Narcotics; D008691:Methadone",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.forsciint.2015.09.021",
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"keywords": "CURES; Methadone; Opioid treatment; Overdose; PDMP; Prescription deaths",
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D002140:California; D016208:Databases, Factual; D062787:Drug Overdose; D011307:Drug Prescriptions; D004335:Drug and Narcotic Control; D005260:Female; D006801:Humans; D033181:Information Dissemination; D008297:Male; D008691:Methadone; D008875:Middle Aged; D009294:Narcotics; D058850:Opiate Substitution Treatment; D063487:Prescription Drug Misuse; D012189:Retrospective Studies; D016320:Substance Abuse Treatment Centers; D019966:Substance-Related Disorders; D055815:Young Adult",
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"title": "Methadone related deaths compared to all prescription related deaths.",
"title_normalized": "methadone related deaths compared to all prescription related deaths"
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"abstract": "We report a retrospective case study of the use of clomethiazole for treatment of non-convulsive status epilepticus in a patient not responding to benzodiazepines, illustrated by EEG and video. Clomethiazole can be considered as a safe oral option for management of non-convulsive status epilepticus when conventional treatment has failed. [Published with video sequences online].",
"affiliations": "Young Epilepsy, Research, Lingfield, Kings College Hospital, Paediatric Neurosciences, London.;Great Ormond Street Hospital, Paediatric Neurology, London, UK.;Young Epilepsy, Research, Lingfield, Great Ormond Street Hospital, Paediatric Neurology, London, UK.",
"authors": "Das|Darshan|D|;Varadkar|Sophia|S|;Das|Krishna B|KB|",
"chemical_list": "D002719:Chlormethiazole; D001569:Benzodiazepines",
"country": "France",
"delete": false,
"doi": "10.1684/epd.2016.0795",
"fulltext": null,
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"issue": "18(1)",
"journal": "Epileptic disorders : international epilepsy journal with videotape",
"keywords": "non convulsive status epilepticus",
"medline_ta": "Epileptic Disord",
"mesh_terms": "D000293:Adolescent; D001569:Benzodiazepines; D001921:Brain; D002719:Chlormethiazole; D004569:Electroencephalography; D006801:Humans; D008297:Male; D012189:Retrospective Studies; D013226:Status Epilepticus; D016896:Treatment Outcome",
"nlm_unique_id": "100891853",
"other_id": null,
"pages": "87-91",
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"pmid": "26842397",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Oral clomethiazole treatment for paediatric non-convulsive status epilepticus.",
"title_normalized": "oral clomethiazole treatment for paediatric non convulsive status epilepticus"
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"companynumb": "GB-UCBSA-2016015512",
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"abstract": "OBJECTIVE\nTo determine the prevalence of epilepsy in Saudi pregnant women and estimate the frequency of seizure types in suffering individuals using different anti-epileptic drug modalities. It also aimed to report the teratogenic effects of anti-epileptic drugs as observed in neonates.\n\n\nMETHODS\nThis prospective study was conducted at King Fahd University Hospital from June 2018 to July 2019. Sixty-eight pregnant women diagnosed with epilepsy were included in this study. Seizure types and their frequencies were recorded along with anti-epileptic drug therapies and their association with fetal/neonatal malformations RESULTS: Out of 68 epileptic pregnant females, 30 (44.1%) experienced focal seizures and 38 (55.9%) experienced generalized seizures. Thirty-nine (57.3%) received monotherapy, 21 (30.9%) received polytherapy and 8 (11.8%) did not take antiepileptic drugs during pregnancy. Thirty-six (52.9%) patients experienced no change in seizure frequency during pregnancy, 19 (27.9%) experienced increase in seizure frequency and 13 (19.1%) showed decreased seizure frequency. The pregnancy outcomes analysis showed 2 (2.9%) intrauterine fetal deaths, whereas 4 (4.9%) neonates showed facial and/or organ malformations.\n\n\nCONCLUSIONS\nThe frequency of seizures was found to increase in only 27.9% of the pregnant women in the sample. Malformation and mortality rates were higher in fetuses/neonates of patients with generalized seizures. It was observed that for the patient group using monotherapy, the rate of healthy babies was higher than that of the group using polytherapy.",
"affiliations": "Department of Physiology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Kingdom of Saudi Arabia. E-mail: monaalsheikh@gmail.com.",
"authors": "AlSheikh|Mona H|MH|",
"chemical_list": "D000927:Anticonvulsants",
"country": "Saudi Arabia",
"delete": false,
"doi": "10.17712/nsj.2020.1.20190077",
"fulltext": "\n==== Front\nNeurosciences (Riyadh)\nNeurosciences\nnsj\nnsj\nNeurosciences\nNeurosciences\n1319-6138\n1319-6138\nRiyadh : Armed Forces Hospital\n\n31982897\nNeurosciences-25-32\n10.17712/nsj.2020.1.20190077\nOriginal Article\nPrevalence of epilepsy in Saudi pregnant women and possible effects of anti-epileptic drugs on pregnancy outcomes\nAlSheikh Mona H. PhD\nFrom the Department of Physiology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Kingdom of Saudi Arabia.\nAddress correspondence and reprint request to: Dr. Mona H. AlSheikh, Department of Physiology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Kingdom of Saudi Arabia. Email: monaalsheikh@gmail.com ORCID ID: https://orcid.org/0000-0003-3095-1969\n1 2020\n25 1 3237\n10 9 2019\n22 10 2019\nCopyright: © Neurosciences\n2020\nhttps://creativecommons.org/licenses/by-nc-sa/3.0/ Neurosciences is an Open Access journal and articles published are distributed under the terms of the Creative Commons Attribution-NonCommercial License (CC BY-NC). Readers may copy, distribute, and display the work for non-commercial purposes with the proper citation of the original work.\nObjectives:\n\nTo determine the prevalence of epilepsy in Saudi pregnant women and estimate the frequency of seizure types in suffering individuals using different anti-epileptic drug modalities. It also aimed to report the teratogenic effects of anti-epileptic drugs as observed in neonates.\n\nMethods:\n\nThis prospective study was conducted at King Fahd University Hospital from June 2018 to July 2019. Sixty-eight pregnant women diagnosed with epilepsy were included in this study. Seizure types and their frequencies were recorded along with anti-epileptic drug therapies and their association with fetal/neonatal malformations.\n\nResults:\n\nOut of 68 epileptic pregnant females, 30 (44.1%) experienced focal seizures and 38 (55.9%) experienced generalized seizures. Thirty-nine (57.3%) received monotherapy, 21 (30.9%) received polytherapy and 8 (11.8%) did not take antiepileptic drugs during pregnancy. Thirty-six (52.9%) patients experienced no change in seizure frequency during pregnancy, 19 (27.9%) experienced increase in seizure frequency and 13 (19.1%) showed decreased seizure frequency. The pregnancy outcomes analysis showed 2 (2.9%) intrauterine fetal deaths, whereas 4 (4.9%) neonates showed facial and/or organ malformations.\n\nConclusion:\n\nThe frequency of seizures was found to increase in only 27.9% of the pregnant women in the sample. Malformation and mortality rates were higher in fetuses/neonates of patients with generalized seizures. It was observed that for the patient group using monotherapy, the rate of healthy babies was higher than that of the group using polytherapy.\n==== Body\nEpilepsy is defined as a brain disorder characterized by an enduring predisposition to generate epileptic seizures, with cognitive, neurobiological, psychological, and social consequences.1 An epileptic seizure is “a transient occurrence of signs and symptoms due to abnormal excessive or synchronous neuronal activity in the brain”.1 According to the World Health Organization (WHO), it is the second most burdensome neurological disorder that can cause cognitive, neurobiological and psychosocial abnormalities in the suffering individuals.2,3 In women with epilepsy (WWE), disruption of menstruation cycle, fertility, pregnancy, fetus development, menopause and sexual dysfunction has been reported.4 The condition becomes more critical when WWE become pregnant. It has been estimated that the maternal death rate for this group is 10 times higher as compared to normal pregnancy cases.5 Moreover, the frequent seizures during pregnancy have been known to jeopardize the cognitive and physical development of the fetus.6 Thus, epilepsy is not only harmful for the mother but may also pose potentially worse consequences for the fetus.\n\nThe management of seizures through anti-epileptic drugs (AEDs) in pregnant WWE is a challenging task because during the risk-benefit assessment, the needs of the suffering WWE against the potential adverse effects of AEDs on the fetus need to be taken into account as well.7 Several studies suggest the association of AEDs with congenital malformations which put physicians in a difficult spot. In this challenging situation, the attending physician is expected to choose between the available treatment options (mono- or polytherapy) during pregnancy. Therefore, the most critical issue is the regulation of the minimum effective dose of AEDs during pregnancy to prevent any damage to the fetus from seizures as well as AEDs.8\n\nA plethora of evidence has reported the prevalence of epilepsy and its possible outcomes in the general population.2,9,10 However, less is known about the prevalence of epilepsy in Saudi pregnant women, the association of AEDs with the frequency of seizures and their impact on fetal development. The quantification of epileptic pregnant patients and their pregnancy outcomes is important in order to provide optimal counseling and patient care. Therefore, the aims of this study were multifold: (1) to determine the prevalence of epilepsy in pregnant females, (2) to estimate the frequency of seizure types in suffering individuals using different anti-epileptic drug modalities, (3) to assess pregnancy outcomes and possible birth defects in WWE taking monotherapy, polytherapy or no therapy during pregnancy.\n\nMethods\n\nStudy Population\n\nThis prospective study was conducted in a Tertiary Care Teaching and Referral Hospital, King Fahd University Hospital, Khobar, Saudi Arabia between June 2018 to July 2019. This hospital has the highest number of antenatal attendances in the eastern province for both normal and high-risk cases. Pregnant patients with active epilepsy admitted to the Obstetrics and Gynecology outpatient clinic and those seeking follow-up from our outpatient clinic were recruited in this study. Inclusion criteria was patients with active epilepsy and on treatment and those who had at least one seizure in the past one year.3 Patients with single episode of seizure older than one year or seizure from a metabolic or other chronic disorder were excluded from the study. Misdiagnosed seizures such as syncopial attacks, and those who had past history of seizures due to eclampsia were also excluded.\n\nInstrument\n\nIn this study, patients’ information was collected through a structured questionnaire ‘Questionnaire for Investigation of Epilepsy in Tropical Countries’3 which was modified according to the study objectives. The following information was obtained from the history, physical and neurological examination of the patients and through QuadraMed® hospital database (ICD-9 coding system);\n\nSeizure semiology according to the classification of the International League Against Epilepsy (ILAE)11; Type and duration of epilepsy; Type and dosage of anti-epileptic drugs; Electroencephalogram (EEG); Magnetic Resonance Imaging (MRI); Frequency of seizures during pregnancy; Fetal or neonatal weight, height, head circumference and presence of malformation.\n\nEthical considerations\n\nThe ethical approval was obtained from the institutional review board of Imam Abdulrahman Bin Faisal University after comprehensive review of the study protocols. The purpose of the study was explained to the patients in both oral and written form and informed consent was obtained. All items in the questionnaire were written in both English and Arabic for patients’ convenience and clear understanding. For data collection, additional support was sought from the trainee students of the gynecology and obstetrics department.\n\nStatistical analysis\n\nIBM SPSS Statistics package, Version 23.0 (IBM Corp, Armonk, NY, USA) was used for statistical analysis of the data. Numbers and percentages were used to represent categorical measurements, whereas, mean and standard deviation were used for numerical measurements. To compare categorical measurements between the groups, chi-square test was used and to compare the numerical measurements that did not show normal distribution between the 2 groups, Mann-Whitney U-test was used. For general comparison between more than two groups that did not show normal distribution, Kruskal-Wallis test was used. Statistical significance was taken as 0.05 in all tests.\n\nResults\n\nA total of 5872 patients were screened out of which 157 (2.67%) had either a past history of epileptic events or had an active epilepsy. From these 157 cases, 89 were excluded; 72 had a past history of seizure due to eclampsia, 13 had syncopial attacks misdiagnosed as epilepsy, and 4 had a single seizure episode older than one year. Among the 68 female patients included in the study, the mean age was 27.49±6.8 (min:17, max:35). It was observed that 39 (57.3%) of the patients included in the study received monotherapy, 21 (30.9%) received polytherapy treatment and 8 (11.8%) did not take antiepileptic drugs during pregnancy. Demographic and clinical information of the patients according to the treatment (monotherapy / polytherapy / non-medication) is shown in Table 1. There were 11 patients (16.2%) who used folic acid before pregnancy, 53 patients (77.9%) started folic acid after learning about pregnancy and 4 patients (5.9%) never used folic acid.\n\nTable 1 Demographic and clinical characteristics of epileptic patients.\n\nVariables\tMonotherapy\n39 (57.3)\tPolytherapy\n21 (30.9)\tWithout medication\n8 (11.8)\tP-value\t\nn (%)\t\nAverage age ±SD (min-max)\t28.79±5.8\t31.2±6.3\t23.6±2.1\t0.12\t\n(17–32)\t(18–35)\t(21–26)\t\t\nAge of seizure onset\t17.8±9.1\t15.7±6.1\t14.1±8.1\t0.6\t\n(1–35)\t(3–32)\t(2–29)\t\t\nDisease duration (years)\t12.6±8.9\t7.3±5.6\t9.2±9.1\t0.7\t\n(1–35)\t(3–32)\t(2–29)\t\t\nDuration of use of AED (years)\t11.7±9.07\t12.3±7.3\t1.8±2.02\t0.1\t\n(0.17–31)\t(0.08–24)\t(0–4)\t\t\nSeizure semiology, n (%)\t\nFocal seizure\t16 (41.0)\t11 (52.4)\t3 (37.5)\t0.36\t\nGeneralized seizure\t23 (59.0)\t10 (47.6)\t5 (62.5)\t\t\nNumber of pregnancies, n (%)\t\nNulliparous\t27 (69.2)\t14 (66.7)\t6 (75.0)\t0.34\t\nMultiparous\t12 (30.8)\t7 (33.3)\t2 (25.0)\t\t\nElectroencephalogram, n (%)\t\nNormal\t15 (38.5)\t5 (23.8)\t5 (62.5)\t0.6\t\nAbnormal\t24 (61.5)\t16 (76.2)\t3 (37.5)\t\t\nCerebral imaging (MRI), n (%)\t\nAbnormal\t7 (17.9)\t6 (28.6)\t0 (0)\t0.5\t\n\nThe AEDs used were as follows; monotherapy users [n=39 (57.3%): lamotrigine (LMT)=20, levetiracetam (LEV)=9, carbamazepine (CBZ)=5, oxcarbazepine (OXC)=3, topiramate (TPM)=1, valproic acid (VPA)=1], polytherapy users [n=21 (30.9%); CBZ + LMT: 6, CBZ + LEV: 6, VPA + LMT: 3, VPA + CBZ: 3, LMT + LEV: 1, TPM + LEV: 1, LEV + OXC: 1, LMT + TPM: 1], n=8 (11.8%) did not use drugs.\n\nThirty (44.1%) of the patients had focal seizures and 38 (55.9%) had generalized seizures. There was no statistical difference in terms of the AED groups (polytherapy / monotherapy) used by patients with focal and generalized seizures (p = 0.36). The EEG was normal in 25 (36.8%) and abnormal (focal slowdown, focal epileptic, secondary generalized epileptic activity) in 43 (63.2%) of the patients. Cerebral imaging (MRI) revealed focal lesions in 13 (19.1%) of the patients. MRI abnormalities included; thrombus in the cerebral vein, signal pathology in the frontal lobe, inactive demyelinating plaques, venous angioma in the frontal lobe, cystic astrocytoma in the temporal lobe, cerebellar atrophy, and/or sequelae of the left frontal tissue.\n\nDuring pregnancy, 36 (52.9%) of the patients experienced no change in seizure frequency, 19 (27.9%) had increased seizure frequency, and 13 (19.1%) had decreased seizure frequency. The relationship between seizure frequency during pregnancy and neonatal birth weight, head circumference and height was found to be statistically insignificant (Table2).\n\nTable 2 Association between the frequency of seizures during pregnancy with neonatal birth weight, head circumference and height.\n\nParameters\tSeizure frequency in pregnancy: unchanged / decreased / increased\tP-value\t\nUnchanged\tDecreased\tIncreased\t\n\t\tMean±SDMedian (Min-Max)\t\t\t\nBirth weight (g)\t3064±6233105 (1360–4210)\t3324±6673410 (1200–4150)\t3122±6753110 (1910–3620)\t0.812\t\nHead circumference (cm)\t33.127±2.46934 (28–37)\t34.965±1.99034 (30–38)\t32.767±2.36933 (29–37)\t0.832\t\nHeight (cm)\t48.47±3.44150 (40–53)\t49.08±3.77749 (41–51)\t47.75±3.30649 (40–52)\t0.626\t\n\nOut of the 68 WWE, malformation or still birth was observed in 6 (8.8%) of the fetuses/neonates. Out of these 6 cases, 2 had intrauterine death, whereas, malformation (facial, organ or both) was seen in the remaining 4 neonates. The clinical data of these 6 patients experiencing fetal/neonatal abnormalities is given in Table 3along with their AED regime and its effect on seizure frequency. These abnormalities included; cleft lip and palate, tetralogy of Fallot, atrial septal defect and fetal gastroschisis (Table3).\n\nTable 3 Clinical data of patients experiencing fetal/neonatal malformation or stillbirth.\n\nSr #\tSeizure Semiology\tMedication used\tFrequency of seizures during pregnancy\tMalformation Category\tMalformation Name\t\nPatient 1\tGeneralized seizure\tCBZ 900 mg/day\tIncreased\tIntrauterine death\tSevere intrauterine growth restriction leading to intrauterine fetal death\t\nPatient 2\tFocal seizure\tCBZ 1000 mg/dayLMT 200 mg/day\tDecreased\tFacial malformation\tCleft lip and cleft palate\t\nPatient 3\tGeneralized seizure\tVPA 500 mg/dayLMT 50 mg/day\tUnchanged\tIntrauterine death\tFetal anencephaly leading to still birth\t\nPatient 4\tFocal seizure\tCBZ 400 mg/day\tUnchanged\tOrgan malformation\tTetralogy of Fallot\t\nPatient 5\tGeneralized seizure\tVPA 1250 mg/dayLMT 800 mg/day\tUnchanged\tOrgan malformation\tAtrial septal defect\t\nPatient 6\tGeneralized seizure\tNo drug use\tUnchanged\tFacial + Organ malformation\tFetal gastroschisis along with cleft palate\t\nCBZ - carbamazepine, VPA - valproic acid, LMT - lamotrigine\t\n\nDiscussion\n\nMany regional studies have reported the perceptions and attitude of the general population towards epilepsy10,12 and its prevalence which is known to be roughly 6.54 among every 1000 Saudi individuals.13 The results revealed the prevalence to be 2.67%, which is significantly lower than some studies14 but higher than the others.3,15 In general, the literature indicates a higher prevalence of epilepsy in under-developed countries as compared to this study.\n\nThis lower prevalence rate could be due to differences in study designs in studies of a similar nature. Another probable cause of this result could be that this study was conducted in a tertiary care hospital. It is well known that community-based studies usually report a higher prevalence as compared to hospital-based studies.16 Moreover, women with no or less formal education mostly have a poor health-seeking attitude which could also explain the lower prevalence.17 Another very important factor that could be responsible for the lower prevalence found in this study is the social stigma associated with this disorder.16\n\nFurthermore, the occurrence of generalized seizure (55.9%) was observed to be more than that of focal seizure (44.1%), which is consistent with the findings of other local studies.13,18 More than half of the pregnant WWE described no change in seizure frequency during pregnancy, which is consistent with the findings of the European and International Registry of Antiepileptic Drugs and Pregnancy.19 Conversely, Patel and Pennell20 reported an increase in seizure frequency among one-third of their patient population of pregnant women. Unfortunately, there is no local study to compare the results. Additionally, no statistically significant association was observed between the change in seizure frequency and neonatal birth parameters. This could be attributed to the small sample size; otherwise, studies suggest that neonates born to AED taking WWE are usually at higher risk for postnatal complications, such as microcephaly and low birth weight among other issues.20\n\nThe goal in the clinical management of epileptic pregnant patients is to reduce seizures with minimal fetal exposure to AEDs. This is often challenging for the attending physician because AEDs are known for their teratogenic effects causing major congenital malformations, deficits in neurocognitive development intrauterine growth retardation and still births.5,20,21 In the current study, major congenital malformations were observed in 6 patients. Two intrauterine deaths were observed in patients suffering from generalized seizures. The rate of stillbirth and congenital malformations in the present study was higher in patients receiving polytherapy as compared to patients receiving monotherapy. A similar trend was observed by Battino and colleagues,19 who found more congenital malformations in neonates born to patients on multiple AEDs. Though many works suggest increased likelihood of malformations in polytherapy cases, the association of these malformations to genetic and environmental factors should not be overlooked.\n\nThe present study also contained some limitations. First, as it was a hospital-based study, it can be considered that the observed prevalence may not be a true reflection of the whole community. Furthermore, it is highly likely that some women might have not disclosed their epileptic status due to social fear and stigmatization. Thus, it may be difficult to generalize the findings of this study. Second, the sample size of the study was small which may have affected the statistical power of the analysis. Lastly, the serum concentration of AEDs was not measured to explore patient compliance with medication and reliance was placed on verbal information which may not be a completely reliable source.\n\nIn conclusion, A 2.67% prevalence of active epilepsy among pregnant women was observed, with higher occurrence rate of generalized seizures as compared to focal onset. It was found that more than 50% of the pregnant patients diagnosed with epilepsy did not experience a change in the frequency of seizures during the period of regular drug use. Malformation and mortality rates were higher in fetuses/neonates of patients with generalized seizures. It was observed that the rate of healthy babies for the patient group receiving monotherapy was higher than that compared to the group on polytherapy. The findings of this study may generate research interest in further exploring the pregnancy outcomes of WWE on different AED regimes in our region. Studies of this kind will help physicians to better optimize AEDs and control seizures during pregnancy, thus enhance overall pregnancy outcomes in epileptic women. More reliable results can be achieved by conducting similar but longitudinal studies at multiple centers with a larger sample size.\n\nAcknowledgment\n\nI would like to acknowledge Shayma I. Almubayadh and Norah M. Almarri, interns at King Fahd University Hospital for helping me in data collection. I am also thankful to the hospital management and statistics department for granted me access to medical records of the patients. I would also like to thank PaperTrue® English language editing company for their paid English language editing of this manuscript.\n\nStatistics\n\nExcerpts from the Uniform Requirements for Manuscripts Submitted to Biomedical Journals updated November 2003.\n\nAvailable from www.icmje.org\n\nDescribe statistical methods with enough detail to enable a knowledgeable reader with access to the original data to verify the reported results. When possible, quantify findings and present them with appropriate indicators of measurement error or uncertainty (such as confidence intervals). Avoid relying solely on statistical hypothesis testing, such as the use of P values, which fails to convey important information about effect size. References for the design of the study and statistical methods should be to standard works when possible (with pages stated). Define statistical terms, abbreviations, and most symbols. Specify the computer software used.\n\nDisclosure. Authors have no conflict of interests, and the work was not supported or funded by any drug company.\n==== Refs\n1 Fisher RS Acevedo C Arzimanoglou A Bogacz A Cross JH Elger CE ILAE Official Report: A practical clinical definition of epilepsy Epilepsia 2014 55 475 482 24730690\n2 Fiest KM Sauro KM Wiebe S Patten SB Kwon C-S Dykeman J Prevalence and incidence of epilepsy: A systematic review and meta-analysis of international studies Neurology 2017 88 296 303 27986877\n3 Watila MM Beida O Kwari S Nyandaiti NW Nyandaiti YW Seizure occurrence, pregnancy outcome among women with active convulsive epilepsy: One year prospective study Seizure 2015 26 7 11 25799895\n4 Morrell MJ Montouris GD Reproductive disturbances in patients with epilepsy Cleve Clin J Med 2004 71 S19 S24\n5 Viale L Allotey J Cheong-See F Arroyo-Manzano D Mccorry D Bagary M Epilepsy in pregnancy and reproductive outcomes: a systematic review and meta-analysis Lancet 2015 386 1845 1852 26318519\n6 Mawer G Briggs M Baker GA Bromley R Coyle H Eatock J Pregnancy with epilepsy: Obstetric and neonatal outcome of a controlled study Seizure 2010 19 112 119 20036166\n7 Tomson T Battino D Teratogenic effects of antiepileptic drugs Lancet Neurol 2012 11 803 813 22805351\n8 Güveli BT Rosti RÖ Güzeltaş A Tuna EB Ataklı D Sencer S Teratogenicity of Antiepileptic Drugs Clin Psychopharmacol Neurosci 2017 15 19 27 28138106\n9 Camfield P Camfield C Incidence, prevalence and aetiology of seizures and epilepsy in children Epileptic Disord 2015 17 117 123 25895502\n10 Algahtani H Shirah B Alzahrani A Shaheen M Perception and attitude of the general population towards epilepsy in Jeddah, Saudi Arabia J Epilepsy Res 2019 9 42 50 31482056\n11 Fisher RS Cross JH French JA Higurashi N Hirsch E Jansen FE Operational classification of seizure types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology Epilepsia 2017 58 522 530 28276060\n12 Neyaz HA Aboauf HA Alhejaili ME Alrehaili MN Knowledge and attitudes towards epilepsy in Saudi families J Taibah Univ Med Sci 2017 12 89 95 31435221\n13 Shahid R Nazish S Zafar A Aljafaari D Alabdali M Ishaque N Epidemiological study of epilepsy from a tertiary care hospital in kingdom of Saudi Arabia Neurosciences 2018 23 223 226 30007998\n14 Viinikainen K Heinonen S Eriksson K Kälviäinen R Community-based, prospective, controlled study of obstetric and neonatal outcome of 179 pregnancies in women with epilepsy Epilepsia 2006 47 186 192 16417548\n15 Katz O Levy A Wiznitzer A Sheiner E Pregnancy and perinatal outcome in epileptic women: A population-based study J Matern Neonatal Med 2006 19 21 25\n16 Banerjee PN Filippi D Allen Hauser W The descriptive epidemiology of epilepsy-A review Epilepsy Res 2009 85 31 45 19369037\n17 Sen G Östlin P Gender inequity in health: why it exists and how we can change it Glob Public Health 2008 3 1 12\n18 Hamdy NA Alamgir MJ Mohammad EGE Khedr MH Fazili S Profile of epilepsy in a regional hospital in Al-qassim, Saudi Arabia Int J Health Sci 2014 8 247 255\n19 Battino D Tomson T Bonizzoni E Craig J Lindhout D Sabers A Seizure control and treatment changes in pregnancy: Observations from the EURAP epilepsy pregnancy registry Epilepsia 2013 54 1621 1627 23848605\n20 Patel SI Pennell PB Management of epilepsy during pregnancy: an update Ther Adv Neurol Disord 2016 9 118 129 27006699\n21 Meador KJ Baker GA Browning N Cohen MJ Clayton-Smith J Kalayjian LA Foetal antiepileptic drug exposure and verbal versus non-verbal abilities at three years of age Brain 2011 134 396 404 21224309\n\n",
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"title": "Prevalence of epilepsy in Saudi pregnant women and possible effects of anti-epileptic drugs on pregnancy outcomes.",
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"abstract": "Advanced Practice Providers recognize and treat the most common side effects patients bring to our attention with the use of antidepressants, including insomnia, weight gain, emotional flattening, and sexual side effects. (https://www.psychcongress.com/article/top-5-side-effects-psychotropics-and-how-manage-them). We are, however, less intuitive and competent at picking up the high risk and rare, problem prone side effects our patients may experience related to the medications we prescribe, particularly in the more medically complex patients. In addition, the medically complex patient may mask a psychiatric concern as the psychiatric provider finds themselves caught up in the ambiguity of numerous somatic symptoms a patient presents with versus the psychiatric concerns that bear our attention. Autoimmune disorders often blur this line all too well affecting both psychiatric and physical well-being.",
"affiliations": "GAP Geriatric and Adult Psychiatric Clinical Care and Research Center, United States. Electronic address: a.roselle@gapcare.org.",
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"title": "Escitalopram related edema in a patient with Hashimoto's thyroiditis.",
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"abstract": "We report the case of a patient with Donohue syndrome who died of heart failure due to obstructive hypertrophic cardiomyopathy. A literature survey revealed that hypertrophic cardiomyopathy was present in 30% of these patients and was often fatal. Therefore, every patient with Donohue syndrome should be screened for hypertrophic cardiomyopathy.",
"affiliations": "1Department of Neonatology,Wilhelmina Children's Hospital,University Medical Centre,Utrecht,The Netherlands.;2Department of Paediatric Cardiology,Wilhelmina Children's Hospital,University Medical Centre,Utrecht,The Netherlands.;3Department of Paediatric Endocrinology,Wilhelmina Children's Hospital,University Medical Centre,Utrecht,The Netherlands.",
"authors": "Termote|Jacqueline U M|JU|;Breur|Johannes M P J|JM|;de Vroede|Monique A M J|MA|",
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"abstract": "Autoimmune cytopenia (AIHA, AITP or AIN) were uncommon paraneoplastic manifestations of HL and have been recognized in patients after HSCT with dismal outcome. We presented a case of 16-yr-old male with Hodgkin's lymphoma who developed severe AIC involving all three cell lineages after autologus bone marrow transplantation. No disease relapse was noted. Treatments with steroid, IVIG and immunosuppresants were in vain and the disease course was complicated with sepsis and deep vein thrombosis. Rituximab was administered along with broad-spectrum antibiotics and low-molecular weight heparin. The condition became stable and pancytopenia recovered after four doses of rituximab treatment. Severe multi-lineage AIC post HSCT is usually refractory to first-line treatment and difficult to manage. Second-line treatment, such as rituximab, and dedicated care for pancytopenia-induced or treatment-related complications may provide a better outcome.",
"affiliations": "Division of Hematology and Oncology, Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.;Division of Hematology and Oncology, Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.;Division of Hematology and Oncology, Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.;Division of Hematology and Oncology, Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.;Division of Hematology and Oncology, Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.;Division of Hematology and Oncology, Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.;Division of Hematology and Oncology, Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.",
"authors": "Hsu|Wan-Yi|WY|;Chiou|Shyh-Shin|SS|;Liao|Yu-Mei|YM|;Shu|Hsiu-Lan|HL|;Zeng|Yu-Sheng|YS|;Wong|Cheong-Chew|CC|;Lin|Pei-Chin|PC|",
"chemical_list": "D000069283:Rituximab; D003520:Cyclophosphamide; D001379:Azathioprine",
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.12644",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "20(1)",
"journal": "Pediatric transplantation",
"keywords": "Hodgkin's disease; anemia; autologous PBSCT; neutropenia; rituximab; thrombocytopenia",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D000293:Adolescent; D001327:Autoimmune Diseases; D001379:Azathioprine; D016026:Bone Marrow Transplantation; D019070:Cell Lineage; D003520:Cyclophosphamide; D018380:Hematopoietic Stem Cell Transplantation; D006689:Hodgkin Disease; D006801:Humans; D008297:Male; D010198:Pancytopenia; D000069283:Rituximab; D018805:Sepsis; D013921:Thrombocytopenia; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D020246:Venous Thrombosis",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "168-71",
"pmc": null,
"pmid": "26670732",
"pubdate": "2016-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful management of multilineage autoimmune cytopenia complicated with severe infection and deep vein thrombosis in a patient with Hodgkin lymphoma post-autologous hematopoietic stem cell transplantation.",
"title_normalized": "successful management of multilineage autoimmune cytopenia complicated with severe infection and deep vein thrombosis in a patient with hodgkin lymphoma post autologous hematopoietic stem cell transplantation"
} | [
{
"companynumb": "TW-CONCORDIA PHARMACEUTICALS INC.-E2B_00008263",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BLEOMYCIN SULFATE"
},
"d... |
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"abstract": "Idiopathic intracranial hypertension (IIH) is uncommon in the paediatric population. Papilloedema is the hallmark sign and patients can suffer permanent vision loss as a consequence. We describe the role of optical coherence tomography (OCT) in the follow-up of two paediatric patients with newly diagnosed IIH. Patient A presented with vomiting and examination showed ophthalmoplaegia and papilloedema. She was treated with acetazolamide, furosemide and therapeutic lumbar punctures. Patient B presented with incidental papilloedema and was treated with acetazolamide and she reported intermittent headache during follow-up. Fundoscopic examinations for both patients showed persistent blurred disc margins but OCT examinations documented improvement of average retinal nerve fibre layers. OCT may be of value in monitoring for recurrence in paediatric IIH.",
"affiliations": "Department of Paediatric Medicine, KK Women's and Children's Hospital, Singapore, Singapore.;Department of Ophthalmology, Tan Tock Seng Hospital, Singapore, Singapore.;Department of Paediatric Ophthalmology, KK Women's and Children's Hospital, Singapore, Singapore.;Neurology Service, Department of Paediatrics, KK Women's and Children's Hospital, Singapore, Singapore.",
"authors": "Loo|Kai Guo Benny|KG|;Lim|Su Ann|SA|;Lim|I-Linn Zena|IL|;Chan|Derrick Wei Shih|DW|",
"chemical_list": "D004232:Diuretics; D000086:Acetazolamide",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2016()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000086:Acetazolamide; D000293:Adolescent; D002648:Child; D004232:Diuretics; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D010211:Papilledema; D011559:Pseudotumor Cerebri; D013129:Spinal Puncture; D041623:Tomography, Optical Coherence; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26941344",
"pubdate": "2016-03-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22981259;23958286;21700384;17974701;24983792;21093727;21696699;12455560;26269534;18772671;19011007",
"title": "Guiding follow-up of paediatric idiopathic intracranial hypertension with optical coherence tomography.",
"title_normalized": "guiding follow up of paediatric idiopathic intracranial hypertension with optical coherence tomography"
} | [
{
"companynumb": "SG-SUN PHARMACEUTICAL INDUSTRIES LTD-2016R1-114960",
"fulfillexpeditecriteria": "1",
"occurcountry": "SG",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "ACETAZOLAMIDE"
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"abstract": "OBJECTIVE\nThe aim of this study was to evaluate the efficacy and safety of local steroid injections to prevent scar contracture after transoral videolaryngoscopic surgery (TOVS) in hypopharyngeal cancer patients.\n\n\nMETHODS\nPatients were enrolled in this study if they had received a local steroid injection during TOVS and had attended an outpatient clinic after at least three months. All patients were being treated for hypopharyngeal cancer and received a single session of triamcinolone acetonide, injected using a 21-gage needle. Retrospective chart reviews were performed, and the degree of scar contracture, pharyngeal stenosis, vocal fold movements, and adverse events were evaluated. Scar contracture was assessed using a scoring system, which compared the endoscopic findings of treatment and matched pair control groups.\n\n\nRESULTS\nA total of 20 patients received local steroid injections during TOVS and were enrolled in the treatment. Scar contracture was seen in 14 patients (70%); however, the degree of scar contracture was significantly decreased when compared to control cases. Vocal fold immobility was observed in five patients, but no pharyngeal stenosis was noted. Adverse effects, such as postoperative laryngeal chondritis or cervical spondylitis, were seen in three patients who had previously been treated with resection to the muscularis propria or definitive irradiation.\n\n\nCONCLUSIONS\nLocal steroid injection during TOVS significantly reduced the degree of postoperative scar contracture. However, caution should be used when treating with local steroid injection during TOVS, as this may complicate wound healing in patients who have already received treatment.",
"affiliations": "Department of Otolaryngology, National Defense Medical College, Saitama, Japan; Department of Otolaryngology-Head and Neck Surgery, Keio University School of Medicine, Tokyo, Japan.;Department of Otolaryngology, National Defense Medical College, Saitama, Japan.;Department of Otolaryngology, National Defense Medical College, Saitama, Japan.;Department of Otolaryngology, National Defense Medical College, Saitama, Japan.;Department of Otolaryngology, National Defense Medical College, Saitama, Japan.;Department of Otolaryngology, National Defense Medical College, Saitama, Japan.;Department of Otolaryngology, National Defense Medical College, Saitama, Japan.;Department of Otolaryngology-Head and Neck Surgery, Keio University School of Medicine, Tokyo, Japan.;Department of Otolaryngology, National Defense Medical College, Saitama, Japan. Electronic address: ashiotan@ndmc.ac.jp.",
"authors": "Uno|Kosuke|K|;Tomifuji|Masayuki|M|;Araki|Koji|K|;Tanaka|Shingo|S|;Taniai|Shinichi|S|;Tanaka|Yuya|Y|;Kimura|Eiko|E|;Ogawa|Kaoru|K|;Shiotani|Akihiro|A|",
"chemical_list": "D005938:Glucocorticoids; D014222:Triamcinolone Acetonide",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.anl.2020.02.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-8146",
"issue": "47(5)",
"journal": "Auris, nasus, larynx",
"keywords": "Local steroid injection; Scar contracture; Transoral videolaryngoscopic surgery",
"medline_ta": "Auris Nasus Larynx",
"mesh_terms": "D000368:Aged; D002921:Cicatrix; D003286:Contracture; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007012:Hypopharyngeal Neoplasms; D015552:Injections, Intralesional; D007828:Laryngoscopy; D008297:Male; D008875:Middle Aged; D057605:Natural Orifice Endoscopic Surgery; D011183:Postoperative Complications; D012189:Retrospective Studies; D014222:Triamcinolone Acetonide; D020535:Video-Assisted Surgery",
"nlm_unique_id": "7708170",
"other_id": null,
"pages": "856-863",
"pmc": null,
"pmid": "32107068",
"pubdate": "2020-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Scar contracture prevention with local steroid injections in transoral videolaryngoscopic surgery.",
"title_normalized": "scar contracture prevention with local steroid injections in transoral videolaryngoscopic surgery"
} | [
{
"companynumb": "JP-STRIDES ARCOLAB LIMITED-2020SP013029",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TRIAMCINOLONE ACETONIDE"
},
"d... |
{
"abstract": "A 64-year-old woman with a medical history of morbid obesity, chronic hepatitis C, essential hypertension, multiple episodes of abdominal cellulitis, diabetes mellitus type 2 on insulin, intravenous and subcutaneous drug abuse presented to the emergency department complaining of left lower chest pain for 6 weeks along with multiple episodes of vomiting. Initial laboratory data revealed leucocytosis of 17 200×103/μL with left shift. She reported multiple episodes of fever spikes. Abdominal and pelvic CT showed a splenic hypodense lesion. Specimens from interventional radiology aspiration and splenectomy grew Propionibacterium acnes Following splenectomy, patient's symptoms resolved. To the best of our knowledge, this would represent the fifth reported case of P. acnes splenic abscess.",
"affiliations": "Department of Internal Medicine, McLaren Regional Medical Center, Flint, Michigan, USA.;Department of Internal Medicine, McLaren Regional Medical Center, Flint, Michigan, USA.",
"authors": "Mohammed|Subhan|S|;Kollu|Vidya S|VS|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002981:Clindamycin",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-225858",
"fulltext": "\n==== Front\nBMJ Case RepBMJ Case RepcasereportsbmjcasereportsBMJ Case Reports1757-790XBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR bcr-2018-22585810.1136/bcr-2018-225858Rare Disease15061523Case ReportRare case of Propionibacterium acnes-related splenic abscess Mohammed Subhan 12Kollu Vidya S 11 Department of Internal Medicine, McLaren Regional Medical Center, Flint, Michigan, USA2 Department of Neurology, University of Florida, Gainesville, Florida, USACorrespondence to Dr Subhan Mohammed, drsubhanaziz@gmail.com2018 21 9 2018 21 9 2018 2018 bcr201822585828 8 2018 © BMJ Publishing Group Limited 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2018This 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/A 64-year-old woman with a medical history of morbid obesity, chronic hepatitis C, essential hypertension, multiple episodes of abdominal cellulitis, diabetes mellitus type 2 on insulin, intravenous and subcutaneous drug abuse presented to the emergency department complaining of left lower chest pain for 6 weeks along with multiple episodes of vomiting. Initial laboratory data revealed leucocytosis of 17 200×103/μL with left shift. She reported multiple episodes of fever spikes. Abdominal and pelvic CT showed a splenic hypodense lesion. Specimens from interventional radiology aspiration and splenectomy grew Propionibacterium acnes. Following splenectomy, patient’s symptoms resolved. To the best of our knowledge, this would represent the fifth reported case of P. acnes splenic abscess.\n\ninfectious diseasesdiabetesinterventional radiologygeneral surgeryspecial-featureunlocked\n==== Body\nBackground\nPropionibacterium acnes (P. acnes) is a relatively slow growing, anaerobic, gram-positive bacteria which is a normal flora found on the skin, oral cavity, gastrointestinal tract, conjunctiva and external ear canal.1–3 P. acnes is commonly considered a contaminant in blood cultures because of its natural habitat on human skin and, hence, is often not actively pursued. P acnes can rarely cause invasive infections like endocarditis, osteomyelitis, mediastinitis, discitis, infections of intraocular lenses, prosthetic joints and heart valves.3 4 This organism has been rarely associated with splenic abscess with only four known reported cases so far.5–8 To the best of our knowledge, this would be the fifth reported case.\n\nCase presentation\nA 64-year-old Caucasian woman with a medical history significant for morbid obesity, intravenous and subcutaneous drug abuse, chronic pain, hepatitis C, diabetes mellitus type 2 on insulin, multiple episodes of abdominal cellulitis with methicillin-resistant Staphylococcus aureus, dyslipidaemia and essential hypertension presented to the emergency department complaining of intermittent lower left-sided chest and shoulder pain for the past 6 weeks. She described the pain as sharp in nature, 10 over 10 in severity, localised to the left lower side of the chest with radiation to the left shoulder tip. She said that her pain got worse with a deep breath or any movements. She denied any previous history of similar pain. She reported feeling nauseated with multiple episodes of non-bilious, non-projectile, non-bloody vomiting. Her review of systems was positive for decreased appetite, subjective fever with frequent rigours and sweats. She denied measuring her temperature at home. Social history was significant for intravenous cocaine and subcutaneous morphine abuse. Family history was positive for premature coronary artery disease in her brother and pancreatic cancer in her son. On physical examination, her vital signs were as follows: blood pressure 175/103 mm Hg, heart rate 113 beats per minute, temperature 36.7°C, respiratory rate 22 per minute and oxygen saturation 98% on room air. Her oral mucosa was dry. There was reproducible chest tenderness in the left lower side. Heart sounds S1 and S2 were heard without any murmurs, rubs or gallops. Lungs were clear to auscultation with good air entry bilaterally. Her abdomen appeared normal on gross inspection. Normal bowel sounds were heard in all four quadrants. There was no reproducible abdominal tenderness on superficial or deep palpation. In view of her risk factors, she was admitted to rule out acute coronary syndrome. She was kept overnight for observation on a telemetry floor where she continued to have fever spikes as high as 38.9°C the following day. She also reported tenderness in the left upper abdomen the next day.\n\nInvestigations\nLaboratory data from emergency department revealed leucocytosis of 17 200×103/μL with left shift. Posterioanterior chest X-ray on admission revealed mild to moderate left-sided pleural effusion. Initial cardiac workup was negative, including ECG, serum troponin and a transthoracic echocardiogram with a normal ejection fraction and wall movement. The negative cardiac workup and continued nausea and vomiting along with left upper abdominal pain the next day prompted an abdominal and pelvic CT scan without contrast which revealed an 8.9 cm hypodensity in the superior aspect of the spleen with ill-defined linear densities in the inferior and anterior aspect without surrounding fluid (figures 1 and 2). The infectious disease consultant recommended interventional radiology-guided aspiration of the hypodense splenic territory. Aspirated material was sent for aerobic and anaerobic cultures. General Surgery consultation was obtained and the patient underwent a diagnostic exploratory laparotomy. Cultures from interventional radiology (IR)-guided aspirate and splenectomy specimen were identified as P. acnes on a micro scan. No special tests were done to identify the subtype of P. acnes. Five sets of blood cultures ordered during hospital course were all negative. Transoesophageal echocardiogram done in view of the patient’s history of intravenous and subcutaneous drug abuse was negative for valvular vegetations. Pathology reports from the splenectomy revealed a specimen weighing approximately 460 g with admixed fibropurulent exudate with some congestion and haemorrhage, consistent with abscess tissue along with some surrounding fibrosis (figure 3). It measured approximately 18×15.5×7.5 cm. She also underwent left-sided thoracentesis for worsening pleural effusion attributed to her splenic abscess. The fluid was negative on stain and culture. Fluid analysis revealed the pleural effusion to be an exudate. Repeat chest X-ray showed resolution of the pleural effusion.\n\nFigure 1 CT scan of the abdomen and pelvis without contrast showing hypodensity in the superior aspect of the spleen: transverse section.\n\nFigure 2 CT scan of the abdomen and pelvis without contrast showing hypodensity in the superior aspect of the spleen: coronal section.\n\nFigure 3 Histopathology of splenectomy specimen showing fibrinopurulent exudate with some congestion and haemorrhage along with surrounding fibrosis.\n\nDifferential diagnosis\nDifferential diagnosis that were considered were splenic haematoma and splenic abscess. In view of fever and patient’s history of drug abuse, splenic abscess was more likely a possibility. Splenic infarct can also present as a hypodense lesion on imaging but the disease course is usually more acute. Our patient had an insidious onset of symptoms which were ongoing for the past 6 weeks. She had an initial transthoracic echocardiogram which was negative for vegetations or thrombus in the heart. She had no history of irregular heart rhythm. Her ECG and overnight telemetry findings were negative for irregular rhythms. This made a splenic infarct a less likely diagnosis. A transoesophageal echocardiogram performed later confirmed the findings of transthoracic echocardiogram.\n\nTreatment\nThe following day of admission, the patient was started on empiric antibiotics with metronidazole and ciprofloxacin due to the possibility of splenic abscess. Infectious disease consultant recommended additional coverage with vancomycin in view of previous history of methicillin-resistant S. aureus cellulitis. A complete splenectomy was performed and the splenic bed was copiously irrigated. Leucocytosis started to improve and patient improved symptomatically. The choice of antibiotic was narrowed down to intravenous clindamycin based on culture and sensitivity reports. Intravenous clindamycin was administered for a total of 7 days.\n\nOutcome and follow-up\nThe patient survived and improved clinically. Her symptoms resolved post splenectomy. No further fever spikes were reported.\n\nDiscussion\nThe word abscess is derived from the Latin word Abscessuss, meaning ‘gathering of humours’.9 In English, it refers to a walled-off cavity filled with inflammatory cells and fluids resulting in tissue destruction. It was originally described in the 16th century.9 Abscesses can involve any organ of the body but splenic involvement is rare. In multiple autopsy series by Nelken et al, Chun et al and Reid and Lang, splenic abscesses occurred in a frequency of 0.1%–0.7%.10–12 Splenic abscesses as described by Nelkan and colleagues were rare and divided into five types: metastatic infections, contiguous infections, trauma, immunodeficiency and embolic.10 The exact cause for splenic abscess in our patient remains unclear but two possibilities are raised by other case reports. One case was reported in a diabetic where it was suggested that self-inoculation of P. acnes during administration of insulin might have resulted in a subclinical focus of infection.6 In another report, a patient had a history of heroin abuse.7 In our patient, subcutaneous drug abuse, multiple episodes of abdominal wall cellulitis, insulin administration or intravenous drug abuse may have been the initial source of infection.\n\nIn a splenic abscess case reported in 2013, the patient initially presented with fever of unknown origin.5 Although our patient had a subjective feeling of fever and chills, she did not record her temperature until she came to the emergency department 6 weeks later and did not have the time course or negative workup which defines ‘a fever of unknown origin’. The most common organisms involved in splenic abscesses varied based on geography and time frame and included S. aureus,12\nKlebsiella pneumoniae,13\nStreptococcus viridans14 and Mycobacterium tuberculosis.15\n\nP. acnes has been implicated in prosthetic device infections including prosthetic heart valves, ventricular shunts, orthopaedic devices, deep bone infections especially the vertebra after lumbar puncture, postoperative infections, mediastinitis and silicone implants.3 4 16 17 Sickle cell disease as a risk factor for splenic abscess was reported by Cockshott and Weaver18 although only one case of P. acnes-related splenic abscess was reported in a sickle cell trait patient who had a history of drug addiction.7\n\nTo the best of our knowledge, only four cases of splenic abscess caused by P. acnes have been reported so far. A brief review of these cases is summarised in table 1.\n\nTable 1 Summary of the case reports for Propionibacterium acnes splenic abscess\n\nCase number\tYear reported\tAge and sex of the patient\tRisk factor\tOutcome\tTreatment\t\n 1.\t1981\t27 year old, male\tSickle cell trait and intravenous drug abuse7\tSurvived\tSplenectomy and intravenous \npenicillin\t\n 2.\t1982\t59 year old, male\tUnclear aetiology with a history of diabetes mellitus with subcutaneous insulin administration6\tSurvived\tSplenectomy and intravenous penicillin\t\n 3*\t2006\tUnidentified\tNot mentioned8\tUnknown\tNot mentioned\t\n 4.\t2013\t64 year old, male\tImmunodeficiency with chronic lymphocytic leukaemia5\tSurvived\tSplenectomy and levofloxacin\t\nPresent case\t2017\t64 year old, female\tHistory of diabetes mellitus on insulin, intravenous and subcutaneous drug abuse\tSurvived\tSplenectomy and clindamycin\t\n*Retrospective study of 67 cases with splenic abscess at one centre without specific details of individual patients.\n\nLearning points\nRisk factors that can lead to Propionibacterium acnes splenic abscess include diabetes mellitus on insulin, subcutaneous and intradermal drug abuse, sickle cell trait and immunodeficiency.\n\nSplenectomy is an effective treatment for P. acnes splenic abscess.\n\nP. acnes is usually sensitive to many classes of antibiotics including penicillin, cephalosporins, cephamycin, carbapenems, fluoroquinolones and clindamycin.\n\nP. acnes is rarely associated with invasive infections. It is a commensal found on skin and is usually treated as a contaminant when growing in cultures. When P. acnes is found to be growing in blood, serious evaluation for possible clinical disease should be considered.\n\nDr Susan Jane Smith reviewed the initial draft and provided general assistance in publication. Dr Afrah Saleem reviewed the final draft for publication and suggested grammatical changes.\n\nContributors: SM: wrote the main manuscript and was involved in literature search; actively involved in the patient care; wrote both the initial and the final draft of the manuscript. VK: assisted in literature search and revision of the 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: Obtained.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nPresented at: Michigan State University Flint Area Medical Education Conference May 2018, American College of Physicians Michigan Chapter Meeting 2017\n==== Refs\nReferences\n1 Public Health Image Library (PHIL) . https://phil.cdc.gov/Details.aspx?pid=3083 (accessed on 22 Mar 2018 ).\n2 Levy PY , Fenollar F , Stein A , et al \nPropionibacterium acnes postoperative shoulder arthritis: an emerging clinical entity . Clin Infect Dis \n2008 ;46 :1884 –6 . 10.1086/588477 18462110 \n3 Perry A , Lambert P \nPropionibacterium acnes: infection beyond the skin . Expert Rev Anti Infect Ther \n2011 ;9 :1149 –56 . 10.1586/eri.11.137 22114965 \n4 Niazi SA , Clarke D , Do T , et al \nPropionibacterium acnes and Staphylococcus epidermidis isolated from refractory endodontic lesions are opportunistic pathogens . J Clin Microbiol \n2010 ;48 :3859 –69 . 10.1128/JCM.01326-10 20739494 \n5 Kiritani S , Kaneko J , Aoki T , et al \nMultiple splenic nodules with fever: a case of splenic abscess due to Propionibacterium acnes . Clin J Gastroenterol \n2013 ;6 :434 –7 . 10.1007/s12328-013-0427-5 26182133 \n6 Gekowski KM , Lopes R , LiCalzi L , et al \nSplenic abscess caused by Propionibacterium acnes . Yale J Biol Med \n1982 55 :65 –9 .7113264 \n7 Gangahar DM , Delany HM \nIntrasplenic abscess: two case reports and review of the literature . Am Surg \n1981 ;47 :488 –91 .7305137 \n8 Chang KC , Chuah SK , Changchien CS , et al \nClinical characteristics and prognostic factors of splenic abscess: a review of 67 cases in a single medical center of Taiwan . World J Gastroenterol \n2006 ;12 :460 –4 . 10.3748/wjg.v12.i3.460 16489650 \n9 abscess . https://en.wiktionary.org/wiki/abscess (accessed on 22 Mar 2018 ).\n10 Nelken N , Ignatius J , Skinner M , et al \nChanging clinical spectrum of splenic abscess. A multicenter study and review of the literature . Am J Surg \n1987 ;154 :27 –34 .3300398 \n11 Chun CH , Raff MJ , Contreras L , et al \nSplenic abscess . Medicine \n1980 ;59 :50 –65 . 10.1097/00005792-198001000-00003 6986009 \n12 Reid SE , Lang SJ \nAbscess of the spleen . Am J Surg \n1954 ;88 :912 –7 . 10.1016/0002-9610(54)90449-3 13207533 \n13 Ferraioli G , Brunetti E , Gulizia R , et al \nManagement of splenic abscess: report on 16 cases from a single center . Int J Infect Dis \n2009 ;13 :524 –30 . 10.1016/j.ijid.2008.08.024 19070526 \n14 Lee WS , Choi ST , Kim KK \nSplenic abscess: a single institution study and review of the literature . Yonsei Med J \n2011 ;52 :288 –92 . 10.3349/ymj.2011.52.2.288 21319348 \n15 Llenas-García J , Fernández-Ruiz M , Caurcel L , et al \nSplenic abscess: a review of 22 cases in a single institution . Eur J Intern Med \n2009 ;20 :537 –9 . 10.1016/j.ejim.2009.04.009 19712861 \n16 Skinner PR , Taylor AJ , Coakham H \nPropionibacteria as a cause of shunt and postneurosurgical infections . J Clin Pathol \n1978 ;31 :1085 –9 . 10.1136/jcp.31.11.1085 739055 \n17 Petrini B , Welin-Berger T , Nord CE \nAnaerobic bacteria in late infections following orthopedic surgery . Med Microbiol Immunol \n1979 ;167 :155 –9 . 10.1007/BF02121181 492071 \n18 Cockshott WP , Weaver EJ \nPrimary tropical splenic abscess: a misnomer . Br J Surg \n1962 ;49 :665 –9 . 10.1002/bjs.18004921822 13880108\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "diabetes; general surgery; infectious diseases; interventional radiology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D018784:Abdominal Abscess; D000900:Anti-Bacterial Agents; D002481:Cellulitis; D002637:Chest Pain; D002981:Clindamycin; D015897:Comorbidity; D005260:Female; D005334:Fever; D016908:Gram-Positive Bacterial Infections; D006801:Humans; D008875:Middle Aged; D009767:Obesity, Morbid; D011425:Propionibacterium acnes; D011860:Radiography, Abdominal; D013156:Splenectomy; D013158:Splenic Diseases; D019966:Substance-Related Disorders; D007507:Therapeutic Irrigation; D016896:Treatment Outcome; D014839:Vomiting",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30244225",
"pubdate": "2018-09-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22114965;3300398;7113264;20739494;18462110;7305137;13880108;19712861;19070526;13207533;492071;6986009;16489650;21319348;26182133;739055",
"title": "Rare case of Propionibacterium acnes-related splenic abscess.",
"title_normalized": "rare case of propionibacterium acnes related splenic abscess"
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"abstract": "Hereditary complement C3 deficiency is associated with recurrent bacterial infections and proliferative glomerulonephritis. We describe a case of an adult with complete deficiency of complement C3 due to homozygous mutations in C3 gene: c.1811delT (Val604Glyfs*2), recurrent bacterial infections, crescentic glomerulonephritis, and end-stage renal failure. Following isolated kidney transplantation he would remain C3 deficient with a similar, or increased, risk of infections and glomerulonephritis. As C3 is predominantly synthesized in the liver, with a small proportion of C3 monocyte derived and kidney derived, he proceeded to simultaneous liver-kidney transplantation. The procedure has been successful with restoration of his circulating C3 levels, normal liver and kidney function at 26 months of follow-up. Simultaneous liver-kidney transplant is a viable option to be considered in this rare setting.",
"affiliations": "Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK.;Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK.;East Kent Hospitals University NHS Foundation Trust, Kent and Canterbury Hospital, Kent, UK.;East Kent Hospitals University NHS Foundation Trust, Kent and Canterbury Hospital, Kent, UK.;Imperial College Healthcare NHS Trust, London, UK.;Newcastle University and National Renal Complement Therapeutics Centre, The Medical School, Newcastle Upon Tyne, UK.;National Renal Complement Therapeutics Centre, Newcastle University, Newcastle, UK.;National Renal Complement Therapeutics Centre, Newcastle University, Newcastle, UK.;Medical Research Council Centre for Transplantation, King's College London, Guy's Hospital, London, UK.;Centre for Inflammatory Disease, Imperial College, London, UK.;King's College London, London, UK.;Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK.;Centre for Inflammatory Disease, Imperial College, London, UK.;Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK.",
"authors": "Nayagam|Jeremy S|JS|0000-0002-0344-0218;McGrath|Samuel|S|;Montasser|Mahmoud|M|;Delaney|Michael|M|;Cairns|Tom D|TD|;Marchbank|Kevin J|KJ|;Denton|Harriet|H|;Yang|Yi|Y|;Sacks|Steven H|SH|;Cook|H Terry|HT|;Shah|Sapna|S|;Heaton|Nigel|N|;Pickering|Matthew C|MC|;Suddle|Abid|A|",
"chemical_list": "D003176:Complement C3",
"country": "United States",
"delete": false,
"doi": "10.1111/ajt.15785",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1600-6135",
"issue": "20(8)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "clinical research/practice; complement biology; immune deficiency; kidney disease: immune/inflammatory; kidney transplantation/nephrology; liver transplantation/hepatology",
"medline_ta": "Am J Transplant",
"mesh_terms": "D000328:Adult; D003176:Complement C3; D005921:Glomerulonephritis; D006801:Humans; D007668:Kidney; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008099:Liver; D008297:Male",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "2260-2263",
"pmc": null,
"pmid": "31970896",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Successful simultaneous liver-kidney transplantation for renal failure associated with hereditary complement C3 deficiency.",
"title_normalized": "successful simultaneous liver kidney transplantation for renal failure associated with hereditary complement c3 deficiency"
} | [
{
"companynumb": "GB-ASTELLAS-2020US035358",
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"occurcountry": "GB",
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"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
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"abstract": "BACKGROUND\nCurrently available third- or later-line therapy for metastatic colorectal cancer (mCRC) is limited in its efficacy, with a weak survival benefit in patients who progressed after two or more lines of standard therapy. Our retrospective study aimed to explore the value of bevacizumab plus chemotherapy in this setting.\n\n\nMETHODS\nPatients with mCRC who received fluoropyrimidine, oxaliplatin, and irinotecan as first- and second-line chemotherapy were selected for inclusion. Treatment consisted of bevacizumab plus chemotherapy. Chemotherapy consisted mainly of oxaliplatin, irinotecan, and fluoropyrimidine.\n\n\nRESULTS\nBetween February 2010 and December 2012, 35 consecutive patients with mCRC were treated with bevacizumab plus chemotherapy as a third- or later-line treatment. No complete responses, seven partial responses (20%), 22 stable disease responses (62.9%), and six progressive disease responses (17.1%) were obtained, producing an objective response rate of 20% and a disease control rate of 82.9%. With a median follow-up of 11.3 months (range: 0.7-48.0 months), the median progression-free survival was 5.98 months (95% confidence interval: 4.76-7.2 months), and the median overall survival was 14.77 months (95% confidence interval: 11.45-18.1 months). In the univariate analysis, patients with a primary colon tumor might have had a longer overall survival than patients with a primary rectal tumor (18.8 months vs 11.1 months, respectively; P=0.037). Common chemotherapy-related toxicities were nausea/vomiting (48.6%), fatigue (34.3%), leucopenia (40%), neutropenia, (42.9%), and anemia (42.9%), with one patient with grade 3 neutropenia, and two patients with grade 3 thrombocytopenia. The common bevacizumab-associated toxicity was hypertension (31.4%). None of the patients discontinued therapy or died because of bevacizumab-associated toxicities.\n\n\nCONCLUSIONS\nOur data showed that adding bevacizumab to third- or later-line therapy might lead to tumor control and improved survival in heavily pretreated mCRC patients. In addition, preliminary data suggested that primary colon cancer was more likely to benefit from bevacizumab-containing regimens. Toxicities were acceptable, and no new toxicity was identified. Further studies are needed to validate these findings.",
"affiliations": "VIP Region, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China ; Department of Oncology, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, People's Republic of China ; State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China ; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People's Republic of China.;VIP Region, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China ; State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China ; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People's Republic of China.;VIP Region, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China ; State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China ; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People's Republic of China.;VIP Region, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China ; State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China ; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People's Republic of China.;VIP Region, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China ; State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China ; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People's Republic of China.;VIP Region, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China ; State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China ; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People's Republic of China.;VIP Region, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China ; State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China ; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People's Republic of China.;VIP Region, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China ; State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China ; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People's Republic of China.;VIP Region, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China ; State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China ; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People's Republic of China.",
"authors": "Yang|Qiong|Q|;Yin|Chenxi|C|;Liao|Fangxin|F|;Huang|Yuanyuan|Y|;He|Wenzhuo|W|;Jiang|Chang|C|;Guo|Guifang|G|;Zhang|Bei|B|;Xia|Liangping|L|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/OTT.S88679",
"fulltext": "\n==== Front\nOnco Targets TherOnco Targets TherOncoTargets and TherapyOncoTargets and therapy1178-6930Dove Medical Press 10.2147/OTT.S88679ott-8-2407Original ResearchBevacizumab plus chemotherapy as third- or later-line therapy in patients with heavily treated metastatic colorectal cancer Yang Qiong 1234*Yin Chenxi 134*Liao Fangxin 134Huang Yuanyuan 134He Wenzhuo 134Jiang Chang 134Guo Guifang 134Zhang Bei 134Xia Liangping 1341 VIP Region, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of China2 Department of Oncology, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, People’s Republic of China3 State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of China4 Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People’s Republic of ChinaCorrespondence: Liangping Xia; Bei Zhang, VIP Region, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, People’s Republic of China, Tel +86 20 8734 3107, Fax +86 20 8734 3392, Email xialiangping@163.com; zhangbei@sysucc.org.cn* These authors contributed equally to this work\n\n2015 01 9 2015 8 2407 2413 © 2015 Yang et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License2015The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Background\nCurrently available third- or later-line therapy for metastatic colorectal cancer (mCRC) is limited in its efficacy, with a weak survival benefit in patients who progressed after two or more lines of standard therapy. Our retrospective study aimed to explore the value of bevacizumab plus chemotherapy in this setting.\n\nMethods\nPatients with mCRC who received fluoropyrimidine, oxaliplatin, and irinotecan as first- and second-line chemotherapy were selected for inclusion. Treatment consisted of bevacizumab plus chemotherapy. Chemotherapy consisted mainly of oxaliplatin, irinotecan, and fluoropyrimidine.\n\nResults\nBetween February 2010 and December 2012, 35 consecutive patients with mCRC were treated with bevacizumab plus chemotherapy as a third- or later-line treatment. No complete responses, seven partial responses (20%), 22 stable disease responses (62.9%), and six progressive disease responses (17.1%) were obtained, producing an objective response rate of 20% and a disease control rate of 82.9%. With a median follow-up of 11.3 months (range: 0.7–48.0 months), the median progression-free survival was 5.98 months (95% confidence interval: 4.76–7.2 months), and the median overall survival was 14.77 months (95% confidence interval: 11.45–18.1 months). In the univariate analysis, patients with a primary colon tumor might have had a longer overall survival than patients with a primary rectal tumor (18.8 months vs 11.1 months, respectively; P=0.037). Common chemotherapy-related toxicities were nausea/vomiting (48.6%), fatigue (34.3%), leucopenia (40%), neutropenia, (42.9%), and anemia (42.9%), with one patient with grade 3 neutropenia, and two patients with grade 3 thrombocytopenia. The common bevacizumab-associated toxicity was hypertension (31.4%). None of the patients discontinued therapy or died because of bevacizumab-associated toxicities.\n\nConclusion\nOur data showed that adding bevacizumab to third- or later-line therapy might lead to tumor control and improved survival in heavily pretreated mCRC patients. In addition, preliminary data suggested that primary colon cancer was more likely to benefit from bevacizumab-containing regimens. Toxicities were acceptable, and no new toxicity was identified. Further studies are needed to validate these findings.\n\nKeywords\nbevacizumabchemotherapymetastatic colorectal cancer\n==== Body\nIntroduction\nWorldwide, colorectal cancer is the third most commonly diagnosed cancer in males and the second most common in females, with an estimated 1.4 million cases and 693,900 deaths occurred in 2012.1 Approximately 40%–50% of newly diagnosed patients have metastatic disease, and the prognosis for metastatic colorectal cancer (mCRC) patients remains poor.2 At the present, chemotherapy with or without target agents was the preferred therapeutic option. Cytotoxic agents for these patients, such as fluoropyrimidines, oxaliplatin, and irinotecan (used in combination and sequentially), prolong progression-free survival (PFS) and overall survival (OS).3 Furthermore, monoclonal antibodies targeting vascular endothelial growth factor (VEGF; bevacizumab) and monoclonal antibodies targeting epidermal growth factor receptor (EGFR; cetuximab and panitumumab, specific for RAS wild-type tumors) have increased the median OS to nearly 30 months.4 However, many patients will experience disease progression after two or more lines of standard therapy and still have a good performance status. Therefore, it is necessary to explore additional treatments for these patients.\n\nTo the best of our knowledge, at least three randomized controlled trials (RCTs) have explored the role of third- or later-line therapy with a survival benefit in mCRC that has progressed after two or more lines of standard therapy. CORRECT first reported that regorafenib might add a survival benefit in these patients, with an objective response rate (ORR) of 1%, a PFS of 1.9 months and an OS of 6.4 months.2 In 2015, at the American Society of Clinical Oncology Gastrointestinal Symposium, Xu et al reported that famitinib also shows a PFS advantage over best supportive care (BSC) in patients with mCRC that progresses after all approved standard therapies (2.8 months vs 1.5 months, respectively; P=0.0053).5 In a Japanese Phase II trial, TAS-102 showed a small superior efficacy with an ORR of 1%, a PFS of 2 months, and an OS of 9 months.6 Nevertheless, the absolute survival benefit from both tyrosine kinase inhibitors (TKIs) and TAS-102 is limited. Much effort is needed to explore more effective therapies and improve the survival of these patients.\n\nBevacizumab is a recombinant, humanized monoclonal antibody targeting VEGF A (VEGF-A), which is a key mediator of tumor angiogenesis. In mCRC, bevacizumab has shown excellent efficacy in both first- and second-line settings in combination with either irinotecan- or oxaliplatin-based chemotherapy.7,8 The ML18147 (TML) and BEBYP trials further demonstrated that bevacizumab can be continued after failing a first-line bevacizumab-containing regimen; these trials showed a significant improvement in PFS and OS.9,10 However, data on the efficacy of bevacizumab in chemorefractory mCRC patients are still limited,11–17 and no data have ever been reported in Chinese patients in this setting.\n\nThe current retrospective study was intended to evaluate the efficacy and safety of bevacizumab plus chemotherapy in Chinese patients with mCRC who have failed two or more lines of standard therapy.\n\nMethods\nPatients\nHistologically confirmed and measurable stage IV CRC patients who were heavily pretreated with oxaliplatin-containing and irinotecan-containing chemotherapy at Sun Yet-sen University Cancer Center between February 2010 and December 2012 were retrospectively reviewed. Prior target drug treatment, such as bevacizumab, cetuximab, and panitumumab, was allowed. Other criteria for eligibility were 1) Eastern Cooperative Oncology Group (ECOG) performance scores (PSs) of 0, 1, or 2; 2) adequate hepatic function (bilirubin <2.0 mg/dL and transaminases levels <3 times the upper normal limit [five times for patients with liver metastasis]); 3) adequate renal function (creatinine <1.5 mg/dL); 4) adequate bone marrow function (absolute neutrophil count [ANC] >1,500/μL, hemoglobin >9.0 g/dL, and platelets >75,000/μL); and 5) a life expectancy of >3 months. Written informed consent was required before chemotherapy.\n\nExclusion criteria included nonhealing wounds, ulcers, bone fractures, thromboembolism that required therapeutic anticoagulation, or major surgery within 6 weeks. Other exclusion criteria were uncontrolled hypertension, bleeding diathesis, active or recent cardiovascular disease or cerebrovascular accident, and pregnancy or lactation in women. The pretreatment characteristics of the patients are presented in Table 1.\n\nTreatment\nThe Institutional Review Board of the Sun Yat-sen Cancer Center approved this retrospective study. After careful review, 35 patients met the eligibility criteria and were included in this retrospective study. All the patients received the first dose of bevacizumab after February 2010, when bevacizumab was approved for mCRC in People’s Republic of China.\n\nAmong the 35 patients, 13 received bevacizumab plus FOLFOX, 17 received bevacizumab plus FOLFIRI, two received bevacizumab plus XELOX, one received bevacizumab plus XELIRI, one received bevacizumab plus irinotecan, and one received bevacizumab plus gemcitabine and raltitrexed. Bevacizumab at a dose of 5 mg/kg or 7.5 mg/kg was administered intravenously (IV) over 90 minutes every 2 or 3 weeks prior to the administration of chemotherapy. FOLFIRI consisted of irinotecan (180 mg/m2) IV over 2 hours and leucovorin (400 mg/m2) IV over 2 hours, followed by an IV bolus of fluorouracil (5-FU) (400 mg/m2) and 46 hours of continuous 5-FU IV (2,400 mg/m2). FOLFOX consisted of oxaliplatin (85 mg/m2) IV over 2 hours and leucovorin (400 mg/m2) IV over 2 hours, followed by an IV bolus of 5-FU (400 mg/m2) and 46 hours of continuous 5-FU IV (2,400 mg/m2). XELOX consisted of oxaliplatin at a dose of 130 mg/m2 as 2–6 hours of infusion on day 1 and Xeloda at a dose of 1 g/m2 twice daily on day 1 to day 14 every 3 weeks. XELIRI consisted of irinotecan at a dose of 125 mg/m2 as a 90-minute infusion on day 1 and day 8 and Xeloda at a dose of 1 g/m2 twice daily on day 1 to day 14 every 3 weeks. Three-weekly irinotecan was at a dose of 350 mg/m2. Gemcitabine and raltitrexed consisted of gemcitabine at a dose of 1 g/m2 as a 30 minute infusion on day 1 and day 8 and raltitrexed at a dose of 3 mg/m2 as a 15 minute infusion on day 1 every 3 weeks. The bevacizumab plus chemotherapy treatment was continued until disease progression or intolerance of therapy.\n\nAssessment\nThe primary endpoint was OS, and secondary endpoints were ORR, PFS, and toxicity. Descriptive statistics were reported as proportions and medians. Tumor responses were assessed by RECIST 1.1 criteria every 6–8 weeks. Radiologic evaluation consisted of chest and abdominopelvic computed tomography. PFS was defined as the time from the beginning of bevacizumab as the third- or later-line treatment to disease progression or death. OS was defined as the time from the beginning of bevacizumab as the third- or later-line treatment to death from any cause. Toxicity evaluations were based on the NCI Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0.\n\nStatistical analysis\nSurvival curves were estimated using the Kaplan–Meier method. All the analyses were performed using SPSS 16.0 for Windows. A P-value less than 0.05 was considered to indicate statistical significance.\n\nResults\nPatient characteristics\nBetween February 2010 and December 2012, 35 consecutive patients with mCRC were treated with bevacizumab plus chemotherapy (mainly oxaliplatin- or irinotecan-containing regimens) as a third- or later-line treatment. Until April 30, 2015, the median follow-up time was 11.3 months (range: 0.7–48.0 months). The median patient age was 56 years (range: 29–80 years). The ECOG performance status was 0 or 1 in 97.2% of the patients. Thirty-three (94.3%) patients had more than three metastatic sites. The previous chemotherapy regimens were irinotecan-containing or oxaliplatin-containing in 30 patients (85.7%), such as FOLFOX, FOLFIRI, and XELOX. The dosage, chemotherapy interval, and cycles were strictly based on the guidelines. Prior to this study, 19 patients had received anti-VEGF- or anti-EGFR-containing therapy (Table 1). All 35 patients identified in this study had progressed on prior therapy according to the RECIST 1.1 evaluation standard. Therefore, these patients were considered as treatment-refractory cases in this study.\n\nEfficacy\nOf the 35 patients, 100% (35/35) and 62.9% (22/35) of patients had experienced progression or died at the last follow-up. The median number of cycles of bevacizumab treatment was 6 (range: 2–17). Treatment discontinuation was caused by disease progression (29/35, 82.9%), inability to tolerate treatment (2/35, 5.7%), palliative surgery (3/35, 8.6%), or another reason (1/35, 2.9%). The response rates were as follows: no patient had a complete response, seven patients had a partial response (PR) (20%), 22 patients had stable disease (62.9%), and six patients had progressive disease (17.1%), giving an ORR of 20% and a disease control rate of 82.9% (Table 2). The median PFS was 5.98 months with a 95% confidence interval of 4.76–7.2 months. The median OS was 14.77 months with a 95% confidence interval of 11.45–18.1 months (Figure 1). In the univariate analysis, the patient’s age, sex, number of metastatic sites, status of Kirsten rat sarcoma viral oncogene (KRAS) mutation, prior anti-VEGF or anti-EGFR treatment, and pretreatment lactate dehydrogenase (LDH) level were not associated with PFS or OS. The OS was 18.56 and 13.77 months for patients treated with or without prior anti-VEGF, respectively; however, there was no statistically significant difference (P=0.58). However, the ORR (all PR) was 42.9% (6/14) in pretreatment high-LDH-level patients, which was higher than the 4.8% (1/21) ORR in pretreatment low-LDH-level patients (P=0.01). Patients with a primary colon tumor may have had a longer OS than patients with a primary rectal tumor, but the PFS was not prolonged (median OS: 18.8 months vs 11.1 months, respectively; P=0.037).\n\nSafety and toxicity\nThe 35 patients received 242 cycles of chemotherapy. There were no treatment-related deaths. Common chemotherapy-related toxicities were nausea/vomiting (48.6%), fatigue (34.3%), leucopenia (40%), neutropenia (42.9%), and anemia (42.9%). Grade 3 neutropenia developed in one patient (2.9%), and thrombocytopenia developed in two patients (5.7%). Grade 3 diarrhea and grade 3 aminotransferase elevation were noted in one patient, respectively. One patient discontinued therapy because of the intolerance of thrombocytopenia, and the other patient discontinued because of diarrhea. Hypertension was the most common bevacizumab-associated toxicity (31.4%). Grade 1 bleeding, and grade 1 proteinuria occurred in one patient. No grade 3 or 4 bevacizumab-associated toxicities occurred. Bowel perforation and thrombosis/embolism were not observed (Table 3).\n\nDiscussion\nMany mCRC patients still have good performance status to tolerate further treatment after standard first-line and second-line therapies, but the alternative third- or later-line therapeutic regimens are limited, and the efficacy has been discouraging. Regorafenib was accepted as the third-line therapy based on better survival than BSC, as it showed a discouraging result, with a PFS of 1.9 months and an OS of 6.4 months.2 Famitinib and TAS-102 also did not show better efficacy, with a PFS of 2 months and an OS of 6–9 months.5,6 Compared with the low ORR (1%–2.2%) and small survival benefit in these three RCTs, our study showed a higher response rate with a PR of 20%, a longer median PFS of 5.98 months and a median OS of 14.77 months.\n\nPrior to our study, several small-sample studies including 19–100 patients explored the role of bevacizumab plus chemotherapy as third- or later-line therapy in mCRC patients who progressed after all standard treatments. The ORR was from 0% to 28.5% (median, 9%), the PFS was from 3.5 to 8.9 months (median, 3.9 months), and the OS was from 7.7 to 13.8 months (median, 9.5 months). The details are shown in Table 4.11–17 Together with those studies, our data suggest that adding bevacizumab to third- or later-line therapy in mCRC patients may lead to tumor control and improved survival. The following reasons may contribute to the potential advantages of bevacizumab in third- or later-line therapy. First, bevacizumab not only inhibits neoangiogenesis, but also normalizes the surviving tumor blood vessels. The later effect results in the accumulation of cytotoxic agents in the tumor, which may enhance the efficacy of chemotherapy. Second, bevacizumab adding a survival advantage as a part of cross-line treatment might imply treatment failure mainly due to resistance to cytotoxic agents but not to anti-angiogenesis drugs.9,10 Moreover, the success of bevacizumab in first- and second-line treatment7,8 and the success of regorafenib and famitinib in later-line therapy2,5 suggest that anti-angiogenesis may play a role throughout the whole course of treatment. After an indirect comparison of later-line treatments, the promising survival benefit of bevacizumab compared with regorafenib or famitinib suggested not only that head-to-head RCTs comparing the monoclonal antibodies and TKIs are urgently needed, but also that anti-angiogenesis should be combined with chemotherapy, rather than utilized alone, in patients with a good PS in the later-line setting.\n\nIn the subgroup analysis, patients with a primary colon tumor may have had a longer OS than those with a primary rectal tumor, which is in accordance with the regorafenib data from the CORRECT trial.2 In our study, PFS before the beginning of salvage therapy, pretreatment target drugs, cycles of bevacizumab, chemotherapy regimen, and performance status in salvage therapy were similar in patients with different primary tumor sites. A subgroup analysis from a Phase III trial (FIRE-3), which compared head-to-head bevacizumab with cetuximab in first-line therapy, showed that a primary rectal tumor might benefit from a cetuximab-containing regimen.4 In summary, these studies suggested that a benefit from the target drugs was associated with the primary tumor site. Presently, the reason that primary colon cancer benefits from anti-VEGFR pathway therapy more than primary rectal cancer has not been elucidated. It was reported that VEGF-A, the target of bevacizumab, is present in higher levels in left-sided colon and rectal cancers than in right-sided colon cancers.18,19\n\nIt has been reported that pretreatment LDH levels can predict the efficacy of first-line bevacizumab-based therapy in mCRC patients.20,21 Our data did not show that patients with a pretreatment high LDH level have a longer OS when treated with third- or later-line bevacizumab-containing therapy. However, the response rate was 42.9% (6/14) in pretreatment high-LDH-level patients, which was higher than the 4.8% (1/21) response rate in pretreatment low-LDH-level patients. Theoretically, LDH can increase the accumulation of lactate in tumors and create an acidic tumor microenvironment, which enhances pericyte deficiency, neovascularization, and sensitivity to antiangiogenesis agents.22,23 Our study could not predict a role for LDH in third- or later-line therapy. This might be explained by the limitation of the small sample and retrospective nature of our study. A larger sample and a prospective study are needed to further answer this question.\n\nThe toxicity profile of bevacizumab plus chemotherapy seemed to be similar to those observed in previous studies,11–17 which included chemotherapy-related and bevacizumab-related toxicities. The common adverse events related to chemotherapy were leucopenia, anemia, fatigue, and nausea/vomiting. The common adverse events related to bevacizumab were hypertension, bleeding, and proteinuria. These toxicities were tolerable, and no dosage was adjusted or therapy was interrupted by the toxicity. Two patients discontinued therapy because of the intolerance of thrombocytopenia and diarrhea. No gastrointestinal perforations and embolisms occurred, most likely due to the small number of patients. No patients discontinued therapy because of bevacizumab-associated toxicities.\n\nSeveral limitations hampered the generalization of the present results to all patients with heavily treated mCRC; these limitations can be partly attributable to the study’s retrospective nature. First, selection bias cannot be excluded because only medically fit patients with very a good performance status might have been treated with bevacizumab-containing third- or later-line therapy. This is suggested by the inclusion of only one patient with an ECOG performance status of 2 in the whole cohort of bevacizumab-treated patients, which might have led to a more favorable OS estimate in these patients. Second, the small cohort in this study may also affect the objectivity of our data. Third, the PFS evaluation could have been biased by the fact that neither independent monitoring nor a centralized review of the radiological responses was performed in our study. Fourth, this study had no data on chemotherapy alone. Nevertheless, our data were equal to or a little better than previous similar data, which were superior to the results of chemotherapy alone in the third- or later-line therapy.2,5 Finally, there were insufficient data on toxicity, particularly on peripheral neuropathy associated with oxaliplatin, not necessarily indicating the absence of peripheral neuropathy associated with oxaliplatin, but rather the lack of detailed medical records.\n\nConclusion\nTo the best of our knowledge, this was the first study to explore the role of bevacizumab-containing regimens as third- or later-line therapy in Chinese patients with heavily treated mCRC. Our data showed that adding bevacizumab to third- or later-line therapy may lead to tumor control and improved survival in mCRC patients. In addition, preliminary data suggested that primary colon cancer was more likely to benefit from bevacizumab-containing regimens as third- or later-line therapy. Further studies are needed to validate these findings.\n\nAcknowledgments\nThis study was supported by grants from Science and Technology Planning Project of Guangdong Province, People’s Republic of China (2011B061300069) and National Natural Science Foundation of China (81272641, 81071872 and 81572409).\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Kaplan–Meier estimates of progression-free (A) and overall survival (B).\n\nNotes: (A) Median progression-free survival: 5.98 months, 95% confidence interval: 4.76–7.2 months. (B) Median overall survival: 14.77 months, 95% confidence interval: 11.45–18.1 months.\n\nTable 1 Baseline demographics and clinical characteristics\n\nCharacteristics\tNo of patients, N (%)\t\nTotal\t35\t\nSex\t\t\n Men\t27 (77.1)\t\n Women\t8 (22.9)\t\nAge (years)\t\nMedian (range)\t56 (29–80)\t\n ≤65\t30 (85.7)\t\n >65\t5 (14.3)\t\nECOG PS\t\n 0\t1 (2.9)\t\n 1\t33 (94.3)\t\n 2\t1 (2.9)\t\nPrimary tumor site\t\n Colon\t24 (68.6)\t\n Rectum\t11 (31.4)\t\nNo of metastatic sites\t\n 1\t2 (5.7)\t\n 2\t0 (0)\t\n ≥3\t33 (94.3)\t\nKRAS status\t\n Wild-type\t17 (48.6)\t\n Mutation type\t10 (28.6)\t\n Unknown\t8 (22.8)\t\nChemotherapy associated with BV\t\n Oxaliplatin-containing\t15 (42.9)\t\n Irinotecan-containing\t19 (54.3)\t\n Other\t1 (2.8)\t\nLine of bevacizumab\t\n 3\t29 (82.9)\t\n ≥4\t6 (17.1)\t\nPrevious target treatment\t\n Anti-VEGF\t9 (25.7)\t\n Anti-EGFR\t10 (28.6)\t\n Neither\t16 (45.7)\t\nPretreatment LDH\t\n Normal\t20 (57.1)\t\n Abnormal\t13 (37.2)\t\n Not reported\t2 (5.7)\t\nAbbreviations: BV, bevacizumab; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; KRAS, Kirsten rat sarcoma viral oncogene; LDH, lactate dehydrogenase; PS, performance status; VEGF, vascular endothelial growth factor.\n\nTable 2 Response to treatment\n\nResponse\tNumber (%)\t\nComplete response (CR)\t0 (0)\t\nPartial response (PR)\t7 (20)\t\nStable disease (SD)\t22 (62.9)\t\nProgressive disease\t6 (17.1)\t\nNot assessable\t0 (0)\t\nObjective response (CR + PR)\t7 (20)\t\nDisease control (CR + PR + SD)\t30 (82.9)\t\nTable 3 Toxicity of bevacizumab plus chemotherapy in third- or later-line therapy\n\nAdverse events\tAll grades, N (%)\tGrade 3/4, N (%)\t\nHematologic\t\n Leucopenia\t14/35 (40)\t0\t\n Neutropenia\t15/35 (42.9)\t1/35 (2.9)\t\n Anemia\t15/35 (42.9)\t0\t\n Thrombocytopenia\t4/35 (11.4)\t2/35 (5.7)\t\nNonhematologic\t\n Fatigue\t12/35 (34.3)\t0\t\n Nausea/vomiting\t17/35 (48.6)\t0\t\n Diarrhea\t7/35 (20)\t1/35 (2.9)\t\n Mucositis\t4/35 (11.4)\t0\t\n Liver toxicity\t8/35 (22.9)\t1/35 (2.9)\t\nBevacizumab-associated AE\t\n Bleeding\t2/35 (5.7)\t0\t\n GI perforation/fistula\t0\t0\t\n Thrombosis/embolism\t0\t0\t\n Hypertension\t11/35 (31.4)\t0\t\n Proteinuria\t2/35 (5.7)\t0\t\nAbbreviations: AE, adverse event; GI, gastrointestinal.\n\nTable 4 Historical data on third- or later-line treatment\n\nReferences\tPublication year\tType of study\tN\tTreatment line\tTreatment regimen\tORR (%)\tDCR (%)\tTTP/PFS\tOS\t\nGrothey et al2\t2013\tPhase III\t255\tThird or later\tBest supportive care\t0.4\t15.4\t1.7\t5.0\t\nGrothey et al2\t2013\tPhase III\t505\tThird or later\tRegorafenib\t1.0\t42.0\t1.9\t6.4\t\nEmmanouilides et al11\t2004\tCohort study\t19\tThird\tBV+5-FU/LV\t0\t47.4\t3.7\tNA\t\nChen et al12\t2006\tPhase II\t100\tThird\tBV+5-FU/LV\t4.0\t50\t3.7\t9.1\t\nKwon et al13\t2007\tPilot study\t14\tThird\tBV+FOLFIRI\t28.5\t85.7\t3.9\t10.9\t\nKang et al14\t2009\tRetrospective\t42\tThird or later\tBV+FOLFOX/FOLFIRI\t9.5\t61.9\t5.3\t9.5\t\nGeva et al15\t2013\tRetrospective\t46\tThird or later\tBV+chemotherapy\t22\t83\t8.9\t13.8\t\nVincenzi et al16\t2009\tPhase II\t48\tFourth\tBV+5-FU/LV\t6.25\t36.65\t3.5\t7.7\t\nLarsen et al17\t2012\tRetrospective\t34\tFourth\tBV+Xeloda\t9\t71\t5.4\t12.2\t\nAbbreviations: BV, bevacizumab; 5-FU, Fluorouracil; DCR, disease control rate; NA, not assessed; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; TTP, time to progress; LV, leucovorin; FOLFIRI, Irinotecan plus Fluorouracil plus leucovorin; FOLFOX, Oxaliplatin plus Fluorouracil plus leucovorin.\n==== Refs\nReferences\n1 Torre LA Bray F Siegel RL Ferlay J Lortet-Tieulent J Jemal A Global cancer statistics, 2012 CA Cancer J Clin 2015 65 2 87 108 25651787 \n2 Grothey A Van Cutsem E Sobrero A Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial Lancet 2013 381 9863 303 312 23177514 \n3 Grothey A Hedrick EE Mass RD Response-independent survival benefit in metastatic colorectal cancer: a comparative analysis of N9741 and AVF2107 J Clin Oncol 2008 26 2 183 189 18182660 \n4 Heinemann V von Weikersthal LF Decker T FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial Lancet Oncol 2014 15 10 1065 1075 25088940 \n5 Xu RH Shen L Wang KM A randomized, double-blind, parallel-group, placebo-controlled, multicenter, phase II clinical study of famitinib in the treatment of advanced metastatic colorectal cancer J Clin Oncol 2015 33 Suppl 3 abstr 513 \n6 Yoshino T Mizunuma N Yamazaki K TAS-102 monotherapy for pretreated metastatic colorectal cancer: a double-blind, randomised, placebo-controlled phase 2 trial Lancet Oncol 2012 13 10 993 1001 22951287 \n7 Venook AP Niedzwiecki D Lenz HJ CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC) J Clin Oncol 2014 32 5S abstr LBA3 \n8 Giantonio BJ Catalano PJ Meropol NJ Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200 J Clin Oncol 2007 25 12 1539 1544 17442997 \n9 Bennouna J Sastre J Arnold D Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial Lancet Oncol 2013 14 1 29 37 23168366 \n10 Masi G Salvatore L Boni L Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial Ann Oncol 2015 26 4 724 730 25600568 \n11 Emmanouilides C Pegram M Robinson R Hecht R Kabbinavar F Isacoff W Anti-VEGF antibody bevacizumab (Avastin) with 5FU/LV as third line treatment for colorectal cancer Tech Coloproctol 2004 8 Suppl 1 S50 S52 15655642 \n12 Chen HX Mooney M Boron M Phase II multicenter trial of bevacizumab plus fluorouracil and leucovorin in patients with advanced refractory colorectal cancer: an NCI Treatment Referral Center Trial TRC-0301 J Clin Oncol 2006 24 21 3354 3360 16849749 \n13 Kwon HC Oh SY Lee S Kim SH Kim HJ Bevacizumab plus infusional 5-fluorouracil, leucovorin and irinotecan for advanced colorectal cancer that progressed after oxaliplatin and irinotecan chemotherapy: a pilot study World J Gastroenterol 2007 13 46 6231 6235 18069765 \n14 Kang BW Kim TW Lee JL Bevacizumab plus FOLFIRI or FOLFOX as third-line or later treatment in patients with metastatic colorectal cancer after failure of 5-fluorouracil, irinotecan, and oxali-platin: a retrospective analysis Med Oncol 2009 26 1 32 37 18498064 \n15 Geva R Vecchione L Tejpar S Piessevaux H Van Cutsem E Prenen H Bevacizumab plus chemotherapy as salvage treatment in chemorefractory patients with metastatic colorectal cancer Onco Targets Ther 2013 6 53 58 23378775 \n16 Vincenzi B Santini D Russo A Bevacizumab in association with de Gramont 5-fluorouracil/folinic acid in patients with oxaliplatin-, irinotecan-, and cetuximab-refractory colorectal cancer: a single-center phase 2 trial Cancer 2009 115 20 4849 4856 19626652 \n17 Larsen FO Boisen MK Fromm AL Jensen BV Capecitabine and bevacizumab in heavily pre-treated patients with advanced colorectal cancer Acta Oncol 2012 51 2 231 233 21936753 \n18 Bendardaf R Buhmeida A Hilska M VEGF-1 expression in colorectal cancer is associated with disease localization, stage, and long-term disease-specific survival Anticancer Res 2008 28 6B 3865 3870 19192642 \n19 Boisen MK Johansen JS Dehlendorff C Primary tumor location and bevacizumab effectiveness in patients with metastatic colorectal cancer Ann Oncol 2013 24 10 2554 2559 23864097 \n20 Scartozzi M Giampieri R Maccaroni E Pre-treatment lactate dehydrogenase levels as predictor of efficacy of first-line bevacizumab-based therapy in metastatic colorectal cancer patients Br J Cancer 2012 106 5 799 804 22315053 \n21 Yin CX Jiang C Liao FX Initial LDH level can predict the survival benefit from bevacizumab in the first-line setting in Chinese patients with metastatic colorectal cancer Onco Targets Ther 2014 7 1415 1422 25143746 \n22 Lee DC Sohn HA Park ZY A lactate-induced response to hypoxia Cell 2015 161 3 595 609 25892225 \n23 Azuma M Shi M Danenberg KD Serum lactate dehydrogenase levels and glycolysis significantly correlate with tumor VEGFA and VEGFR expression in metastatic CRC patients Pharmacogenomics 2007 8 12 1705 1713 18086000\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1178-6930",
"issue": "8()",
"journal": "OncoTargets and therapy",
"keywords": "bevacizumab; chemotherapy; metastatic colorectal cancer",
"medline_ta": "Onco Targets Ther",
"mesh_terms": null,
"nlm_unique_id": "101514322",
"other_id": null,
"pages": "2407-13",
"pmc": null,
"pmid": "26366095",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": "16849749;18086000;25892225;23177514;18498064;25600568;21936753;15655642;18069765;25143746;23168366;25088940;22951287;19626652;25651787;17442997;18182660;19192642;23864097;23378775;22315053",
"title": "Bevacizumab plus chemotherapy as third- or later-line therapy in patients with heavily treated metastatic colorectal cancer.",
"title_normalized": "bevacizumab plus chemotherapy as third or later line therapy in patients with heavily treated metastatic colorectal cancer"
} | [
{
"companynumb": "CN-ROCHE-1633817",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": null,
"dru... |
{
"abstract": "Immune-related adverse events (irAEs) associated with immune checkpoint inhibitors are becoming more common; however, irAEs involving blood vessels are rare. We report a patient with limb arteriolar vasculitis induced by pembrolizumab plus chemotherapy. He was 60-year-old man who received first-line treatment with pembrolizumab plus chemotherapy for postoperative lung cancer recurrence. Two weeks after the first administration, he experienced Raynaud's phenomenon. We initiated a vasodilator, but his symptoms worsened, and we considered an irAE. We initiated oral prednisolone, and his symptoms gradually improved. A few weeks later, we performed skin biopsies of both of the patient's feet, and pathological examination revealed arteriolar thrombosis with slight perivascular lymphocytic infiltration. Infiltration of neutrophils with karyorrhexis in the subendothelium was also seen. He also developed acute kidney injury, likely owing to thrombosis. Physical examination of bilateral fingers and toes in patients with lung cancer should be performed carefully after administering pembrolizumab therapy.",
"affiliations": "Department of Thoracic Surgery, Kitakyushu Municipal Medical Center, 2-1-1 Bashaku, Kokurakita-ku, Kitakyushu, Fukuoka 802-8561 Japan.;Department of Thoracic Surgery, Kitakyushu Municipal Medical Center, 2-1-1 Bashaku, Kokurakita-ku, Kitakyushu, Fukuoka 802-8561 Japan.;Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582 Japan.;Department of Thoracic Surgery, Kitakyushu Municipal Medical Center, 2-1-1 Bashaku, Kokurakita-ku, Kitakyushu, Fukuoka 802-8561 Japan.;Department of Thoracic Surgery, Kitakyushu Municipal Medical Center, 2-1-1 Bashaku, Kokurakita-ku, Kitakyushu, Fukuoka 802-8561 Japan.;Department of Dermatology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka 807-8555 Japan.;Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582 Japan.;Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582 Japan.",
"authors": "Takada|Kazuki|K|0000-0001-6377-9291;Hamatake|Motoharu|M|;Kohashi|Kenichi|K|;Shimamatsu|Shinichiro|S|;Hirai|Fumihiko|F|;Ohmori|Shun|S|;Tagawa|Tetsuzo|T|;Mori|Masaki|M|",
"chemical_list": null,
"country": "Singapore",
"delete": false,
"doi": "10.1007/s13691-020-00454-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2192-3183",
"issue": "10(1)",
"journal": "International cancer conference journal",
"keywords": "Immune-related adverse events; Lung cancer; Pembrolizumab; Raynaud’s phenomenon; Vasculitis",
"medline_ta": "Int Cancer Conf J",
"mesh_terms": null,
"nlm_unique_id": "101734231",
"other_id": null,
"pages": "83-86",
"pmc": null,
"pmid": "33489708",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article",
"references": "28885881;27718847;27979383;26412456;30280658;26970723;29433584;28314758;26028407;32167195;26712084;27534573;20147741",
"title": "Limb arteriolar vasculitis induced by pembrolizumab plus chemotherapy in a patient with lung cancer.",
"title_normalized": "limb arteriolar vasculitis induced by pembrolizumab plus chemotherapy in a patient with lung cancer"
} | [
{
"companynumb": "JP-TEVA-2021-JP-1879419",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "METHODS\n78-year-old African-American man.\nChronic lymphocytic leukemia first diagnosed in 2003, with a subsequent relapse in 2006 and another in 2010.\nIn late 2011, the patient was admitted to the hospital for cholelithiasis, at which time his treating physician incidentally discovered severe anemia. The anemia worsened as time went on, and the patient became transfusion dependent. Hypogammaglobulinemia secondary to chronic lymphocytic leukemia (CLL) required that the patient receive intravenous immunoglobulin. Despite transfusion therapy, the anemia failed to lessen; laboratory results eventually led to the diagnosis of a drug-induced warm autoantibody that triggered hemolytic anemia.\nThe patient had taken rituximab in 2003; rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone (R-CHOP) in 2006; fludarabine, cyclophosphamide, and rituximab (FCR) in 2010; and intravenous Immunoglobulin (IVIG) and prednisone in 2011.",
"affiliations": "Medical Laboratory Sciences Program, University of North Florida, Jacksonville, FL n00670173@gmail.com.;Southeastern division, Immucor, Inc., Norcross, GA.;Mayo Clinic, Jacksonville, FL.",
"authors": "Sartori|Alex|A|;Staley|Brian|B|;Skipper|Angela|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1309/LMLWQDB2Q6LS7VQG",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-5027",
"issue": "45(3)",
"journal": "Laboratory medicine",
"keywords": "autoimmune; chronic lymphocytic leukemia; drug induced; hemolytic anemia; transfusion; warm autoantibody",
"medline_ta": "Lab Med",
"mesh_terms": "D001741:African Americans; D000368:Aged; D000744:Anemia, Hemolytic, Autoimmune; D000971:Antineoplastic Combined Chemotherapy Protocols; D001803:Blood Transfusion; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008297:Male",
"nlm_unique_id": "0250641",
"other_id": null,
"pages": "e105-8",
"pmc": null,
"pmid": "25157090",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Drug-induced autoimmune hemolytic anemia in a 78-year-old African-American man with chronic lymphocytic leukemia.",
"title_normalized": "drug induced autoimmune hemolytic anemia in a 78 year old african american man with chronic lymphocytic leukemia"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2015US-107677",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINCRISTINE SULFATE"
},
... |
{
"abstract": "An anterior mediastinal mass has a broad differential. We report a case of a large anterior mediastinal malignancy in a pediatric patient presenting with left-sided supraclavicular pain without symptoms of cardiopulmonary compromise. The mass was revealed with CT imaging and diagnosis of T-cell lymphoblastic lymphoma was confirmed after supraclavicular lymph node biopsy. The patient was initially treated with methylprednisolone for cytoreduction and a combination of rasburicase and allopurinol for asymptomatic tumor lysis syndrome. There was then a 34-day induction phase of chemotherapy with vincristine, daunorubicin, PEG-asparaginase, and intrathecal methotrexate. CSF sampling and bone marrow biopsies were both negative at the end of induction. The patient is currently in the consolidation phase, taking cyclophosphamide, cytarabine, and 6-MP, and is tolerating the treatment well.",
"affiliations": "University of South Dakota Sanford School of Medicine.;Department of Pediatrics, University of South Dakota Sanford School of Medicine, Yankton, South Dakota.",
"authors": "Tidwell|Cody|C|;Willman|April|A|",
"chemical_list": "D011241:Prednisone; D003630:Daunorubicin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0038-3317",
"issue": "72(10)",
"journal": "South Dakota medicine : the journal of the South Dakota State Medical Association",
"keywords": null,
"medline_ta": "S D Med",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D003630:Daunorubicin; D006801:Humans; D010146:Pain; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011241:Prednisone; D012074:Remission Induction; D013601:T-Lymphocytes; D016896:Treatment Outcome",
"nlm_unique_id": "101265265",
"other_id": null,
"pages": "442-445",
"pmc": null,
"pmid": "31816203",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "T-Cell Lymphoblastic Lymphoma Presenting as Acute Clavicular Pain.",
"title_normalized": "t cell lymphoblastic lymphoma presenting as acute clavicular pain"
} | [
{
"companynumb": "NVSC2020US030005",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEGASPARGASE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "We report a rare fatal case of acute metformin overdose in a 19-year-old woman.",
"affiliations": "Division of Clinical Pharmacology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa. ebrism003@myuct.ac.za.",
"authors": "Ebrahim|I|I|;Blockman|M|M|",
"chemical_list": "D002316:Cardiotonic Agents; D007004:Hypoglycemic Agents; D017693:Sodium Bicarbonate; D008687:Metformin",
"country": "South Africa",
"delete": false,
"doi": "10.7196/SAMJ.2017.v107i2.10971",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "107(2)",
"journal": "South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde",
"keywords": null,
"medline_ta": "S Afr Med J",
"mesh_terms": "D000138:Acidosis; D001784:Blood Gas Analysis; D002316:Cardiotonic Agents; D062787:Drug Overdose; D017809:Fatal Outcome; D005260:Female; D006323:Heart Arrest; D006801:Humans; D007003:Hypoglycemia; D007004:Hypoglycemic Agents; D007022:Hypotension; D008133:Long QT Syndrome; D008687:Metformin; D017693:Sodium Bicarbonate; D055815:Young Adult",
"nlm_unique_id": "0404520",
"other_id": null,
"pages": "110-111",
"pmc": null,
"pmid": "28220733",
"pubdate": "2017-01-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Metabolic acidosis in a patient with metformin overdose.",
"title_normalized": "metabolic acidosis in a patient with metformin overdose"
} | [
{
"companynumb": "ZA-INVENTIA-000164",
"fulfillexpeditecriteria": "1",
"occurcountry": "ZA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"drugadditional": null,
... |
{
"abstract": "There have been a few reports on the administration of rituximab for relapsing-remitting multiple sclerosis (RRMS) in the acute phase. We report the case of a 62-year-old woman with an acute lesion of RRMS. Although corticosteroid therapy and plasmapheresis were not effective, the lesion improved with the administration of rituximab. We believe that the B cells were promptly depleted after the infusion of rituximab, and that the inflammatory reactions related to the B cells were suppressed. We suggest that the administration of rituximab can be considered as a treatment option for acute-phase RRMS when conventional therapies are not effective.",
"affiliations": "Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Japan.;Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Japan.;Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Japan.;Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Japan.",
"authors": "Shima|Ayano|A|;Hamaguchi|Tsuyoshi|T|;Tada|Yasutake|Y|;Yamada|Masahito|M|",
"chemical_list": "D005938:Glucocorticoids; D007155:Immunologic Factors; D000069283:Rituximab",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.3408-19",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 3146259510.2169/internalmedicine.3408-19Case ReportTreatment with Rituximab in the Acute Phase of Relapsing Remitting Multiple Sclerosis Shima Ayano 1Hamaguchi Tsuyoshi 1Tada Yasutake 1Yamada Masahito 1\n1 Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, JapanCorrespondence to Dr. Ayano Shima, medamashima@med.kanazawa-u.ac.jp\n\n28 8 2019 1 1 2020 59 1 121 124 30 5 2019 16 7 2019 Copyright © 2020 by The Japanese Society of Internal MedicineThe Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).There have been a few reports on the administration of rituximab for relapsing-remitting multiple sclerosis (RRMS) in the acute phase. We report the case of a 62-year-old woman with an acute lesion of RRMS. Although corticosteroid therapy and plasmapheresis were not effective, the lesion improved with the administration of rituximab. We believe that the B cells were promptly depleted after the infusion of rituximab, and that the inflammatory reactions related to the B cells were suppressed. We suggest that the administration of rituximab can be considered as a treatment option for acute-phase RRMS when conventional therapies are not effective. \n\nrelapsing remitting multiple sclerosisrituximabtreatment\n==== Body\nIntroduction\nRituximab, a monoclonal antibody against CD20 surface antigen on B cells, can reduce disease activity in patients with relapsing-remitting multiple sclerosis (RRMS). The administration of rituximab can also reduce the number of relapses when used as a disease-modifying therapy (1-3). There have been a few reports on the administration of rituximab for acute-phase RRMS. We herein report a case involving a patient with an acute lesion of RRMS that was resistant to the first-line and second-line therapies, which improved with the administration of rituximab.\n\nCase Report\nA 62-year-old woman without any significant medical history presented with right homonymous hemianopsia and progressive left hemiparesis. Magnetic resonance imaging (MRI) of the brain revealed areas of hyperintensity in the white matter of the left occipital and temporal lobes and the right corona radiata on T2-weighted imaging (T2WI) and fluid-attenuated inversion recovery (FLAIR) with heterogeneous enhancement after the administration of gadolinium (Fig. 1A-D). An enzyme-linked immunosorbent assay (ELISA) and cell-based assay (CBA) were negative for serum anti-aquaporin 4 (AQP4) antibodies. A CBA for anti-myelin oligodendrocyte glycoprotein antibodies was also negative. The patient's serum was also negative for antinuclear antibodies and antibodies for collagen diseases. The concentrations of serum soluble interleukin-2 receptor (sIL-2R) and beta-2-microglobulin (β2-MG) were normal. A cerebrospinal fluid (CSF) analysis revealed normal concentrations of protein and glucose without pleocytosis. The myelin basic protein (MBP) concentration was elevated (256.0 pg/mL, normal <102 pg/mL), although the immunoglobulin G (IgG) index (0.53) and the concentrations of sIL-2R and β2-MG were normal. Neither oligoclonal bands (OCB) nor malignant cells were found in the CSF. Blood and the CSF cultures were negative. A biopsy of the left occipital lobe lesion showed inflammatory demyelination, focal demyelination, numerous CD68 foamy macrophages and reactive astrocytes, and perivascular and parenchymal lymphocytic infiltration with predominant CD4+ T cells and a smaller population of CD8+ T cells and CD20+ B cells. The findings were consistent with those observed in multiple sclerosis (MS) (Fig. 2). The patient was treated with intravenous methylprednisolone (IVMP, 1,000 mg/day for 3 days) and with a tapering course of oral prednisolone. The symptoms and lesions on MRI showed improvement after the treatment.\n\nFigure 1. Magnetic resonance imaging (MRI) of the brain at the time of the first attack (A-D), the second attack (E) and the third attack (F). Axial fluid-attenuated inversion recovery (FLAIR) images revealed areas of hyperintensity in the white matter of the left occipital lobe (A), right corona radiata, and left occipital lobe (C), with heterogeneous enhancement on post-gadolinium T1-weighted images (T1WI) (B and D). FLAIR images showed hyperintense lesions in the left corona radiata (E) and the right cerebral peduncle (F).\n\nFigure 2. A histological examination of the left occipital lobe lesion of the first attack. Hematoxylin and Eosin staining (A) revealed perivascular and parenchymal lymphocytic infiltrates. Klüver-Barrera staining (B) and immunohistochemical staining of myelin basic protein (C) showed demyelination. Axons were preserved on immunohistochemistry with an antibody against phosphorylated neurofilament (SMI-31) (D). Immunohistochemical studies showed numerous CD68+ foamy macrophages (E), parenchymal and perivascular infiltration of CD4+ T cells (F) and a smaller population of CD8+ T cells (G), and a few perivascular CD20+ B cells (H). All scale bars =100 μm.\n\nAt five months after the first attack, the patient experienced recurrence with an asymptomatic lesion in the left corona radiata (Fig. 1E). The diagnosis of RRMS was made in accordance with the revised McDonald's criteria (4). The patient was treated with IVMP, which resulted in the improvement of the lesion. Interferon-β was initiated after the second attack. At two months after the second attack (7 months after the first attack), the patient experienced recurrence again, with weakness of the left lower limb and MRI revealing an area of hyperintensity in the right cerebral peduncle on T2WI and FLAIR (Fig. 1F). Improvement was observed after treatment with IVMP.\n\nAt ten months after the first attack, the patient presented with a sensory disturbance on the left side of the face, weakness of the left upper and lower extremities, and dysarthria. A neurological examination revealed sensory disturbance on the left side of the face, dysarthria, left hemiparesis, hyperreflexia of the left lower limb, and limb ataxia. MRI showed a hyperintense edematous lesion extending from the right mesencephalic tegmentum to the crus cerebri on T2WI and FLAIR with heterogeneous enhancement after gadolinium administration (Fig. 3A-D). Laboratory investigations, including the serum levels of sIL-2R and β2-MG, were normal. An ELISA to detect serum anti-AQP4 antibodies was negative. The patient's serum was also negative for antinuclear antibodies and antibodies for collagen diseases. CSF analyses for MBP, IgG index (0.63), sIL-2R, and β2-MG were normal and neither OCB nor malignant cells were found in the CSF. Interferon-β was discontinued, and the patient was treated with two courses of IVMP, three courses of immunoadsorption plasmapheresis (IAPP), and three courses of plasma exchange. However, her symptoms deteriorated. She developed ophthalmoplegia, could not eat due to dysphagia, and required assistance while walking. Brain MRI revealed that the brainstem lesion extended to the pons (Fig. 3E-H). The patient was treated with intravenous immunoglobulin (IVIg), but her condition deteriorated further, and she became drowsy. She was treated with rituximab (1,000 mg/day on days 1 and 15) after the institutional committee for the evaluation of highly difficult new medical technologies approved the treatment, and after obtaining written consent from the patient's family. Her symptoms started to improve immediately after the administration of rituximab, and the peripheral blood B cell count dropped rapidly to undetectable levels. At one month after the administration of rituximab, the patient could eat, and brain MRI showed a reduction in the size of the brainstem lesion without enhancement (Fig. 3I-L). The patient could walk by herself and was discharged from our hospital three months after the administration of rituximab without any complications. At ten months after the administration of rituximab, her B cell count recovered to over 800/mm3, and dimethyl fumarate was initiated. There has been no recurrence for approximately 23 months since the administration of rituximab.\n\nFigure 3. Serial MRI scans of the brain at ten months after the first episode before treatment (A-D), after treatment with corticosteroids, plasmapheresis, and intravenous immunoglobulin (E-H), and after the administration of rituximab (I-L). Axial fluid-attenuated inversion recovery (FLAIR) images showed a hyperintense lesion extending from the right mesencephalic tegmentum to the crus cerebri (A and C), with heterogeneous enhancement on post-gadolinium T1-weighted images (T1WI) (B and D). FLAIR images revealed that the brainstem lesion extended to the pons (E and G) with enhancement on post-gadolinium T1WI (F and H). FLAIR images showed a reduction in the size of brainstem lesion (I and K) without enhancement on post-gadolinium T1WI (J and L) after the administration of rituximab.\n\nDiscussion\nWe believe that the present case report is the first to describe the clinical course of a patient with RRMS who was treated with rituximab in the acute phase of the disease.\n\nIn the present case, the lesion biopsied at the time of the first attack showed pathological findings consistent with those of acute-phase lesions of RRMS. The lesions on brain MRI and the symptoms of the first 3 attacks improved immediately after the administration of IVMP. However, the latest attack was resistant to immunotherapy with corticosteroids, plasmapheresis, and IVIg, with rituximab being the only effective treatment. These findings suggest that the mechanism underlying the last recurrence differed from that of the first 3 attacks.\n\nAccording to previous case reports, 5 patients with clinically isolated syndrome (CIS) or MS are reported to have been treated with rituximab in the acute phase of the disease, and 4 the 5 patients showed improvement after the administration of rituximab (5-7). The detailed clinical course was reported in 2 of these cases. Both patients had CIS and improved soon after the first administration of rituximab (6,7). Similarly, the symptoms of the patient in the current case report started to improve promptly after the administration of rituximab. We believe that the B cells were promptly depleted after the infusion of rituximab, and that inflammatory reactions related to B cells might have been suppressed due to the loss of the B cell functions, such as antigen-presentation, activation of T cells, and cytokine production (8).\n\nBecause the present patient had atypical features of MS, such as late onset, edematous and relatively large lesions on brain MRI, no OCB in CSF, and resistance to the conventional immunotherapies, we could not exclude the possibility that the disease of this patient differed from typical RRMS. We believe that rituximab could be effective in the acute phase of RRMS, especially for the patients who show no improvement with conventional therapies.\n\nConclusion\nOur findings suggest that the administration of rituximab can be considered as a treatment option for acute-phase RRMS when conventional therapies are not effective.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nHauser SL , Waubant E , Arnold DL , et al \nB-cell depletion with rituximab in relpsing-remitting multiple sclerosis . N Engl J Med \n358 : 676 -688 , 2008 .18272891 \n2. \nBar-Or A , Calabresi PA , Arnold D , et al \nRituximab in relapsing-remitting multiple sclerosis: a 72-week, open-label, phase I trial . Ann Neurol \n63 : 359 -400 , 2008 .\n3. \nNaismith RT , Piccio L , Lyons JA , et al \nRituximab add-on therapy for brealthrough relapsing multiple sclerosis: a 52-week phase Ⅱ trial . Neurology \n74 : 1860 -1867 , 2010 .20530322 \n4. \nPolman CH , Reingold SC , Banwell B , et al \nDiagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria . Ann Neurol \n69 : 292 -302 , 2011 .21387374 \n5. \nSánchez P , Meca-Lallana V , Barbosa A , et al \nTumefactive demyelinating lesions of 15 patients: Clinico-radiological features, management and review of the literature . J Neurol Sci \n381 : 32 -38 , 2017 .28991707 \n6. \nFan X , Mahta A , Jaqer PLDe , Kesari S \nRituximab for tumefactive inflammatory demyelination: a case report . Clin Neurol Neurosurg \n114 : 1326 -1328 , 2012 .22475882 \n7. \nSempere AP , Feliu-Rey E , Sanchez-Perez R , Nieto-Navarro J \nNeurological picture. Rituximab for tumefactive demyelination refractory to corticosteroids and plasma exchange . J Neurol Neurosurg Psychiatry \n84 : 1338 -1339 , 2013 .23804236 \n8. \nSospedra M \nB cells in multiple sclerosis . Curr Opin Neurol \n31 : 256 -262 , 2018 .29629941\n\n",
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"mesh_terms": "D000208:Acute Disease; D001402:B-Lymphocytes; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007155:Immunologic Factors; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting; D010956:Plasmapheresis; D000069283:Rituximab",
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"title": "Treatment with Rituximab in the Acute Phase of Relapsing Remitting Multiple Sclerosis.",
"title_normalized": "treatment with rituximab in the acute phase of relapsing remitting multiple sclerosis"
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"abstract": "This single-centre, retrospective, observational pilot study was performed to evaluate the safety and efficacy of intravenous and oral itraconazole prophylaxis in paediatric haematopoietic stem cell transplantation (HCT). Study end-points were proven invasive fungal infection (IFI), survival, adverse reactions and graft-vs.-host disease (GVHD); 53 children and one young adult (median age 8.6 yr; range 0.4-18.3) transplanted between November 2001 and August 2004 were included in this study. Itraconazole was given intravenously from day +3 after HCT until oral medication became possible and continued until day +100 after HCT. Two proven new IFI in the itraconazole group (candidiasis, n = 1; aspergillosis, n = 1) were observed. After a median follow-up of 1.6 yr (0.3-6.1), six deaths (8%) were seen; 24 patients (45%) developed GVHD degree I-II, three children (6%) had GVHD degree III-IV. In 11 of 53 patients (21%), itraconazole prophylaxis was discontinued prematurely, mostly because of fever of unknown origin (n = 7). In total, 21 of 53 (40%) of the children had abnormal results of laboratory investigations during the prophylaxis. The results of this pilot study indicate that itraconazole prophylaxis during HCT in children is feasible and safe, despite abnormal laboratory results. The efficacy in terms of prevention of IFI, however, has to be addressed in a prospective large-scale study.",
"affiliations": "Department of Paediatric Hematology and Oncology, Children's Hospital, Hannover Medical University, Hannover, Germany. grigull.lorenz@mh-hannover.de",
"authors": "Grigull|L|L|;Kuehlke|O|O|;Beilken|A|A|;Sander|A|A|;Linderkamp|C|C|;Schmid|H|H|;Seidemann|K|K|;Sykora|K W|KW|;Schuster|F R|FR|;Welte|K|K|",
"chemical_list": "D000935:Antifungal Agents; D017964:Itraconazole",
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"mesh_terms": "D000284:Administration, Oral; D000293:Adolescent; D000935:Antifungal Agents; D002648:Child; D002675:Child, Preschool; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D017964:Itraconazole; D008297:Male; D009181:Mycoses; D010865:Pilot Projects; D012189:Retrospective Studies; D016896:Treatment Outcome",
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"title": "Intravenous and oral sequential itraconazole antifungal prophylaxis in paediatric stem cell transplantation recipients: a pilot study for evaluation of safety and efficacy.",
"title_normalized": "intravenous and oral sequential itraconazole antifungal prophylaxis in paediatric stem cell transplantation recipients a pilot study for evaluation of safety and efficacy"
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"abstract": "Non-Hodgkin lymphoma can disseminate to the central nervous system at initiation of treatment for systemic lymphoma or spread during the relapse of systematic lymphoma with CNS involvement, which is defined as secondary central nervous system lymphoma (SCNSL). The incidence of SCNSL depends on the pathological type of lymphoma and is especially high in aggressive lymphoma. SCNSL has a poor prognosis because of the lack of effective treatment regimens. This article presents a rare case of SCNSL; an individualized treatment regimen was designed according to the genetic analyses of the patient tumor and included a Bruton's tyrosine kinase (BTK) inhibitor. After six cycles of treatment and another two cycles of rituximab, most lesions lost their metabolic activity. However, in the final stage of treatment, our patient unfortunately suffered from respiratory failure, which revealed that we should pay attention to Pneumocystis jirovecii pneumonia during ibrutinib treatment.",
"affiliations": "Lung Hospital, Changsha Central Hospital, University of South China, Changsha, Hunan Province, People's Republic of China.;Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan Province, People's Republic of China.;Department of Radiology, Xiangya Hospital, Central South University, Changsha, Hunan Province, People's Republic of China.;Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan Province, People's Republic of China.;Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan Province, People's Republic of China.",
"authors": "Li|Qian|Q|;Liu|Wei|W|;Li|Kai|K|;Tian|Yifu|Y|;Li|Huan|H|",
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"fulltext": "\n==== Front\nOnco Targets Ther\nOnco Targets Ther\nott\nott\nOncoTargets and therapy\n1178-6930\nDove\n\n300805\n10.2147/OTT.S300805\nCase Report\nDiagnosis and Individualized Treatment of Secondary Central Nervous System Lymphoma: A Case Report\nLi et al\nLi et al\nLi Qian 1\nLiu Wei 2\nLi Kai 3\nTian Yifu 4\nLi Huan 2\n1 Lung Hospital, Changsha Central Hospital, University of South China, Changsha, Hunan Province, People’s Republic of China\n2 Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan Province, People’s Republic of China\n3 Department of Radiology, Xiangya Hospital, Central South University, Changsha, Hunan Province, People’s Republic of China\n4 Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan Province, People’s Republic of China\nCorrespondence: Huan Li Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan Province, People’s Republic of ChinaTel +8615116337538 Email csulihuan@csu.edu.cn\n13 5 2021\n2021\n14 31673175\n06 1 2021\n28 4 2021\n© 2021 Li et al.\n2021\nLi et al.\nhttps://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).\nAbstract\n\nNon-Hodgkin lymphoma can disseminate to the central nervous system at initiation of treatment for systemic lymphoma or spread during the relapse of systematic lymphoma with CNS involvement, which is defined as secondary central nervous system lymphoma (SCNSL). The incidence of SCNSL depends on the pathological type of lymphoma and is especially high in aggressive lymphoma. SCNSL has a poor prognosis because of the lack of effective treatment regimens. This article presents a rare case of SCNSL; an individualized treatment regimen was designed according to the genetic analyses of the patient tumor and included a Bruton’s tyrosine kinase (BTK) inhibitor. After six cycles of treatment and another two cycles of rituximab, most lesions lost their metabolic activity. However, in the final stage of treatment, our patient unfortunately suffered from respiratory failure, which revealed that we should pay attention to Pneumocystis jirovecii pneumonia during ibrutinib treatment.\n\nKeywords\n\nsecondary central nervous system lymphoma\ndiffuse large B cell lymphoma\nibrutinib\nindividualized therapy\nPneumocystis jirovecii pneumonia\nNational Natural Science Foundation of China 10.13039/501100001809 Youth Foundation of Xiangya Hospital This work was supported in part by the National Natural Science Foundation of China (Grant No. 81900201) and Youth Foundation of Xiangya Hospital (No. 2017Q09) to H.L.\n==== Body\nIntroduction\n\nThe incidence of secondary nervous system lymphoma (SCNSL) is low, and most patients experience relapse. According to previous articles, only 2–10% of non-Hodgkin’s lymphoma patients were reported to have CNS involvement.1–4 Pathologic stratification revealed that high-grade lymphoma has a higher risk of CNS involvement than low-grade lymphoma, and the risk for Burkitt lymphoma and lymphoblastic lymphoma is especially high. The risk factors also include advanced disease, high levels of serum lactate dehydrogenase (LDH) and the International Prognostic Index. Schmitz et al have established and validated a risk score for it called Central Nervous System International Prognostic Index (CNS-IPI) since 2016.5 The risk model has been widely used now for predicting central nervous system relapse in patients with diffuse large B-cell lymphoma treated with R-CHOP.\n\nBecause of the rarity of this disease, the best treatment regimen for SCNSL is still unknown, and most reports are based on retrospective studies. This paper summarizes previous treatment trials and advocates for the use of new combination drugs that provide patients with individualized therapy with good clinical outcomes. This patient agreed to let us collect her personal information for research and publication.\n\nCase Presentation\n\nA 53-year-old married female with a medical history of diabetes was sent to our hospital because of daily persistent headaches in August 2018. Without any positive physical neurological examinations, a contrast-enhanced magnetic resonance imaging (MRI) scan of the brain suggested multiple enhancing masses in the corpus callosum and around the ventricles (Figure 1A–C). To make an accurate diagnosis, an imaging-guided stereotactic needle biopsy was performed. Pathology (Figure 2) confirmed diffuse large B cell lymphoma (DLBCL; non-germinal center B cell (GCB)) after observing infiltrating neoplastic lymphoid cells that expressed CD45RO, CD20, PAX-5, MUM1, and Bcl-6 and that did not express CD3, CD10, CD30, cyclin D1, EBER (in situ hybridization), CD5, GFAP, CK-Pan and TdT (Ki-67+ approx. 70% of cells). 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) was carried out, and the results demonstrated that many peripheral lymph nodes and extranodal organs or sites other than her brain, such as axillary lymph nodes, inferior diaphragmatic lymph nodes, and lymph nodes around the kidney area, were involved. Moreover, the vertebral arch of L3, sacrum, left side of the acetabulum, left femoral head and right femoral neck also showed FDG uptake. Our patient had negative cerebral spinal fluid (CSF) test results and negative marrow tests based on morphology and flow cytometry. Her LDH level was above the upper limit of normal, and an HIV test was negative. The genetic features of biopsy samples suggested MGMT (O6-methylguanine-DNA methyltransferase) promoter methylation and CD79B and MyD88 L265P mutations.Figure 1 Different treatment periods of cranial MRI. (A–C) Multiple enhancing masses were shown in the corpus callosum and around the ventricles before our interventions. (D–F) Partial response after two cycles of treatment. (G–I) No obvious masses after finishing our treatment. (J–L) 30 months follow-up.\n\nFigure 2 (A) Haematoxylin–eosin (H&E) staining of biopsy samples (40× magnification). Immunohistochemical staining showed that tumor cells were positive for CD20 (B), PAX-5 (C) and MUM1 (E), but not for CD30 (D) and Cyclin D1 (F).\n\nConsidering the central nervous system (CNS) involvement of systemic DLBCL at the initial diagnosis and MGMT promoter methylation, we designed a methotrexate (MTX)-based immunochemotherapy regimen by referring to the MARIETTA trial (NCT02329080)6 which was sponsored by International Extranodal Lymphoma Study Group (IELSG) and we decided to combine two standardized chemotherapy regimens, high dose methotrexate-based regimen (MT-R: methotrexate, temozolomide and rituximab)7 for intracranial lesions and traditional R-CHOP (rituximab, vincristine, cyclophosphamide, prednisone and anthracycline)8 immunochemotherapy regimen for extracranial lesions. Eventually, the details of the first cycle treatment for our patient were as follows: rituximab (375 mg/m2, day (d) 0); high-dose intravenous MTX (3.5 g/m2, d1) with leucovorin for rescue, as previously described;9 vincristine (2 mg, d3); cyclophosphamide (0.75 g/m2 once per day, d3–4); prednisone (60 mg, d3–7); and temozolomide (150 mg/m2 once per day, d3–7) for the first chemotherapy cycle (Figure 3, chemotherapy regimen A). Because anthracyclines cannot penetrate the blood-brain barrier and produce severe bone marrow suppression, which may affect the intracranial chemotherapy dose, we omitted the anthracyclines that were also adopted in the SCNSL1 trial in these treatment regimens.10 Essential supportive treatments were added, which included hydration and the alkalization of the urine before/after MTX infusion, ranitidine hydrochloride and granulocyte colony-stimulating factor (G-CSF). In the second cycle of our patient’s treatment, considering our patient suffered from diabetes which is a proven risk factor for high-dose methotrexate-associated AKI in lymphoma patients.11 Fotemustine, another alkylating agent, was also proved to be effective in glioma patients with MGMT promoter methylation compared to unmethylated MGMT.12 Meanwhile, fotemustine, teniposide and dexamethasone (FTD) regimen has been applied in central nervous system lymphoma and been verified with no difference in 3 years PFS and OS when compared to HD-MA regimen (high-dose methotrexate plus cytarabine) in treating newly diagnosed primary central nervous system lymphoma.13 Our patient strongly believed that the massive amount of fluid infusion related to HD-MTX can interfere with her quality of life and refused to continue the regimen we designed in first cycle. In order to find a more suitable regimen, we referred previous clinical trials and her genetic features. Finally, we designed a new combination called chemotherapy regimen B (Figure 3, chemotherapy regimen B). In this regimen, we replaced MTX and temozolomide with fotemustine (140 mg/m2, d3) and teniposide (65 mg/m2 once a day, d1–3) in the second cycle of chemotherapy as the proved effect by clinical trials13 and we also added ibrutinib (420 mg once per day) to our patient’s daily treatment in view of the CD79B and MyD88 L265P mutations in the tumors.14,15 In the meantime, previous research has confirmed methotrexate is antagonistic to ibrutinib.14 The ibrutinib-containing clinical trial (NCT03964090) for aggressive B-cell Lymphomas with secondary involvement of the central nervous system was also omit methotrexate because of the antagonistic effect. In summary, we changed our protocol to ibrutinib (420 mg once per day); rituximab (375 mg/m2, d0); vincristine (2 mg, d3); cyclophosphamide (0.75 g/m2 once per day, d3–4); prednisone (60 mg, d3–7); fotemustine (140 mg/m2, d3) and teniposide (65 mg/m2 once a day, d1–3) (Figure 3, chemotherapy regimen B). An MRI scan was obtained before the third cycle of our new immunochemotherapy. The masses in her head were significantly reduced, which was judged as a PR (partial response) according to the Response Evaluation Criteria in Lymphoma (RECIL) 2017 standards16 (Figure 1D–F), and she recovered from an unbearable headache. During the treatment period, our patient suffered from only Grade 1 fatigue and Grade 3 hematologic toxicity according to the Common Terminology Criteria for Adverse Events version 4.Figure 3 Schematic representation of chemotherapy regimens. Chemotherapy regimen A was applied to our patient in the first cycle and chemotherapy regimen B was adapted in the second to sixth cycle.\n\nUnfortunately, after six cycles of treatment, our patient experienced severe myelosuppression and had an extremely low white cell count (300/mm3). Afterwards, she suffered from fulminant respiratory failure accompanied with low-grade fever and dry cough. Piperacillin-tazobactam treatment had no therapeutic efficacy, and she was arranged to be monitored and cared for in the intensive care unit (ICU). Her CT lung screening revealed pulmonary consolidation in the inferior lobes surrounded by a wide range of ground-glass opacity effusions on both sides (Figure 4). The beta-D-glucan assay test was positive and the sputum sample was negative for hyphae and spores. With the help of conventional mechanical ventilation, several broad-spectrum antibiotics, and antifungal therapy with voriconazole and trimethoprim-sulfamethoxazole (TMP-SMX) were also added. Adjunctive dexamethasone (5 mg/d) was used to reduce the serious inflammatory conditions. We sent the patient’s blood sample for the detection of potential pathogens by next-generation sequencing (NGS) technology as previous reported with her parents’ permission.17 The results confirmed a PCP infection, and we increased the dose of TMP-SMX. A re-examination with chest CT after 10 days of treatment showed that the majority of the previous lesions had resolved, and her dyspnea improved without ventilatory support. Our patient recovered from PCP, and we rechecked her lymphoma status by PET/CT. There was no abnormal FDG uptake in the region that previously had high metabolic activity (Figure 5). Meanwhile, the lesions in the brain displayed the same metabolic signal as normal brain tissues. Bone marrow biopsy also confirmed complete remission after chemotherapy. We recommended that our patient receive another two cycles of rituximab injections. After finishing treatment, MRI was conducted again to evaluate the status in her head, and images revealed that the corpus callosum and ventricle lesions were much smaller than they were initially, and our patient was judged as complete response (Figure 1G–I) and our patient checked the MRI again after 30 months follow-up (Figure 1J–L). She refused further whole-brain radiation therapy (WBRT) or autologous stem cell transplantation (ASCT) for consolidation and continues to be followed. All the treatment procedures were shown in Figure 6.Figure 4 CT images after respiratory failure happened. Mediastinal emphysema was occurred after receiving invasive mechanical ventilation. Mediastinal window (A) and lung window (B).\n\nFigure 5 The changes of FDG uptake before and after treatment. FDG uptake signals disappeared in brain (A), axillary lymph nodes (B), lymph nodes around the kidney area (C) and right femoral neck (D) after our interventions. The red arrows showed a solitary lesion outside the ventricle, which was also disappeared after our treatment.\n\nFigure 6 A Chart of the patient’s medical procedures.\n\nDiscussion\n\nSCNSL is defined as lymphoma involvement both within and outside of the CNS at the time of diagnosis or as the CNS relapse of a systemic lymphoma18 and is a rare and fatal disease that often occurs in non-Hodgkin lymphoma.19 In our study, we described an SCNSL patient with a definitive diagnosis and individualized therapy. This case may help us establish a better, standard way to cure this kind of disease by combining clinical and genetic features.\n\nMost pathological types of SCNSL can be categorized as DLBCL. To date, however, there has been little discussion about the treatment of SCNSL. In our case, high-dose MTX-based regimens were effective therapeutics for PCNSL, but they were not an excellent cure for disease outside of the CNS.20 In turn, R-CHOP regimens are standard treatments for aggressive B cell lymphoma, and none of these drugs can easily penetrate the blood–brain barrier. Until now, few studies have investigated the proper treatment method. A multicenter study directed by Ferreri,21 which is the largest published Phase II trial before we treated our patient, proposed a novel treatment with induction phase, intensification phase and consolidation phase. In short, R-CHOP was applied for one or two cycles to control extra-CNS disease at first. High-dose methotrexate and cytarabine combined with rituximab and intrathecal liposomal cytarabine were adapted for controlling lesions in central nervous system as induction phase. Intensification phase was only proceeded when patients achieved complete response (CR) or partial response (PR) and the phase was consisted of R-HDS (rituximab, high doses of cyclophosphamide, cytarabine, and etoposide) regimen. Autologous stem-cell transplantation (ASCT) was done as consolidation. The results showed that the 2-year event-free survival (EFS) and 5-year EFS were 50% and 40%, respectively. Moreover, the 5-year overall survival (OS) of all included patients was 41%; in particular, the patients who underwent HD-ASCT achieved a better 5-year OS (68%). However, in a total of 38 patients, 10 patients still experienced treatment failure, the inclusion of three different types of B cell lymphoma in clinical trials created a selection bias, and the subtype of DLBCL was also unknown. Another prospective trial called MARIETTA study was published recently and was supported to be the largest trial for secondary CNS lymphoma until now.6,22 Treatment consisted of a sequential combination of two standardized chemotherapy regimens, MATRix (methotrexate, cytarabine, thiotepa, and rituximab) and RICE (rituximab, etoposide, ifosfamide, and carboplatin), followed by carmustine-thiotepa and autologous HSCT as a consolidation therapy. Seventy-nine patients were enrolled, and 2-year progression-free survival was 71% in patients with CNS disease at initial lymphoma diagnosis. Although the result was encouraging, identification of the most effective treatment options in secondary CNS lymphoma was still unknown and more prospective clinical trials are needed to address the most effective and individualized treatment options.\n\nMGMT promoter methylation was detected in our patient’s tumor sample, and it has been frequently observed in high-grade glioma.23 MGMT promoter methylation is a good index for prognosis and indicates that tumors are more susceptible to alkylating agent-based therapies.24 In DLBCL, MGMT promoter methylation indicates a favorable prognosis and was found in 75.9% of patient samples from the Middle East.25 Temozolomide as an alkylating agent is a widely used alkylating drug with rapid and nearly complete oral absorption26 that is recommended for the treatment of PCNSL.27 Because of its impressive curative effect, we added temozolomide in the first cycle of treatment with patient permission. However, our patient’s complaints and several risk factors noticed above forced us to change to a more suitable regimen for her.\n\nAs we known, BCR is a very important transmembrane receptor that regulates B cell proliferation, differentiation and migration.28 An in vitro study conducted by Louis’ group introduced a new pathway called chronic active BCR signaling that is distinct from tonic BCR signaling.29 Bruton’s tyrosine kinase (BTK) is an essential molecule involved in BCR signaling and in vitro experiment confirmed that the BCR signaling pathway plays an essential role in ABC-type B cell malignancies.\n\nIbrutinib, a first-in-class inhibitor of BTK, was first available for mantle cell lymphoma and chronic lymphocytic leukemia (CLL).30,31 Because of the encouraging results in vitro, 80 patients with relapsed and refractory DLBCL were included in a study of oral ibrutinib.15 Interestingly, the response rate in the activated B-cell type was much higher than that in the germinal center B-cell type (37% vs 5%, P=0.0106). In a preclinical study, the distribution of ibrutinib was tested in mouse models.32 The results revealed that the ibrutinib concentration in the brain was strongly associated with the concentration in plasma. Furthermore, an effective concentration above the IC50 of ibrutinib was observed, which confirmed the therapeutic effect in intracranial lesions. Clinical research was also conducted by Louis and Wilson’s group in which 18 patients were chosen, most of whom suffered from relapsed/refractory ABC-type PCNSL.14 Clinical trials confirmed that ibrutinib and its primary metabolite, PCI-45227, maintained a therapeutic concentration in CSF. The overall response rate (ORR) among patients was 94% after treatment with ibrutinib combined with chemotherapy with temozolomide, etoposide, liposomal doxorubicin, dexamethasone and rituximab, which was defined as the DA-TEDDi-R regimen. Moreover, a previous study also confirmed that lymphomas with both MYD88 L265P and CD79B mutations were much more sensitive to ibrutinib treatment.15 Meanwhile, the combination of ibrutinib and MTX may decrease the efficacy of both drugs.14 We decided to add ibrutinib to the treatment schema and to replace MTX. A Phase 2 clinical trial also confirmed that the fotemustine, teniposide and dexamethasone combination achieved an ORR, 2-year progression-free survival (PFS) and 3-year OS that were similar to those of high-dose MTX plus cytarabine regimens in PCNSL patients.13 In the meantime, fotemustine is also an alkylating agent12 that may benefit our patient and we cannot find any regimens without MTX and containing temozolomide which have the same therapeutic effect in published data. In order to maintain both therapeutic effects after omitting MTX and the therapeutic regimens should include ibrutinib and alkylating agent according to genetic features of lymphoma, we changed our chemotherapy protocol as follows: ibrutinib (420 mg once per day); rituximab (375 mg/m2, d0); vincristine (2 mg, d3); cyclophosphamide (0.75 g/m2 once per day, d3–4); prednisone (60 mg, d3–7); fotemustine (140 mg/m2, d3) and teniposide (65 mg/m2 once a day, d1–3) since the second cycle of chemotherapy (Figure 3, chemotherapy regimen B). Fortunately, our patient experienced remission after another five cycles of treatment (Figure 6).\n\nNevertheless, our patient suffered from a severe pulmonary infection after six cycles of therapy. Clinical laboratory examinations revealed that the presumptive diagnosis of the pathogen was Pneumocystis jirovecii. Several factors are known to be partially responsible for infections with Pneumocystis jirovecii. In a previous study, a missense mutation in the BTK gene caused a congenital disease called X-linked agammaglobulinemia (XLA), and patients with this disease were susceptible to Pneumocystis because of the Toll-like signaling deficiency that resembles the blocking effect of ibrutinib.33 This hypothesis was also proven by Ahn’s group.34 Ninety-six patients suffering from CLL were treated with ibrutinib in a clinical trial, and five patients experienced the onset of PCP. The estimated incidence of PCP was 2.05 cases per 100 patient-years in previously untreated patients with CLL on single-agent ibrutinib. The prevalence of PCP was also proven by Ryan’s group.35 They pointed out that prevalence of PCP in BTKi-monotherapy patients not on prophylaxis was 2.4% (2 of 85). Additionally, our patient’s immune system was impaired by high-intensity chemotherapy and was weakened by glucocorticoids. All these elements contributed to severe adverse reactions. However, it is controversial whether prophylaxis septrin should be given. Memorial Sloan Kettering Cancer Center guidelines recommend PCP prophylaxis for patients with lymphoid cancer who are receiving chemotherapy with a purine analogue or alemtuzumab or are receiving an average daily-dose equivalent to ≥20 mg of prednisone for ≥4 weeks.36 But there are no guidelines for ibrutinib-related treatment regimens. Previous study suggests that the prevalence of PCP is relatively low and routine prophylaxis may not be indicated,35 but the authors also showed that PCP prophylaxis was effective, as there were no cases of PCP in patients on prophylaxis. Additionally, by reviewing medical records of patients with lymphoid cancer at the Ohio State University, the most common type of infections during ibrutinib treatment was invasive fungal (61%) other than PCP.37 Medical records at Memorial Sloan Kettering Cancer Center also confirmed that the much higher incidence of invasive fungal infections in patients with PCNSL compared to PCP.36 In our case, prophylaxis septrin may not be conventional in ibrutinib monotherapy. However, both cytotoxic chemotherapy and corticosteroids other than ibrutinib may also contribute our patient’s PCP infections. Fortunately, after diagnosis, TMP-SMX was rapidly administered, and our patient recovered from respiratory failure.\n\nConclusion\n\nWe diagnosed a rare case of an SCNSL. With the help of whole-genome sequencing, ibrutinib and chemotherapeutics were included in our patient’s treatment schedule. However, PCP occurred and caused respiratory failure in our patient. Although we diagnosed PCP in time and the patient recovered, we still note the possible danger of PCP, and TMP-SMX can be used as drug prophylaxis in chemotherapy regimens that include high-dose of cytotoxic chemotherapy and ibrutinib.\n\nEthics Statement\n\nThe written informed consent was obtained from the patient and the patient agreed to publish her details of her case and any accompanying images. This study was approved by the ethics committee of Xiangya Hospital, Central South University (Changsha, China) to publish the case details.\n\nDisclosure\n\nThe authors declare no conflicts of interest.\n==== Refs\nReferences\n\n1. Bernstein SH, Unger JM, Leblanc M, Friedberg J, Miller TP, Fisher RI. Natural history of CNS relapse in patients with aggressive non-Hodgkin’s lymphoma: a 20-year follow-up analysis of SWOG 8516 – the Southwest Oncology Group. J Clin Oncol. 2009;27 (1 ):114–119. doi:10.1200/JCO.2008.16.8021 19047289\n2. Hollender A, Kvaloy S, Lote K, Nome O, Holte H. Prognostic factors in 140 adult patients with non-Hodgkin’s lymphoma with systemic central nervous system (CNS) involvement. A single centre analysis. Eur J Cancer. 2000;36 (14 ):1762–1768. doi:10.1016/S0959-8049(00)00171-4 10974623\n3. Hollender A, Kvaloy S, Nome O, Skovlund E, Lote K, Holte H. Central nervous system involvement following diagnosis of non-Hodgkin’s lymphoma: a risk model. Ann Oncol. 2002;13 (7 ):1099–1107. doi:10.1093/annonc/mdf175 12176790\n4. Boehme V, Zeynalova S, Kloess M, et al. Incidence and risk factors of central nervous system recurrence in aggressive lymphoma–a survey of 1693 patients treated in protocols of the German high-grade non-Hodgkin’s Lymphoma Study Group (DSHNHL). Ann Oncol. 2007;18 (1 ):149–157. doi:10.1093/annonc/mdl327 17018708\n5. Schmitz N, Zeynalova S, Nickelsen M, et al. CNS international prognostic index: a risk model for CNS relapse in patients with diffuse large B-cell lymphoma treated with R-CHOP. J Clin Oncol. 2016;34 (26 ):3150–3156. doi:10.1200/JCO.2015.65.6520 27382100\n6. Ferreri AJM, Doorduijn JK, Re A, et al. MATRix-RICE therapy and autologous haematopoietic stem-cell transplantation in diffuse large B-cell lymphoma with secondary CNS involvement (MARIETTA): an international, single-arm, phase 2 trial. Lancet Haematol. 2021;8 (2 ):e110–e121. doi:10.1016/S2352-3026(20)30366-5 33513372\n7. Glass J, Won M, Schultz CJ, et al. Phase I and II study of induction chemotherapy with methotrexate, rituximab, and temozolomide, followed by whole-brain radiotherapy and postirradiation temozolomide for primary CNS lymphoma: NRG Oncology RTOG 0227. J Clin Oncol. 2016;34 (14 ):1620–1625. doi:10.1200/JCO.2015.64.8634 27022122\n8. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346 (4 ):235–242. doi:10.1056/NEJMoa011795 11807147\n9. DeAngelis LM, Seiferheld W, Schold SC, Fisher B, Schultz CJ. Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93–10. J Clin Oncol. 2002;20 (24 ):4643–4648. doi:10.1200/JCO.2002.11.013 12488408\n10. Ferreri AJ, Tarella C, Ciceri F. Reply to A. Korfel et al. J Clin Oncol. 2016;34 (15 ):1830–1831. doi:10.1200/JCO.2016.66.4722 27001567\n11. Wang Y, Wei L, Guan Y, Wang Q, Xie Q, Hao C. Diabetes is a risk factor for high-dose methotrexate-associated AKI in lymphoma patients. Ren Fail. 2020;42 (1 ):1111–1117. doi:10.1080/0886022X.2020.1838926 33164656\n12. Fabi A, Metro G, Russillo M, et al. Treatment of recurrent malignant gliomas with fotemustine monotherapy: impact of dose and correlation with MGMT promoter methylation. BMC Cancer. 2009;9 :101. doi:10.1186/1471-2407-9-101 19335893\n13. Wu J, Duan L, Zhang L, et al. Fotemustine, teniposide and dexamethasone versus high-dose methotrexate plus cytarabine in newly diagnosed primary CNS lymphoma: a randomised phase 2 trial. J Neurooncol. 2018;140 (2 ):427–434. doi:10.1007/s11060-018-2970-x 30109672\n14. Lionakis MS, Dunleavy K, Roschewski M, et al. Inhibition of B cell receptor signaling by ibrutinib in primary CNS Lymphoma. Cancer Cell. 2017;31 (6 ):833–843. doi:10.1016/j.ccell.2017.04.012 28552327\n15. Wilson WH, Young RM, Schmitz R, et al. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med. 2015;21 (8 ):922–926. doi:10.1038/nm.3884 26193343\n16. Younes A, Hilden P, Coiffier B, et al. International Working Group consensus response evaluation criteria in lymphoma (RECIL 2017). Ann Oncol. 2017;28 (7 ):1436–1447. doi:10.1093/annonc/mdx097 28379322\n17. Ye M, Wei W, Yang Z, et al. Rapid diagnosis of Propionibacterium acnes infection in patient with hyperpyrexia after hematopoietic stem cell transplantation by next-generation sequencing: a case report. BMC Infect Dis. 2016;16 :5. doi:10.1186/s12879-015-1306-0 26743541\n18. Maciocia P, Badat M, Cheesman S, et al. Treatment of diffuse large B-cell lymphoma with secondary central nervous system involvement: encouraging efficacy using CNS-penetrating R-IDARAM chemotherapy. Br J Haematol. 2016;172 (4 ):545–553. doi:10.1111/bjh.13867 26684148\n19. Schmitz N, Wu HS. Advances in the treatment of secondary CNS lymphoma. J Clin Oncol. 2015;33 (33 ):3851–3853. doi:10.1200/JCO.2015.63.1143 26282665\n20. Rubenstein JL, Gupta NK, Mannis GN, Lamarre AK, Treseler P. How I treat CNS lymphomas. Blood. 2013;122 (14 ):2318–2330. doi:10.1182/blood-2013-06-453084 23963042\n21. Ferreri AJ, Donadoni G, Cabras MG, et al. High doses of antimetabolites followed by high-dose sequential chemoimmunotherapy and autologous stem-cell transplantation in patients with systemic B-cell lymphoma and secondary CNS involvement: final results of a multicenter phase II trial. J Clin Oncol. 2015;33 (33 ):3903–3910. doi:10.1200/JCO.2015.61.1236 26282634\n22. Dietrich J. The best matrix for the brain: advances in secondary CNS lymphoma. Lancet Haematol. 2021;8 (2 ):e96–e97. doi:10.1016/S2352-3026(20)30431-2 33513377\n23. Thon N, Kreth S, Kreth FW. Personalized treatment strategies in glioblastoma: MGMT promoter methylation status. Onco Targets Ther. 2013;6 :1363–1372. doi:10.2147/OTT.S50208 24109190\n24. Weller M, Stupp R, Reifenberger G, et al. MGMT promoter methylation in malignant gliomas: ready for personalized medicine? Nat Rev Neurol. 2010;6 (1 ):39–51. doi:10.1038/nrneurol.2009.197 19997073\n25. Al-Kuraya K, Narayanappa R, Siraj AK, et al. High frequency and strong prognostic relevance of O6-methylguanine DNA methyltransferase silencing in diffuse large B-cell lymphomas from the Middle East. Hum Pathol. 2006;37 (6 ):742–748. doi:10.1016/j.humpath.2006.02.007 16733216\n26. Dresemann G. Temozolomide in malignant glioma. Onco Targets Ther. 2010;3 :139–146. doi:10.2147/OTT.S5480 20856849\n27. Rubenstein JL, Hsi ED, Johnson JL, et al. Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma: CALGB 50202 (Alliance 50202). J Clin Oncol. 2013;31 (25 ):3061–3068. doi:10.1200/JCO.2012.46.9957 23569323\n28. Treanor B. B-cell receptor: from resting state to activate. Immunology. 2012;136 (1 ):21–27. doi:10.1111/j.1365-2567.2012.03564.x 22269039\n29. Davis RE, Ngo VN, Lenz G, et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature. 2010;463 (7277 ):88–92. doi:10.1038/nature08638 20054396\n30. Herrera AF, Jacobsen ED. Ibrutinib for the treatment of mantle cell lymphoma. Clin Cancer Res. 2014;20 (21 ):5365–5371. doi:10.1158/1078-0432.CCR-14-0010 25361916\n31. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369 (1 ):32–42. doi:10.1056/NEJMoa1215637 23782158\n32. Goldwirt L, Beccaria K, Ple A, Sauvageon H, Mourah S. Ibrutinib brain distribution: a preclinical study. Cancer Chemother Pharmacol. 2018;81 (4 ):783–789. doi:10.1007/s00280-018-3546-3 29476222\n33. Kanegane H, Nakano T, Shimono Y, Zhao M, Miyawaki T. Pneumocystis jiroveci pneumonia as an atypical presentation of X-linked agammaglobulinemia. Int J Hematol. 2009;89 (5 ):716–717. doi:10.1007/s12185-009-0322-5 19399581\n34. Ahn IE, Jerussi T, Farooqui M, Tian X, Wiestner A, Gea-Banacloche J. Atypical Pneumocystis jirovecii pneumonia in previously untreated patients with CLL on single-agent ibrutinib. Blood. 2016;128 (15 ):1940–1943. doi:10.1182/blood-2016-06-722991 27503501\n35. Ryan CE, Cheng MP, Issa NC, Brown JR, Davids MS. Pneumocystis jirovecii pneumonia and institutional prophylaxis practices in CLL patients treated with BTK inhibitors. Blood Adv. 2020;4 (7 ):1458–1463. doi:10.1182/bloodadvances.2020001678 32282880\n36. Varughese T, Taur Y, Cohen N, et al. Serious infections in patients receiving ibrutinib for treatment of lymphoid cancer. Clin Infect Dis. 2018;67 (5 ):687–692. doi:10.1093/cid/ciy175 29509845\n37. Rogers KA, Mousa L, Zhao Q, et al. Incidence of opportunistic infections during ibrutinib treatment for B-cell malignancies. Leukemia. 2019;33 (10 ):2527–2530. doi:10.1038/s41375-019-0481-1 31086260\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1178-6930",
"issue": "14()",
"journal": "OncoTargets and therapy",
"keywords": "Pneumocystis jirovecii pneumonia; diffuse large B cell lymphoma; ibrutinib; individualized therapy; secondary central nervous system lymphoma",
"medline_ta": "Onco Targets Ther",
"mesh_terms": null,
"nlm_unique_id": "101514322",
"other_id": null,
"pages": "3167-3175",
"pmc": null,
"pmid": "34012272",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "29476222;19335893;20856849;20054396;27503501;22269039;28379322;23569323;28552327;26282634;27382100;27001567;23963042;19399581;26282665;23782158;26193343;31086260;11807147;10974623;26684148;17018708;33513372;29509845;30109672;27022122;24109190;16733216;32282880;19997073;33513377;12176790;26743541;12488408;25361916;33164656;19047289",
"title": "Diagnosis and Individualized Treatment of Secondary Central Nervous System Lymphoma: A Case Report.",
"title_normalized": "diagnosis and individualized treatment of secondary central nervous system lymphoma a case report"
} | [
{
"companynumb": "CN-ROCHE-2849169",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "4",
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{
"abstract": "BACKGROUND\nThe severe cutaneous adverse drug reactions (SCARs) are rare but could be life-threatening. These include drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis.\n\n\nOBJECTIVE\nThe purpose of this study was the evaluation of the clinical characteristics of patients with the diagnosis of SCARs.\n\n\nMETHODS\nPatients who were diagnosed with SCARs between January 2011 and May 2016 by pediatric allergy clinics in the provinces of Ankara, Trabzon, Izmir, Adana, and Bolu were included in this multicenter study. Clinical and laboratory findings, the time between suspected drug intake and development of clinical findings, treatments they have received, and length of recovery time were recorded.\n\n\nRESULTS\nFifty-eight patients with SCARs were included in this study. The median age of the patients was 8.2 years (interquartile range, 5.25-13 years) and 50% (n = 29) were males. Diagnosis was Stevens-Johnson syndrome/TEN in 60.4% (n = 35), DRESS in 27.6% (n = 16), and acute generalized exanthematous pustulosis in 12% (n = 7) of the patients. In 93.1% of the patients, drugs were the cause of the reactions. Antibiotics ranked first among the drugs (51.7%) and antiepileptic drugs were the second (31%) most common. A patient who was diagnosed with TEN developed lagophthalmos and a patient who was diagnosed with DRESS developed secondary diabetes mellitus. Only 1 patient with the diagnosis of TEN died.\n\n\nCONCLUSIONS\nSCARs in children are not common but potentially serious. Early diagnosis and appropriate treatment of SCARs will reduce the incidence of morbidity and mortality.",
"affiliations": "Department of Pediatric Allergy and Immunology, Ankara Children's Hematology Oncology Training and Research Hospital, Ankara, Turkey.;Department of Pediatric Allergy and Immunology, Ankara Children's Hematology Oncology Training and Research Hospital, Ankara, Turkey.;Department of Pediatric Allergy and Immunology, Izmir Dr. Behcet Uz Children's Hospital, Izmir, Turkey.;Division of Pediatric Allergy and Immunology, Department of Children's Health and Diseases, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey.;Department of Pediatric Allergy and Immunology, Izmir Dr. Behcet Uz Children's Hospital, Izmir, Turkey.;Department of Pediatric Allergy and Immunology, Adana Obstetrics and Pediatrics Hospital, Adana, Turkey.;Division of Pediatric Allergy and Immunology, Department of Children's Health and Diseases, Faculty of Medicine, Abant Izzet Baysal University, Bolu, Turkey.;Department of Pediatric Allergy and Immunology, Ankara Children's Hematology Oncology Training and Research Hospital, Ankara, Turkey.;Department of Pediatric Allergy and Immunology, Izmir Dr. Behcet Uz Children's Hospital, Izmir, Turkey.;Department of Pediatric Allergy and Immunology, Ankara Children's Hematology Oncology Training and Research Hospital, Ankara, Turkey.;Department of Pediatric Allergy and Immunology, Ankara Children's Hematology Oncology Training and Research Hospital, Ankara, Turkey.;Department of Pediatric Allergy and Immunology, Ankara Children's Hematology Oncology Training and Research Hospital, Ankara, Turkey.;Division of Pediatric Allergy and Immunology, Department of Children's Health and Diseases, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey.;Division of Pediatric Allergy and Immunology, Department of Children's Health and Diseases, Faculty of Medicine, Mugla Sitki Kocman University, Mugla, Turkey. Electronic address: cankocabas@yahoo.com.",
"authors": "Dibek Misirlioglu|Emine|E|;Guvenir|Hakan|H|;Bahceci|Semiha|S|;Haktanir Abul|Mehtap|M|;Can|Demet|D|;Usta Guc|Belgin Emine|BE|;Erkocoğlu|Mustafa|M|;Toyran|Muge|M|;Nacaroglu|Hikmet Tekin|HT|;Civelek|Ersoy|E|;Buyuktiryaki|Betul|B|;Ginis|Tayfur|T|;Orhan|Fazil|F|;Kocabas|Can Naci|CN|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000927:Anticonvulsants; D007073:Immunoglobulin E",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jaip.2017.02.013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "5(3)",
"journal": "The journal of allergy and clinical immunology. In practice",
"keywords": "Acute generalized exanthematous pustulosis; Children; DRESS; Eosinophilia; Severe cutaneous adverse drug reactions; Stevens-Johnson syndrome; Toxic epidermal necrolysis",
"medline_ta": "J Allergy Clin Immunol Pract",
"mesh_terms": "D056150:Acute Generalized Exanthematous Pustulosis; D000293:Adolescent; D000900:Anti-Bacterial Agents; D000927:Anticonvulsants; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D063926:Drug Hypersensitivity Syndrome; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D007073:Immunoglobulin E; D008297:Male; D015995:Prevalence; D012189:Retrospective Studies; D012867:Skin; D013262:Stevens-Johnson Syndrome; D014421:Turkey",
"nlm_unique_id": "101597220",
"other_id": null,
"pages": "757-763",
"pmc": null,
"pmid": "28351788",
"pubdate": "2017",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Severe Cutaneous Adverse Drug Reactions in Pediatric Patients: A Multicenter Study.",
"title_normalized": "severe cutaneous adverse drug reactions in pediatric patients a multicenter study"
} | [
{
"companynumb": "TR-VISTAPHARM, INC.-VER201712-001619",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
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"drugadditional":... |
{
"abstract": "OBJECTIVE\nTo evaluate the efficacy of systemic infliximab for the induction of remission in patients with retinal vasculitis, inadequately responsive to other immunomodulatory therapy, based on fluorescein angiography grading for retinal vasculitis evaluation.\n\n\nMETHODS\nWe analyzed 60 patients with retinal vasculitis, from the Massachusetts Eye Research and Surgery Institution in Cambridge, MA. Response to therapy was based on analysis of serial fluorescein angiography and fundus photography, including a baseline angiogram before initiation of infliximab.\n\n\nRESULTS\nSixty patients received infliximab therapy between July 2007 and July 2012 at Massachusetts Eye Research and Surgery Institution for a diagnosis of retinal vasculitis. All had previously showed a poor clinical response to other immunomodulatory regimens, or ceased therapy due to intolerable side effects. The initial dose of infliximab was 5 mg/kg in all patients and remained at this dose for the extent of treatment in 57 (95%) patients. At 6 months, 45 of 51 (88.23%) patients were maintaining remission with therapy, 5 (9.8%) were in partial remission, and 1 patient had failed. At 12 months, 39 of 39 (100%) patients were maintaining remission with therapy.\n\n\nCONCLUSIONS\nInfliximab is effective for the treatment of recalcitrant noninfectious retinal vasculitis, refractory to conventional immunomodulatory therapy.",
"affiliations": "*Massachusetts Eye Research and Surgery Institution, Cambridge, Massachusetts; †Ocular Immunology and Uveitis Foundation, Cambridge, Massachusetts; and ‡Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.",
"authors": "Sharma|Pramod K|PK|;Markov|Gueorgui T|GT|;Bajwa|Asima|A|;Foster|C Stephen|CS|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D000069285:Infliximab",
"country": "United States",
"delete": false,
"doi": "10.1097/IAE.0000000000000624",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0275-004X",
"issue": "35(12)",
"journal": "Retina (Philadelphia, Pa.)",
"keywords": null,
"medline_ta": "Retina",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D005260:Female; D005451:Fluorescein Angiography; D006801:Humans; D060828:Induction Chemotherapy; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D031300:Retinal Vasculitis; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "8309919",
"other_id": null,
"pages": "2641-6",
"pmc": null,
"pmid": "26200508",
"pubdate": "2015-12",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "LONG-TERM EFFICACY OF SYSTEMIC INFLIXIMAB IN RECALCITRANT RETINAL VASCULITIS.",
"title_normalized": "long term efficacy of systemic infliximab in recalcitrant retinal vasculitis"
} | [
{
"companynumb": "US-JNJFOC-20151202255",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
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{
"abstract": "Severe critical illness-induced immune suppression, termed immunoparalysis, is associated with longer duration of organ dysfunction in septic children. mRNA studies have suggested differential benefit of hydrocortisone in septic children based on their immune phenotype, but this has not been shown using a functional readout of the immune response. This study represents a secondary analysis of a prospectively conducted immunophenotyping study of pediatric severe sepsis to test the hypothesis that hydrocortisone will be differentially associated with clinical outcomes in children with or without immunoparalysis.\n\n\n\nChildren with severe sepsis/septic shock underwent blood sampling within 48 h of sepsis onset. Immune function was measured by quantifying whole blood ex vivo LPS-induced TNFα production capacity, with a TNFα response < 200 pg/ml being diagnostic of immunoparalysis. The primary outcome measure was number of days in 14 with MODS. Univariate and multivariable negative binomial regression models were used to examine associations between hydrocortisone use, immune function, and duration of MODS.\n\n\n\nOne hundred two children were enrolled (age 75 [6-160] months, 60% male). Thirty-one subjects received hydrocortisone and were more likely to be older (106 [52-184] vs 38 [3-153] months, p = 0.04), to have baseline immunocompromise (32 vs 8%, p = 0.006), to have higher PRISM III (13 [8-18] vs 7 [5-13], p = 0.0003) and vasoactive inotrope scores (20 [10-35] vs 10 [3-15], p = 0.0002) scores, and to have more MODS days (3 [1-9] vs 1 [0-3], p = 0.002). Thirty-three subjects had immunoparalysis (TNFα response 78 [52-141] vs 641 [418-1047] pg/ml, p < 0.0001). Hydrocortisone use was associated with longer duration of MODS in children with immunoparalysis after adjusting for covariables (aRR 3.7 [1.8-7.9], p = 0.0006) whereas no association with MODS duration was seen in children without immunoparalysis (aRR 1.2 [0.6-2.3], p = 0.67).\n\n\n\nHydrocortisone use was independently associated with longer duration of MODS in septic children with immunoparalysis but not in those with more robust immune function. Prospective clinical trials using a priori immunophenotyping are needed to understand optimal hydrocortisone strategies in this population.",
"affiliations": "The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA. katherine.bline@nationwidechildrens.org.;The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.;The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.;The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.;The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.;The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.;The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.;The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.;The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.;The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.;The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.",
"authors": "Bline|Katherine E|KE|0000-0002-2399-8075;Moore-Clingenpeel|Melissa|M|;Hensley|Josey|J|;Steele|Lisa|L|;Greathouse|Kristin|K|;Anglim|Larissa|L|;Hanson-Huber|Lisa|L|;Nateri|Jyotsna|J|;Muszynski|Jennifer A|JA|;Ramilo|Octavio|O|;Hall|Mark W|MW|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D006854:Hydrocortisone",
"country": "England",
"delete": false,
"doi": "10.1186/s13054-020-03266-x",
"fulltext": "\n==== Front\nCrit Care\nCritical Care\n1364-8535 1466-609X BioMed Central London \n\n32887651\n3266\n10.1186/s13054-020-03266-x\nResearch\nHydrocortisone treatment is associated with a longer duration of MODS in pediatric patients with severe sepsis and immunoparalysis\nhttp://orcid.org/0000-0002-2399-8075Bline Katherine E. katherine.bline@nationwidechildrens.org 12 Moore-Clingenpeel Melissa 13 Hensley Josey 1 Steele Lisa 1 Greathouse Kristin 1 Anglim Larissa 1 Hanson-Huber Lisa 1 Nateri Jyotsna 1 Muszynski Jennifer A. 12 Ramilo Octavio 14 Hall Mark W. 12 1 grid.240344.50000 0004 0392 3476The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH USA \n2 grid.240344.50000 0004 0392 3476Division of Critical Care Medicine, Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205 USA \n3 grid.240344.50000 0004 0392 3476Biostatistics Resource at Nationwide Children’s Hospital, Columbus, OH USA \n4 grid.240344.50000 0004 0392 3476Division of Infectious Diseases, Nationwide Children’s Hospital, Columbus, OH USA \n4 9 2020 \n4 9 2020 \n2020 \n24 54531 5 2020 26 8 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nSevere critical illness-induced immune suppression, termed immunoparalysis, is associated with longer duration of organ dysfunction in septic children. mRNA studies have suggested differential benefit of hydrocortisone in septic children based on their immune phenotype, but this has not been shown using a functional readout of the immune response. This study represents a secondary analysis of a prospectively conducted immunophenotyping study of pediatric severe sepsis to test the hypothesis that hydrocortisone will be differentially associated with clinical outcomes in children with or without immunoparalysis.\n\nMethods\nChildren with severe sepsis/septic shock underwent blood sampling within 48 h of sepsis onset. Immune function was measured by quantifying whole blood ex vivo LPS-induced TNFα production capacity, with a TNFα response < 200 pg/ml being diagnostic of immunoparalysis. The primary outcome measure was number of days in 14 with MODS. Univariate and multivariable negative binomial regression models were used to examine associations between hydrocortisone use, immune function, and duration of MODS.\n\nResults\nOne hundred two children were enrolled (age 75 [6–160] months, 60% male). Thirty-one subjects received hydrocortisone and were more likely to be older (106 [52–184] vs 38 [3–153] months, p = 0.04), to have baseline immunocompromise (32 vs 8%, p = 0.006), to have higher PRISM III (13 [8–18] vs 7 [5–13], p = 0.0003) and vasoactive inotrope scores (20 [10–35] vs 10 [3–15], p = 0.0002) scores, and to have more MODS days (3 [1–9] vs 1 [0–3], p = 0.002). Thirty-three subjects had immunoparalysis (TNFα response 78 [52–141] vs 641 [418–1047] pg/ml, p < 0.0001). Hydrocortisone use was associated with longer duration of MODS in children with immunoparalysis after adjusting for covariables (aRR 3.7 [1.8–7.9], p = 0.0006) whereas no association with MODS duration was seen in children without immunoparalysis (aRR 1.2 [0.6–2.3], p = 0.67).\n\nConclusion\nHydrocortisone use was independently associated with longer duration of MODS in septic children with immunoparalysis but not in those with more robust immune function. Prospective clinical trials using a priori immunophenotyping are needed to understand optimal hydrocortisone strategies in this population.\n\nKeywords\nSepsisPediatricHydrocortisoneShockImmunoparalysisMODSImmuneissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nSeptic shock is a leading cause of morbidity and mortality in children, with over 7000 pediatric deaths due to sepsis in the USA each year [1, 2]. Septic shock is characterized by a dysregulated systemic immune response to infection that results in organ dysfunction. The failure of more than one organ, termed “multiple organ dysfunction syndrome (MODS),” confers a > 10-fold increase in risk of mortality in critically ill children [3]. Current management guidelines for pediatric sepsis largely focus on supportive care, including fluid resuscitation and vasoactive medications, in addition to early empiric antibiotics [4]. Hydrocortisone is frequently prescribed as an adjunctive treatment for children with septic shock who have known adrenal insufficiency, those with a history of recent corticosteroid use, and those who remain hemodynamically unstable despite fluid resuscitation and initiation of vasoactive support [5, 6]. The use of hydrocortisone in septic shock, however, remains controversial, with clinical trials in adults yielding conflicting results [7–9]. The current version of the pediatric Surviving Sepsis guidelines is unable to recommend for or against hydrocortisone use, largely due to a lack of evidence. The first prospective clinical trial of hydrocortisone use in pediatric septic shock is currently underway (NCT03401398).\n\nThe immune response to pediatric critical illness is highly dynamic, with acquired immune suppression frequently accompanying systemic inflammation. When severe, this compensatory immune suppression is termed “immunoparalysis.” We and others have consistently shown that immunoparalysis is associated with adverse outcomes from critical illness in children including sepsis, trauma, and cardiopulmonary bypass [10–13]. We recently observed, in a prospective, single-center, 102-subject cohort of children with severe sepsis/septic shock, that both immunoparalysis and hydrocortisone treatment were associated with longer duration of organ dysfunction. Prior transcriptomic work has suggested the possibility of a differential effect of hydrocortisone on pediatric sepsis outcomes depending on the host immune phenotype [14]. We therefore designed this secondary analysis of our data set to test the hypothesis that the relationships between hydrocortisone treatment and duration of MODS will be variable, depending on the presence or absence of immunoparalysis.\n\nMethods\nStudy population\nThis is a secondary analysis of a prospective observational study which was conducted in the 54-bed medical-surgical pediatric intensive care unit (PICU) at Nationwide Children’s Hospital, a quaternary-care children’s hospital with over 3000 annual admissions. Children < 18 years of age who were admitted to the PICU were eligible for enrollment if they met consensus criteria for severe sepsis or septic shock [15] within the preceding 48 h. Subjects were excluded if a limitation-of-care order was in place, if there was expected progression to brain death by the primary treating team, or if they were admitted to the cardiothoracic ICU. Written informed consent was obtained from subjects’ legal guardians prior to participation, and if appropriate, subjects’ assent was obtained. The protocol was approved by the Institutional Review Board at Nationwide Children’s Hospital.\n\nImmune function\nWhole blood samples were collected within 48 h of sepsis onset. Complete blood count (CBC) testing was done as part of routine care by the primary treating team, and all subjects had a CBC with differential completed within the first 48 h of sepsis onset. If multiple CBCs were obtained, the absolute cell counts reported are the lowest values within the first 48 h. Plasma from un-stimulated blood samples was collected after centrifugation of whole blood at 1000×g for 5 min and stored at − 80 °C to quantify interleukin (IL)-10 and IL-6, reflecting the systemic inflammatory response. Plasma TNFα levels were not measured, as previous studies have demonstrated that circulating TNFα comprises less than 10% of the measured ex vivo TNFα production capacity [16].\n\nInnate immune function was measured by whole blood ex vivo lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α production capacity. Briefly, 50-μl aliquots of heparinized whole blood were added to stimulation tubes containing LPS (500 pg/ml, phenol-extracted from Salmonella abortus equi [Sigma, St. Louis, MO]). Stimulation tubes were then incubated at 37 °C for 4 h. After incubation, supernatants were collected and stored at − 80 °C for batched cytokine analysis. TNFα from LPS-stimulated supernatants were quantified by the Immulite 1000 automated chemiluminometer (Siemens Healthcare Diagnostics, Deerfield, IL). Immunoparalysis was defined as an LPS-induced TNFα production capacity (hereafter referred to as the TNFα response) < 200 pg/ml [17, 18].\n\nClinical data and outcome measurements\nFor subjects with community-acquired sepsis, sepsis onset was defined as the initial time of presentation to any emergency department that resulted in hospitalization. For subjects who developed nosocomial sepsis, sepsis onset was defined as the time of transfer to the PICU. The electronic medical record was used to collect clinical data. Baseline immune compromise was defined as the presence of a congenital immunodeficiency, an oncologic diagnosis, or the receipt of chronic immunosuppressive therapy. Complex chronic conditions were defined as previously published [19]. The highest Pediatric Risk of Mortality (PRISM) III score within the first 24 h of sepsis onset was used to measure initial illness severity. The highest vasoactive inotrope score (VIS) in the first 48 h, which is calculated using the combined doses of inotropic and vasopressor infusions [20], was used as a surrogate measure of subjects’ shock state.\n\nMODS was defined as dysfunction of more than one organ system according to previously published criteria [21] and represented only new organ dysfunction, not chronic organ dysfunction. The primary outcome measure was the number of days with MODS in the first 14 days from sepsis onset. Non-survivors were assigned the maximum number of MODS days (fourteen).\n\nStatistical analysis\nValues are reported as median and interquartile range (IQR) or n and % as appropriate. Simple comparisons were made using chi-square or Fisher’s exact tests for categorical variables and Wilcoxon rank-sum tests for continuous variables. Univariate and multivariable negative binomial regression models were used to examine associations with duration of MODS. Coefficients for all negative binomial regression models were exponentiated to reflect risk ratios, or the percent increase in duration of MODS for a unit increase in the given predictor variable. Variable selection for the multivariable models was based on stepwise selection with an entry criterion of p < 0.15 and an exit criterion of p > 0.1, in addition to Akaike’s Information Criterion (AIC, a measure of goodness of fit); VIS, baseline immune compromise, and hydrocortisone were retained in all models regardless of statistical significance on clinical grounds. To explore the possibility that an association between hydrocortisone use and outcomes may simply reflect the initial shock state of the subject, we performed secondary analysis limited to the subgroup of subjects with septic shock (those treated with vasoactive drugs). Statistical analyses were performed using SAS 9.4 (SAS Institute, Cary, NC) and Prism 7.0 (GraphPad Software, La Jolla, CA, USA).\n\nResults\nSubjects\nA total of 102 subjects were enrolled between January 2012 and April 2014 with a median age of 75 (6–160) months. Subject demographic and clinical characteristics are shown in Table 1. Forty-eight patients had a complex chronic condition, most commonly including diagnoses of developmental delay or seizure disorder. There were 16 patients with baseline immune compromise due to receipt of solid organ or bone marrow transplant (n = 5), oncologic diagnosis (n = 6), congenital immunodeficiency (n = 2), or receipt of immunosuppressive medications for autoimmune disease (n = 3). Thirty-one subjects (30%) received hydrocortisone. Of those, 14 (45%) were known to have adrenal insufficiency, recent steroid use, or evidence of adrenal insufficiency with a cortisol level < 18 μg/dl in the setting of sepsis. Hydrocortisone-treated subjects were more likely to be older and to have baseline immune compromise, as well as a higher PRISM compared to those that did not receive hydrocortisone (Table 1). In the entire cohort, subjects that received hydrocortisone had a longer duration of MODS compared to those who did not receive hydrocortisone (3 [1–9] vs 1 [1–3] days, p = 0.0002). In the subset with septic shock, this relationship was similar (3.5 [2–9] vs 2 [0–3] days, p < 0.0001). All subjects who died were treated with hydrocortisone. There was no difference in the incidence of nosocomial infection between subjects treated with or without hydrocortisone in the cohort as a whole (2/31 [6%] vs 8/71 [11%], p = 0.72) or in the subgroup with septic shock (1/26 [4%] vs 5/54 [9%], p = 0.66).\nTable 1 Cohort characteristics\n\nCharacteristics\tAll (N = 102)\tNo hydrocortisone (N = 71)\tHydrocortisone (N = 31)\tp value\t\nMedian or N\tIQR or %\tMedian or N\tIQR or %\tMedian or N\tIQR or %\t\nAge, months\t74.5\t(6, 160)\t38\t(3, 153)\t106\t(52, 184)\t0.0441\t\nMale\t61\t60\t40\t56\t21\t68\t0.2799\t\nComplex chronic condition\t48\t47\t29\t41\t19\t62\t0.0571\t\nBaseline immune compromise\t16\t16\t6\t8\t10\t32\t0.0057\t\nRBC transfusion in first 48 h\t48\t47\t21\t44\t17\t55\t0.2983\t\nAcute comorbidities\t18\t18\t14\t20\t4\t13\t0.4063\t\nPRISM\t9\t(5, 14)\t7\t(5, 13)\t13\t(8, 18)\t0.0003\t\nPELOD*\t7\t(5, 9)\t6\t(5, 9)\t8\t(5, 11)\t0.0813\t\nVIS\t11.5\t(5, 20)\t10\t(3, 15)\t20\t(10, 35)\t0.0002\t\nMortality\t6\t6\t0\t0\t6\t19\t0.0005\t\nImmune function:\t\n Plasma IL6* (pg/mL)\t78.85\t(22.7, 258)\t63.9\t(24, 140)\t112\t(17.9, 811)\t0.2916\t\n Plasma IL10* (pg/mL)\t30.55\t(10, 85.45)\t21.5\t(10, 75.9)\t35.9\t(11.4, 95.7)\t0.3586\t\n Ex vivo TNFα# (pg/mL)\t433\t(143.5, 821)\t465\t(237.5, 956.5)\t180.5\t(52.3, 633)\t0.0063\t\n AMC# (cells/mm3)\t326.5\t(93, 648)\t320\t(93, 728)\t412\t(75, 545)\t0.6675\t\nRBC red blood cell, PRISM Pediatric Risk of Mortality Score, PELOD Pediatric Logistic Organ Dysfunction, AMC absolute monocyte count\n\n*Highest value in first 48 h\n\n#Lowest value in first 48 h\n\n\n\nIn multivariable analysis, the receipt of hydrocortisone in the first 48 h, the presence of a complex chronic condition, and receipt of a red blood cell transfusion in the first 48 h were all independently associated with a higher adjusted relative risk (aRR) for longer duration of MODS in the complete cohort (Table 2). In the subset of subjects with septic shock, there was an even stronger independent association between hydrocortisone use and longer duration of MODS.\nTable 2 Adjusted risk of longer duration of MODS in entire cohort and those with septic shock\n\nVariable\tEntire cohort\tSeptic shock subset\t\naRR\tLower CL\tUpper CL\tp-value\taRR\tLower CL\tUpper CL\tp value\t\nBaseline immune compromise\t0.95\t0.49\t1.85\t0.891\t0.56\t0.28\t1.14\t0.1117\t\nCCC\t1.97\t1.22\t3.19\t0.0054\t1.73\t1.09\t2.76\t0.0198\t\nVIS\t1.01\t1.00\t1.03\t0.0166\t1.01\t1.00\t1.02\t0.1236\t\nRBC Transfusion\t1.83\t1.18\t2.83\t0.0066\t1.47\t0.94\t2.28\t0.0882\t\nHydrocortisone\t1.79\t1.06\t3.04\t0.0295\t2.74\t1.60\t4.70\t0.0002\t\nCCC complex chronic condition, VIS Vasoactive Inotrope Score, RBC red blood cell\n\n\n\nHydrocortisone and immune function\nAll subjects underwent immune function testing during the first 48 h of sepsis, though 22/31 (70%) of the subjects in the hydrocortisone-treated group had blood sampling done after receiving at least one dose of hydrocortisone (median of 15.4 h). In the cohort as a whole, subjects in the hydrocortisone-treated group had lower TNFα responses and lower absolute lymphocyte counts compared to subjects not treated with hydrocortisone (p = 0.0063 and 0.0027 respectively) (Table 1). The degree of systemic inflammation, as evidenced by plasma IL-6 and IL-10 levels, was similar between groups. Among subjects that received hydrocortisone, immune function and plasma cytokine levels were similar between subjects whose blood sample was obtained before versus after their first dose of hydrocortisone (TNFα response: 247 (65–408) vs 172 (52–545) pg/mL, p = 0.86; IL-6: 167 (16–376) vs 70 (18–3214) pg/mL, p = 0.533; IL-10: 36 (15–76) vs 45 (13–116) pg/mL, p = 0.675). After adjusting for covariables, hydrocortisone treatment in the first 48 h of sepsis was independently associated with a longer duration of MODS in subjects with immunoparalysis (aRR = 3.72, 95% CI 1.76–7.87, p = 0.0006) (Fig. 1a). This was not true for subjects without immunoparalysis (aRR = 1.16, 95% CI 0.58–2.32, p = 0.67). This relationship was even stronger in the septic shock subgroup (Fig. 1b), with hydrocortisone use being associated with a longer duration of MODS only in subjects with immunoparalysis (aRR = 4.57, 96% CI 2.31–9.07, p < 0.0001 vs aRR = 1.54, 95% CI 0.69–3.43, p = 0.29).\nFig. 1 Forest plot of the adjusted relative risk of variables on duration of MODS in the total cohort (a) and the subjects with septic shock (b). In both the total cohort and septic shock subset, subjects with immunoparalysis had a higher risk of a greater duration of MODS when receiving hydrocortisone treatment (aRR 3.72 [1.76, 7.87] and aRR 4.57 [2.31, 9.07], respectively)\n\n\n\nDiscussion\nOurs is the first study to examine the relationships between the functional immune response, hydrocortisone use, and clinical outcomes in septic children. We were able to identify differential risk for prolonged organ dysfunction in children treated with hydrocortisone depending on their immune function in the acute phase of sepsis, with children with immunoparalysis demonstrating more prolonged MODS. Our data are in agreement with previously published mRNA studies [14] and highlight the need to incorporate prospective immunophenotyping into the design of future clinical trials of hydrocortisone in septic children.\n\nSevere sepsis/septic shock remains a major source of morbidity and mortality worldwide. A recent multi-national point prevalence study found a 25% mortality associated with pediatric severe sepsis [22] while another US multi-center study found a strong correlation between higher organ dysfunction scores and lower health-related quality of life in pediatric survivors of septic shock [23]. The mainstays of pediatric sepsis management include early fluid resuscitation, timely antibiotic administration, and hemodynamic support [6, 24, 25] though hydrocortisone is frequently used as adjuvant therapy in children with fluid and catecholamine-resistant shock as well as those with a priori risk factors for adrenal insufficiency. Hydrocortisone use in sepsis remains highly controversial, however. Evidence suggests that low-dose hydrocortisone treatment is associated with a shorter time to shock reversal in septic adults [26], but its reported effects on mortality have been inconsistent and at least one study has suggested an increase in nosocomial infection risk with hydrocortisone use [8]. Retrospective, observational pediatric data raise the possibility of equivocal or even harmful effects of hydrocortisone in the treatment of sepsis [27–29], but data from pediatric randomized controlled trials are, as yet, lacking. The current version of the pediatric Surviving Sepsis guidelines recommends neither for nor against the use of hydrocortisone [4].\n\nWhile it is used in septic patients primarily for its hemodynamic-supporting mineralocorticoid activity, hydrocortisone does have some glucocorticoid activity which has the potential to exacerbate or perpetuate sepsis-induced immune suppression. The host immune response to sepsis is highly dynamic. The initial pro-inflammatory response is quickly accompanied by a compensatory downregulation of systemic immune function. This is termed “immunoparalysis” when severe and is characterized by a marked reduction of the ability of whole blood to produce TNFα upon ex vivo stimulation with LPS. We and others have repeatedly shown associations between reduction in the TNFα response and adverse outcomes including nosocomial infection, prolonged organ dysfunction, and death in critically ill children [13, 16, 18]. We recently published the results of a single-center, prospective immune phenotyping study of 102 children with severe sepsis/septic shock in which the use of hydrocortisone and severe reduction in the TNFα response were both associated with longer durations of MODS [17]. The degree to which hydrocortisone influences the host immune response in this setting is unknown. The current study represents a secondary analysis of this cohort, with emphasis on the relationships between hydrocortisone use, immunoparalysis, and MODS.\n\nOur observation that hydrocortisone use was associated with a differential outcome depending on the subject’s immunophenotype is complementary to a recent biomarker study conducted by Wong et al. Their group developed a panel of 5 plasma proteins (the PERSEVERE panel) that has been validated to risk-stratify children with acute septic shock [30]. They also developed a 100-gene leukocyte transcriptomic panel that segregates children with acute septic shock into endotypes that are characterized by under-activation (endotype A) or overactivation (endotype B) of genes related to adaptive immunity and glucocorticoid receptor signaling [31]. In a secondary analysis of 288 children with acute septic shock, subjects in the intermediate and high-risk PERSEVERE groups who exhibited endotype B, hydrocortisone use was associated with a more than 10-fold reduction in in the risk of death or prolonged MODS. Hydrocortisone use was not associated with clinical outcomes in subjects with endotype A. This suggested that hydrocortisone benefit may be limited to children with a more activated immune state. Our study takes this line of reasoning further and, for the first time, provides evidence of an association between hydrocortisone use and worse outcomes in children who have severe functional innate immune impairment. It is therefore possible that prior clinical trials of hydrocortisone use in sepsis may have failed to correctly identify beneficial or harmful effects due to an inability to adjust for subjects’ immunologic state. Since immunoparalysis is typically occult, and biomarkers of immunoparalysis are not currently measured in the clinical laboratory, it will be crucial to include prospective immune phenotyping in the design of future clinical trials of hydrocortisone in septic children.\n\nAdditionally, our results showed that receipt of a RBC transfusion was also associated with a higher risk of a longer duration of MODS, an observation that was recently the subject of another secondary analysis of this data set [32]. We also found that the presence of baseline immune compromise was associated with fewer MODS days in patients with immunoparalysis. In this patient population, immune suppression may be a modifiable risk factor through the tapering of immunosuppressive medication. Further, the presence of known baseline immune compromise may prompt earlier and more aggressive sepsis treatment. This is an area of active investigation.\n\nThis study was limited by its single center design and small sample size. Despite this, we were able to demonstrate significant associations between hydrocortisone use, immune function, and outcomes. The use of hydrocortisone in this study was not protocolized, and the resulting variability in prescription may have influenced our results. Perhaps most importantly, the majority of subjects who received hydrocortisone in our cohort underwent immune function testing after having received at least one dose of hydrocortisone. It is therefore unclear if hydrocortisone contributed to the development of immunoparalysis or if subjects at high risk for immunoparalysis are also more likely to receive hydrocortisone. The cause-and-effect relationship between hydrocortisone and innate immune suppression in critically ill children is an active area of investigation for our research group. The presence of a differential relationship between hydrocortisone use and outcomes depending on the host immune response, however, remains a key confounder of future clinical trials of hydrocortisone in pediatric sepsis. Lastly, this study focuses primarily on the TNFα response, which represents only one measure of immune function. While other aspects of immune function including phagocytosis, intracellular killing, antigen presentation, adaptive immune responses, and immunologic memory may be of interest in this population, a large body of literature suggests that the TNFα response is a highly clinically relevant readout of immune function in septic children.\n\nConclusion\nThe administration of hydrocortisone to children with immunoparalysis in the setting of severe sepsis/septic shock was associated with a longer duration of multiple-organ dysfunction syndrome whereas this association was not seen in children without immunoparalysis. While cause and effect relationships cannot be determined from this study, these data highlight the need to include prospective immunophenotyping in clinical trials of hydrocortisone in septic children.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNo acknowledgements.\n\nAuthors’ contributions\nAll authors participated in the study design and reviewed and approved the manuscript. JH, LS, KG, and LA participated in subject enrollment and clinical data collection. LHH and JN performed laboratory analyses. MMC performed statistical analyses. KB and MH created the initial draft of the manuscript.\n\nFunding\nThere was no source of funding for the research related to this manuscript.\n\nAvailability of data and materials\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nThis study was approved by the Institutional Review Board at Nationwide Children’s Hospital in Columbus, OH.\n\nConsent for publication\nThis manuscript does not contain any individual person’s data in any form.\n\nCompeting interests\nDr. Mark Hall is a consultant for La Jolla Pharmaceuticals. This work is unrelated to the content of this manuscript.\n==== Refs\nReferences\n1. Watson RS Carcillo JA Linde-Zwirble WT Clermont G Lidicker J Angus DC The epidemiology of severe sepsis in children in the United States Am J Respir Crit Care Med 2003 167 5 695 701 10.1164/rccm.200207-682OC 12433670 \n2. Hartman ME Linde-Zwirble WT Angus DC Watson RS Trends in the epidemiology of pediatric severe sepsis* Pediatr Crit Care Med 2013 14 7 686 693 10.1097/PCC.0b013e3182917fad 23897242 \n3. Typpo K Watson RS Bennett TD Farris RWD Spaeder MC Petersen NJ Outcomes of day 1 multiple organ dysfunction syndrome in the PICU Pediatr Crit Care Med 2019 20 10 914 922 10.1097/PCC.0000000000002044 31589198 \n4. Weiss SL Peters MJ Alhazzani W Agus MSD Flori HR Inwald DP Surviving Sepsis Campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children Pediatr Crit Care Med 2020 21 2 e52 e106 10.1097/PCC.0000000000002198 32032273 \n5. Darmaros LF Delgado AF Carvalho WB Corticosteroids in septic shock: what should the decision in pediatrics be? Rev Assoc Med Bras (1992) 2016 62 6 482 484 10.1590/1806-9282.62.06.482 27849223 \n6. Davis AL, Carcillo JA, Aneja RK, Deymann AJ, Lin JC, Nguyen TC, et al. American College of Critical Care Medicine clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock. Crit Care Med 2017;45(6):1061–1093.\n7. Bollaert PE Charpentier C Levy B Debouverie M Audibert G Larcan A Reversal of late septic shock with supraphysiologic doses of hydrocortisone Crit Care Med 1998 26 4 645 650 10.1097/00003246-199804000-00010 9559600 \n8. Sprung CL Annane D Keh D Moreno R Singer M Freivogel K Hydrocortisone therapy for patients with septic shock N Engl J Med 2008 358 2 111 124 10.1056/NEJMoa071366 18184957 \n9. Annane D Briegel J Keh D Moreno R Singer M Sprung CL Clinical equipoise remains for issues of adrenocorticotropic hormone administration, cortisol testing, and therapeutic use of hydrocortisone Crit Care Med 2003 31 8 2250 2251 10.1097/01.CCM.0000080485.75448.45 \n10. Cornell TT Sun L Hall MW Gurney JG Ashbrook MJ Ohye RG Clinical implications and molecular mechanisms of immunoparalysis after cardiopulmonary bypass J Thorac Cardiovasc Surg 2012 143 5 1160 1166 10.1016/j.jtcvs.2011.09.011 21996297 \n11. Tschoeke SK Ertel W Immunoparalysis after multiple trauma Injury 2007 38 12 1346 1357 10.1016/j.injury.2007.08.041 18048039 \n12. Manzoli TF Troster EJ Ferranti JF Sales MM Prolonged suppression of monocytic human leukocyte antigen-DR expression correlates with mortality in pediatric septic patients in a pediatric tertiary intensive care unit J Crit Care 2016 33 84 89 10.1016/j.jcrc.2016.01.027 26928303 \n13. Muszynski JA Nofziger R Greathouse K Nateri J Hanson-Huber L Steele L Innate immune function predicts the development of nosocomial infection in critically injured children Shock 2014 42 4 313 321 10.1097/SHK.0000000000000217 24978895 \n14. Wong HR Atkinson SJ Cvijanovich NZ Anas N Allen GL Thomas NJ Combining prognostic and predictive enrichment strategies to identify children with septic shock responsive to corticosteroids Crit Care Med 2016 44 10 e1000 e1003 10.1097/CCM.0000000000001833 27270179 \n15. Goldstein B Giroir B Randolph A International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics Pediatr Crit Care Med 2005 6 1 2 8 10.1097/01.PCC.0000149131.72248.E6 15636651 \n16. Hall MW Geyer SM Guo CY Panoskaltsis-Mortari A Jouvet P Ferdinands J Innate immune function and mortality in critically ill children with influenza: a multicenter study Crit Care Med 2013 41 1 224 236 10.1097/CCM.0b013e318267633c 23222256 \n17. Muszynski JA Nofziger R Moore-Clingenpeel M Greathouse K Anglim L Steele L Early immune function and duration of organ dysfunction in critically III children with sepsis Am J Respir Crit Care Med 2018 198 3 361 369 10.1164/rccm.201710-2006OC 29470918 \n18. Hall MW Knatz NL Vetterly C Tomarello S Wewers MD Volk HD Immunoparalysis and nosocomial infection in children with multiple organ dysfunction syndrome Intensive Care Med 2011 37 3 525 532 10.1007/s00134-010-2088-x 21153402 \n19. Feudtner C Christakis DA Connell FA Pediatric deaths attributable to complex chronic conditions: a population-based study of Washington State, 1980-1997 Pediatrics 2000 106 1 Pt 2 205 209 10888693 \n20. Gaies MG Gurney JG Yen AH Napoli ML Gajarski RJ Ohye RG Vasoactive-inotropic score as a predictor of morbidity and mortality in infants after cardiopulmonary bypass Pediatr Crit Care Med 2010 11 2 234 238 10.1097/PCC.0b013e3181b806fc 19794327 \n21. Villeneuve A Joyal JS Proulx F Ducruet T Poitras N Lacroix J Multiple organ dysfunction syndrome in critically ill children: clinical value of two lists of diagnostic criteria Ann Intensive Care 2016 6 1 40 10.1186/s13613-016-0144-6 27130424 \n22. Weiss SL Fitzgerald JC Pappachan J Wheeler D Jaramillo-Bustamante JC Salloo A Global epidemiology of pediatric severe sepsis: the sepsis prevalence, outcomes, and therapies study Am J Respir Crit Care Med 2015 191 10 1147 1157 10.1164/rccm.201412-2323OC 25734408 \n23. Zimmerman JJ Banks R Berg RA Zuppa A Newth CJ Wessel D Trajectory of mortality and health-related quality of life morbidity following community-acquired pediatric septic shock Crit Care Med 2020 48 3 329 337 10.1097/CCM.0000000000004123 32058370 \n24. Sterling SA Miller WR Pryor J Puskarich MA Jones AE The impact of timing of antibiotics on outcomes in severe sepsis and septic shock: a systematic review and meta-analysis Crit Care Med 2015 43 9 1907 1915 10.1097/CCM.0000000000001142 26121073 \n25. de Oliveira CF de Oliveira DS Gottschald AF Moura JD Costa GA Ventura AC ACCM/PALS haemodynamic support guidelines for paediatric septic shock: an outcomes comparison with and without monitoring central venous oxygen saturation Intensive Care Med 2008 34 6 1065 1075 10.1007/s00134-008-1085-9 18369591 \n26. Annane D Bellissant E Bollaert PE Briegel J Keh D Kupfer Y Corticosteroids for severe sepsis and septic shock: a systematic review and meta-analysis BMJ 2004 329 7464 480 10.1136/bmj.38181.482222.55 15289273 \n27. Nichols B Kubis S Hewlett J Yehya N Srinivasan V Hydrocortisone therapy in catecholamine-resistant pediatric septic shock: a pragmatic analysis of clinician practice and association with outcomes Pediatr Crit Care Med 2017 18 9 e406 ee14 10.1097/PCC.0000000000001237 28658197 \n28. Markovitz BP Goodman DM Watson RS Bertoch D Zimmerman J A retrospective cohort study of prognostic factors associated with outcome in pediatric severe sepsis: what is the role of steroids? Pediatr Crit Care Med 2005 6 3 270 274 10.1097/01.PCC.0000160596.31238.72 15857523 \n29. Zimmerman JJ Donaldson A Barker RM Meert KL Harrison R Carcillo JA Real-time free cortisol quantification among critically ill children Pediatr Crit Care Med 2011 12 5 525 531 10.1097/PCC.0b013e3181fe4474 21057361 \n30. Wong HR Weiss SL Giuliano JS Jr Wainwright MS Cvijanovich NZ Thomas NJ The temporal version of the pediatric sepsis biomarker risk model PLoS One 2014 9 3 e92121 10.1371/journal.pone.0092121 24626215 \n31. Wong HR Cvijanovich NZ Anas N Allen GL Thomas NJ Bigham MT Developing a clinically feasible personalized medicine approach to pediatric septic shock Am J Respir Crit Care Med 2015 191 3 309 315 10.1164/rccm.201410-1864OC 25489881 \n32. Srouji LS Moore-Clingenpeel M Hensley J Steele L Greathouse K Anglim L Shock severity modifies associations between RBC transfusion in the first 48 hours of sepsis onset and the duration of organ dysfunction in critically ill septic children Pediatr Crit Care Med 2020 21 8 e475 ee84 32195902\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1364-8535",
"issue": "24(1)",
"journal": "Critical care (London, England)",
"keywords": "Hydrocortisone; Immune; Immunoparalysis; MODS; Pediatric; Sepsis; Shock",
"medline_ta": "Crit Care",
"mesh_terms": "D000293:Adolescent; D000893:Anti-Inflammatory Agents; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D006854:Hydrocortisone; D016867:Immunocompromised Host; D007223:Infant; D007902:Length of Stay; D008297:Male; D009102:Multiple Organ Failure; D010372:Pediatrics; D011446:Prospective Studies; D018805:Sepsis; D013997:Time Factors",
"nlm_unique_id": "9801902",
"other_id": null,
"pages": "545",
"pmc": null,
"pmid": "32887651",
"pubdate": "2020-09-04",
"publication_types": "D016428:Journal Article",
"references": "19794327;27270179;23897242;21153402;26121073;31589198;28509730;24978895;24626215;9559600;23222256;18048039;10888693;18184957;18369591;15289273;25734408;29470918;15857523;28658197;26928303;32058370;12433670;21996297;12973194;32032273;15636651;27849223;27130424;21057361;32195902;25489881",
"title": "Hydrocortisone treatment is associated with a longer duration of MODS in pediatric patients with severe sepsis and immunoparalysis.",
"title_normalized": "hydrocortisone treatment is associated with a longer duration of mods in pediatric patients with severe sepsis and immunoparalysis"
} | [
{
"companynumb": "US-PFIZER INC-2020395630",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROCORTISONE SODIUM SUCCINATE"
},
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{
"abstract": "OBJECTIVE\nDespite treatment, prognosis of unresectable squamous cell carcinoma of the head and neck (SCCHC) is dismal. Cetuximab therapy has proven to increase the clinical activity of radiation therapy and chemotherapy in patients with locoregional advanced disease with an acceptable toxicity profile. We designed a phase 2 trial to evaluate the efficacy of docetaxel, cisplatin, and 5-fluorouracil (TPF) plus cetuximab (C-TPF) as an induction regimen in patients with unresectable SCCHN.\n\n\nMETHODS\nA single-arm phase 2 trial was conducted. Eligible patients included those with untreated unresectable SCCHC, World Health Organization performance status of 0 to 1, 18 to 70 years of age. Treatment consisted of four 21-day cycles of TPF (docetaxel, 75 mg/m(2) day 1; cisplatin, 75 mg/m(2) day 1; 5-fluorouracil [5-FU], 750 mg/m(2) day 1-5) and cetuximab, 250 mg/m(2) weekly (loading dose of 400 mg/m(2)). Prophylactic granulocyte colony-stimulating factor and antibiotic support were given. After induction, sequential accelerated radiation therapy with concomitant boost (69.9 Gy) and weekly cetuximab therapy were delivered in the absence of disease progression. The primary endpoint was objective response rate (ORR) to C-TPF.\n\n\nRESULTS\nFifty patients were enrolled across 8 centers. Median age was 54 years; disease was stage IV; oropharynx and hypopharynx were the most common primary sites. Eighty-two percent received 4 cycles of C-TPF, and 86% started sequential treatment based on radiation therapy and cetuximab. ORR after C-TPF was 86% (95% confidence interval [CI]: 73%-94%) and 24% had complete response (CR). With a median follow-up of 40.7 months, median overall survival (OS) was 40.7 months. The 2-year actuarial locoregional control (LRC) rate was 57%. The most common drug-related grade 3 or 4 toxicities during induction were neutropenia (24%), neutropenic fever (24%), and diarrhea (20%). There were 3 treatment-related deaths (6%).\n\n\nCONCLUSIONS\nC-TPF yields high ORR and CR as induction treatment in unresectable SCCHN. However, hematologic toxicity is too high to recommend this regimen at the current dose.",
"affiliations": "Medical Oncology Department, Institut Català d'Oncologia L'Hospitalet, Barcelona, Spain. Electronic address: rmesia@iconcologia.net.;Medical Oncology Department, Institut Català d'Oncologia L'Hospitalet, Barcelona, Spain.;Medical Oncology Department, Hospital Clínic i Provincial, Barcelona, Spain.;Medical Oncology Department, Hospital Clínico San Carlos, Madrid, Spain.;Radiation Oncology Department, Institut Català d'Oncologia L'Hospitalet, Barcelona, Spain.;Medical Oncology Department, Hospital General Yagüe, Burgos, Spain.;Medical Oncology Department, Hospital del Mar, Barcelona, Spain.;Medical Oncology Department, Hospital Virgen de las Nieves, Granada, Spain.;Department of Otorhinolaryngology, Hospital de Bellvitge, Barcelona, Spain.;Medical Oncology Department, Hospital Clínico San Carlos, Madrid, Spain.;Medical Oncology Department, Gregorio Marañón University Hospital, Madrid, Spain.;Medical Oncology Department, Institut Català d'Oncologia L'Hospitalet, Barcelona, Spain.;Medical Oncology Department, Gregorio Marañón University Hospital, Madrid, Spain.;Medical Oncology Department, Hospital Clínico de Salamanca, Salamanca, Spain.",
"authors": "Mesía|Ricard|R|;Vázquez|Silvia|S|;Grau|Juan J|JJ|;García-Sáenz|Jose A|JA|;Lozano|Alicia|A|;García|Carlos|C|;Carles|Joan|J|;Irigoyen|Antonio|A|;Mañós|Manel|M|;García-Paredes|Beatriz|B|;del Barco|Elvira|E|;Taberna|Miren|M|;Escobar|Yolanda|Y|;Cruz|Juan J|JJ|;|||",
"chemical_list": "D043823:Taxoids; D016179:Granulocyte Colony-Stimulating Factor; D000077143:Docetaxel; D000068818:Cetuximab; D002945:Cisplatin; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0360-3016",
"issue": "94(2)",
"journal": "International journal of radiation oncology, biology, physics",
"keywords": null,
"medline_ta": "Int J Radiat Oncol Biol Phys",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002294:Carcinoma, Squamous Cell; D000068818:Cetuximab; D002945:Cisplatin; D000077143:Docetaxel; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil; D016179:Granulocyte Colony-Stimulating Factor; D006258:Head and Neck Neoplasms; D006801:Humans; D060828:Induction Chemotherapy; D008297:Male; D008875:Middle Aged; D043823:Taxoids",
"nlm_unique_id": "7603616",
"other_id": null,
"pages": "289-96",
"pmc": null,
"pmid": "26675064",
"pubdate": "2016-02-01",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A Phase 2 Open Label, Single-Arm Trial to Evaluate the Combination of Cetuximab Plus Taxotere, Cisplatin, and 5-Flurouracil as an Induction Regimen in Patients With Unresectable Squamous Cell Carcinoma of the Head and Neck.",
"title_normalized": "a phase 2 open label single arm trial to evaluate the combination of cetuximab plus taxotere cisplatin and 5 flurouracil as an induction regimen in patients with unresectable squamous cell carcinoma of the head and neck"
} | [
{
"companynumb": "ES-SA-2015SA221944",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN"
},
"drugadditional": null,
... |
{
"abstract": "A 73 year-old female patient was scheduled for lumbar peritoneal shunt three weeks after subarachnoid hemorrhage. Before induction of general anesthesia, her ECG showed ventricular tachycardia (VT) without any complaints. Administration of lidocaine and direct current shocks were ineffective and VT continued. Operation was postponed and transthoracic echocardiography revealed diffuse hypokinesis. Emergent angiogram revealed midventricular ballooning with slight hypoki- nesis in basal and apical regions without significant coronary artery lesion. Atypical takotsubo cardiomyopathy was diagnosed. Intra aortic balloon pumping and continuous infusion of amiodaron and catecholamines were started, but her ventricular motion decreased. She died next morning. In this case, the physical/psychological stress before operation was con- sidered to be a trigger of the event. Although tako- tsubo cardiomyopathy is usually a transient disease, it must be kept in mind that an acute and lethal case with no response to any treatment like ours exists.",
"affiliations": null,
"authors": "Umemitya|Maki|M|;Kusaka|Yusuke|Y|;Ishii|Hisanari|H|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-4892",
"issue": "65(11)",
"journal": "Masui. The Japanese journal of anesthesiology",
"keywords": null,
"medline_ta": "Masui",
"mesh_terms": "D000368:Aged; D000768:Anesthesia, General; D001145:Arrhythmias, Cardiac; D004452:Echocardiography; D004562:Electrocardiography; D005260:Female; D006352:Heart Ventricles; D006801:Humans; D007423:Intra-Aortic Balloon Pumping; D017180:Tachycardia, Ventricular; D054549:Takotsubo Cardiomyopathy",
"nlm_unique_id": "0413707",
"other_id": null,
"pages": "1176-1181",
"pmc": null,
"pmid": "30351809",
"pubdate": "2016-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Lethal Atypical Takotsubo Cardiomyopathy Detected by Sustained Ventricular Arrhythmia Just before Induction of General Anesthesia.",
"title_normalized": "a case of lethal atypical takotsubo cardiomyopathy detected by sustained ventricular arrhythmia just before induction of general anesthesia"
} | [
{
"companynumb": "JP-B.BRAUN MEDICAL INC.-2091126",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DEXTROSE\\LIDOCAINE HYDROCHLORIDE"
},
... |
{
"abstract": "OBJECTIVE\nTo describe an 'unexpected' case of abrupt personality following the introduction of lacosamide.\n\n\nMETHODS\nA description of an 82-year-old male receiving neurological follow-up since 2010 due to epilepsy secondary to haemorrhagic stroke. We report a case of abrupt personality change in an 82-year-old male following the introduction of lacosamide with a return to the previous state after its discontinuation. We explored possible mechanisms and pharmacokinetic concerns explaining this personality change.\n\n\nRESULTS\nIn fact, a few days after introducing lacosamide, the patient was described as 'gentle', 'calm' and apologetic for his past aggressions against his family and caregivers which was in complete contrast to his usual personality. There was also marked insistence and the use of sexualised language towards women in his close circle, especially his home nurses. In view of his insistent behaviour towards his nurses and unusual sexualised language, lacosamide was withdrawn. A few days later, the patient displayed his usual, vindictive, aggressive and forceful character. He no longer made any sexualised remarks to his home nurses.\n\n\nCONCLUSIONS\nTo our knowledge, this is the first case of a sudden behavioural and personality change reported by family, friends and carers following the introduction of lacosamide.",
"affiliations": "Service de Pharmacologie Médicale et Clinique, Centre Midi-Pyrénées de PharmacoVigilance, de Pharmacoépidémiologie et d'Informations sur le Médicament, CHU de Toulouse, INSERM U1027, Faculté de Médecine, Université de Toulouse, Toulouse, France.;Service de Neurologie, Centre Hospitalier d'Auch, Auch, France.;Service de Pharmacologie Médicale et Clinique, Centre Midi-Pyrénées de PharmacoVigilance, de Pharmacoépidémiologie et d'Informations sur le Médicament, CHU de Toulouse, INSERM U1027, Faculté de Médecine, Université de Toulouse, Toulouse, France.;Service de Pharmacologie Médicale et Clinique, Centre Midi-Pyrénées de PharmacoVigilance, de Pharmacoépidémiologie et d'Informations sur le Médicament, CHU de Toulouse, INSERM U1027, Faculté de Médecine, Université de Toulouse, Toulouse, France.",
"authors": "Hamard|Jacques|J|;Rigal|Mathieu|M|;Gony|Mireille|M|;Bagheri|Haleh|H|https://orcid.org/0000-0001-9585-9341",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/fcp.12692",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0767-3981",
"issue": null,
"journal": "Fundamental & clinical pharmacology",
"keywords": "behavioural disorder; epilepsy; neuropharmacology; neuropsychiatry",
"medline_ta": "Fundam Clin Pharmacol",
"mesh_terms": null,
"nlm_unique_id": "8710411",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33960008",
"pubdate": "2021-05-07",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Lacosamide-induced personality changes: An unexpected adverse effect.",
"title_normalized": "lacosamide induced personality changes an unexpected adverse effect"
} | [
{
"companynumb": "FR-JNJFOC-20210702789",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BICALUTAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nRhinitis and rhinosinusitis are commonly encountered in pregnant women. Intranasal corticosteroid (INCS) sprays are generally safe and effective in the treatment of these conditions in the general population. However, the use of some of these INCS sprays during pregnancy is still controversial.\n\n\nOBJECTIVE\nTo review the current literature about the safety of intranasal corticosteroid sprays during pregnancy.\n\n\nMETHODS\nUsing different search engines, each type of INCS was reviewed separately (triamcinolone, beclomethasone, budesonide, fluticasone propionate, fluticasone furoate, mometasone, and ciclesonide). A total of 51 full-length articles were examined for eligibility. After applying inclusion and exclusion criteria, a total of three articles were reviewed.\n\n\nRESULTS\nNo significant association with congenital organ malformations has been linked to intranasal use of beclomethasone, budesonide, fluticasone propionate, fluticasone furoate, or mometasone. Intranasal triamcinolone, however, has been found to have a significant association with respiratory tract defects. Data about the safety of intranasal ciclesonide during pregnancy are not available.\n\n\nCONCLUSIONS\nLacking sufficient clinical trials on the use of intranasal corticosteroid sprays in pregnancy, we suggest that the intranasal use of fluticasone furoate, mometasone, and budesonide is safe if they are used at the recommended therapeutic dose after a proper medical evaluation. Intranasal fluticasone propionate might be a safe option in the absence of other INCS options due to its questionable efficacy during pregnancy. Risk-benefit ratio should always be considered before prescribing any intranasal corticosteroid sprays during pregnancy.",
"affiliations": "College of Medicine, King Saud University, Riyadh, Saudi Arabia.;Division of Otolaryngology, Head and Neck Surgery, Department of Surgery, King Abdulaziz Medical City, National Guard Health Affairs, P.O. Box 22490, Riyadh, 11426, Saudi Arabia. Alhedaithy@hotmail.com.;Rhinology and Endoscopic Skull Base Surgery Unit, Otolaryngology, Head and Neck Surgery Department, King Saud University Medical City, Riyadh, Saudi Arabia.",
"authors": "Alhussien|Ahmed H|AH|;Alhedaithy|Riyadh A|RA|;Alsaleh|Saad A|SA|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D059085:Nasal Sprays",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00405-017-4785-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0937-4477",
"issue": "275(2)",
"journal": "European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery",
"keywords": "Corticosteroids; Intranasal; Pregnancy; Rhinitis; Safety; Sinusitis",
"medline_ta": "Eur Arch Otorhinolaryngol",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000281:Administration, Intranasal; D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D059085:Nasal Sprays; D011247:Pregnancy; D011248:Pregnancy Complications; D012220:Rhinitis; D012852:Sinusitis",
"nlm_unique_id": "9002937",
"other_id": null,
"pages": "325-333",
"pmc": null,
"pmid": "29164323",
"pubdate": "2018-02",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "27045580;26800862;9226055;25644617;11421996;11800526;24390829;22448448;21848757;11032642;11678947;10383539;20110036;18751155;20816182;10074986;15576899;11449204;9801739;12432972;17825692;19621070;17478662;9847429;26601995;15586794;12759093;16443147;15114430;15709453;10401850;19284267;9564799;22801015;15281473;12704351;9195148;10518811;17844873;8757203;18662584;2906890;9848901;19690439;23597528",
"title": "Safety of intranasal corticosteroid sprays during pregnancy: an updated review.",
"title_normalized": "safety of intranasal corticosteroid sprays during pregnancy an updated review"
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"abstract": "There are many factors involved in the effectiveness and efficiency of psychiatric drug treatment. One of them is psychotropic drug metabolism, which takes place mostly in the liver through the P450 enzyme system. However, there are genotypic variants of this system's enzymes that can directly affect both the efficacy and the onset of side effects of a given therapeutic regimen. These genotypic changes could partly explain the lack of efficacy of treatment in certain patients. We report the case of a patient diagnosed with bipolar type I disorder that presented multiple and frequent manic episodes in which the efficacy and tolerability of several pharmacological regimens with mood stabilizers and antipsychotics was scarce. The choice of medical treatment should be based on its efficacy and side effect profile. This decision can be made more accurately using the information provided by pharmacogenetic analysis. This case illustrates the importance of pharmacogenetic studies in clinical practice. The results of pharmacogenetic analysis helped to decide on a better treatment plan to achieve clinical improvement and reduce drug-induced adverse effects.",
"affiliations": "Department of Psychiatry and Mental Health, Zamora Hospital, Zamora, Spain.;Department of Psychiatry and Mental Health, Zamora Hospital, Zamora, Spain.;Biosciences Institute of Salamanca, University of Salamanca, Salamanca, Spain.;Department of Psychiatry and Mental Health, Zamora Hospital, Zamora, Spain.;Department of Psychiatry and Mental Health, Zamora Hospital, Zamora, Spain.;Biosciences Institute of Salamanca, University of Salamanca, Salamanca, Spain.",
"authors": "Franco-Martin|Manuel A|MA|;Sans|Francisco|F|;García-Berrocal|Belen|B|;Blanco|Cristina|C|;Llanes-Alvarez|Carlos|C|;Isidoro-García|María|M|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.9758/cpn.2018.16.3.349",
"fulltext": "\n==== Front\nClin Psychopharmacol NeurosciClin Psychopharmacol NeurosciClinical Psychopharmacology and Neuroscience1738-10882093-4327Korean College of Neuropsychopharmacology 3012198810.9758/cpn.2018.16.3.349cpn-16-349Case ReportUsefulness of Pharmacogenetic Analysis in Psychiatric Clinical Practice: A Case Report Franco-Martin Manuel A. 12Sans Francisco 1García-Berrocal Belen 23Blanco Cristina 1Llanes-Alvarez Carlos 1Isidoro-García María 24\n1 Department of Psychiatry and Mental Health, Zamora Hospital, Zamora, \nSpain\n2 Biosciences Institute of Salamanca, University of Salamanca, Salamanca, \nSpain\n4 Department of Medicine, University of Salamanca, Salamanca, \nSpain\n3 Department of Clinical Biochemistry, University Hospital of Salamanca, Salamanca, \nSpainAddress for correspondence: Manuel A. Franco-Martin, MD, PhD, Department of Psychiatric and Mental Health, Zamora Hospital, Av. Hernán Cortés 40, Zamora 49021, Spain, Tel: +34-980-520200, Fax: +34-980-517431, E-mail: mfm@intras.es, mfrancom@sanidadcastillayleon.es, ORCID: https://orcid.org/0000-0002-3639-25238 2018 31 8 2018 16 3 349 357 02 1 2017 13 2 2017 19 5 2017 Copyright © 2018, Korean College of Neuropsychopharmacology2018This 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 unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.There are many factors involved in the effectiveness and efficiency of psychiatric drug treatment. One of them is psychotropic drug metabolism, which takes place mostly in the liver through the P450 enzyme system. However, there are genotypic variants of this system’s enzymes that can directly affect both the efficacy and the onset of side effects of a given therapeutic regimen. These genotypic changes could partly explain the lack of efficacy of treatment in certain patients. We report the case of a patient diagnosed with bipolar type I disorder that presented multiple and frequent manic episodes in which the efficacy and tolerability of several pharmacological regimens with mood stabilizers and antipsychotics was scarce. The choice of medical treatment should be based on its efficacy and side effect profile. This decision can be made more accurately using the information provided by pharmacogenetic analysis. This case illustrates the importance of pharmacogenetic studies in clinical practice. The results of pharmacogenetic analysis helped to decide on a better treatment plan to achieve clinical improvement and reduce drug-induced adverse effects.\n\nBipolar disorderAntipsychotic drugsPharmacogeneticsCytochrome P450Individualized medicine\n==== Body\nINTRODUCTION\nBipolar type I disorder is a frequently severe and long-term mental disorder, with a 12-month prevalence between 0.5%1) and 1.2%.2) Psychopharmacologic treatment seeks to achieve effective control of affective or psychotic symptoms and mood stabilization, with the ultimate goal of normalizing the patient’s life and minimizing the risks associated with the disease. The most frequently used drugs are mood stabilizers and antipsychotic drugs, alone or in combination.3) However, clinical experience shows that there is wide interpatient variability in psychopharmacological treatment response, which could lead to an irregular clinical course and a poor prognosis.4,5) This variability in response may be associated with diverse individual factors such as diet, polypharmacy, or genetic variations that could alter the activity of psychotropic-drug-metabolizing enzymes and protein transporters leading to individual differences in plasma concentrations of the active substance and, consequently, to such response variability.5) To deal with this, clinicians often need to switch from one therapeutic regimen to another based on lack of efficacy, low tolerance or non-adherence.3,6) The switching process must consider confirmation of compliance, optimize the benefits of the drug being used before starting the replacement,7) and take into account the pharmacokinetic and pharmacodynamic characteristics of the drugs used. Accordingly, the US Food and Drug Administration (FDA) recommended that patients should be subjected to a genetic test prior to the administration of certain antipsychotic drugs such as aripiprazole or clozapine.7,8) A retrospective assessment of the value of pharmacogenetics for prescribing psychotropic drugs has shown that inappropriate medication selection has generated an increase in the use of healthcare resources associated with mental disorders.9)\n\nPharmacogenetic studies provide information about the influence of genetic factors in drug transport and metabolism, which helps in the choice of an appropriate drug treatment that maximizes therapeutic efficacy while minimizing side effects.10)\n\nRegarding psychotropic drugs, their metabolism is mainly hepatic, via cytochrome P450, so they may be affected by competitive interactions with other drugs that use the same metabolic pathway, either as substrates, inductors or inhibitors.11)\n\nIn the case of antipsychotics, cytochrome P450 enzymes CYP2D6, CYP1A2, and CYP3A4/5 are the most relevant, and polymorphisms of the alleles of these proteins are associated with altered plasma levels of medication.12) Approximately 40% of antipsychotics are metabolized via CYP2D6, 23% via CYP3A4 and 18% via CYP1A2.13) Specifically, CYP2D6 is involved in the metabolism of haloperidol, risperidone, olanzapine, and aripiprazole; CYP1A2 is involved in the metabolism of clozapine and olanzapine; and CYP3A4 takes part in the metabolism of haloperidol, clozapine, quetiapine, ziprasidone and aripiprazole.14–16) It is estimated that between 10% and 20% of the western population have genetic variants that affect the functioning of these enzymes.13) Consequently, the standard dose of a psychoactive drug may result in plasma concentrations that may be sub-therapeutic or toxic depending on the patient’s cytochrome P450 genotype. Hence, the results of pharmacogenetic studies could significantly contribute to appropriate selection of drug treatment.17,18) In addition, many specific transport proteins are located in the BBB (blood–brain barrier) and intestine. MDR1 multidrug resistance 1, P-glycoprotein (P-gp) or ABCB1 is an ATP-binding cassette superfamily protein involved in pharmacokinetics of diverse antipsychotics. Genetic variants in MDR1 gene can affect the efflux of drugs out of the cell or the permeability of the BBB. So, Pharmacogenetic analysis of MDR1 can contribute to improve application of personalized medicine in schizophrenia treatment.\n\nHowever, despite the FDA’s recommendation on the use of pharmacogenetics and the results of clinical studies showing its usefulness to establish the most effective treatment, it is hardly used for assessing the hepatic metabolism of antipsychotics.\n\nIn this case report, the pharmacogenetic study of cytochrome P450 and the efflux transporter MDR1 provided valuable information. The metabolic capacity of the patient have been of great importance to achieve the stabilization of a complex clinical situation that was causing great suffering to the individual, impoverishing his quality of life and involving high costs for the healthcare system.\n\nCASE\nWe present the case of a 33-year-old Caucasian male patient. During periods of clinical stability, he used to work with high performance. He has no siblings, practically no social life and few leisure interests. He smokes 20 cigarettes a day and denies regular consumption of recreational drugs or alcohol, although he admits to the occasional use cannabis, which has triggered episodes of behavioural disorders. He has spent long periods off work due to his psychiatric condition, which has led to the loss of his current job.\n\nHe refers no psychiatric family history. Somatic history shows obesity and gynecomastia.\n\nPast psychiatric history: he was first diagnosed with bipolar type I disorder in 2003, at the age of 20 years, and was admitted to a psychiatric unit for the first time in 2006. From the clinical perspective, he suffers a very unstable condition with a poor and slow response to treatment and frequent relapses involving startling manic symptoms and severe behavioural disorders. Besides, he has experienced severe drug-induced side effects, the most remarkable being extrapyramidal symptoms, sedation, weight gain and dyslipidaemia. Because of the numerous and troublesome adverse effects, the patient has become reluctant to take medication, which has led to irregular treatment adherence and frequent relapses. Altogether, he has been admitted 18 times since 2006, with an average of twice a year. Thirteen of these admissions were to the acute unit of the Department of Psychiatry in Zamora Hospital, making a total of 256 days. The remaining 5 admissions were to the convalescence unit of the same department, involving a total of 41 days. This is strong proof of the great complexity and difficulty in achieving clinical stabilization of the patient. Moreover, keeping the patient in the inpatient care unit became an almost constant need from the months of November 2014 to March 2015, due to the combination of poor clinical response and the numerous side effects of the medication.\n\nMental Status Examination (March 2015)\nThe patient was conscious and well oriented, but showed partial insight. He suffered from reduced cognitive capacity, with cognitive slowing, inattention and distractibility. His mood oscillated from euphoria and grandiosity to irritability and dysphoria, which made his personal approach inappropriate. He exhibited pressure of speech, with racing thoughts and, occasionally, flight of ideas, which caused his communication to be incoherent. He felt restless, with episodes of psychomotor agitation and frequent verbal and physical aggressiveness, disruptive behaviour, and no sense of social distance. He had global impressions of severe insomnia, although he did not complain about it because he did not feel tired. He denied experiencing hallucinations or delusional thoughts, but revealed clear megalomaniac feelings and expressions.\n\nInvestigations\nAn electroencephalographic record conducted in March 2006 showed normal bioelectric brain activity. In May 2012, the results of a simple contrast computed tomography scan reported no abnormal findings.\n\nPharmacological Treatment\nThe poor and short lasting response to pharmacological treatment has led the patient to undergo different drug trials, combining mood stabilizers (lithium, valproic acid and carbamazepine), antipsychotics and benzodiazepines. Haloperidol and atypical antipsychotics such as risperidone, olanzapine, paliperidone, quetiapine, aripiprazole or asenapine have been tested, the latter specifically indicated for the treatment of moderate to severe acute mania associated with bipolar disorder. Poor efficacy and tolerability (including weight gain, metabolic disorders, sexual dysfunction and persistent sedation) were present throughout most of the antipsychotic treatment. This situation became more apparent during the months of January, February and March 2015, when the patient was admitted on an almost continuous basis (Table 1).\n\nOne of the reasons for antipsychotic treatment failure is poor compliance secondary to tolerability issues. In fact, the patient’s family suggested it as a possibility and, therefore, the first readmission was attributed to this problem. However, this probability was ruled out by supervising medication intake during the admissions.\n\nAccordingly, a pharmacogenetic study was requested in March 2015, after performing a theoretical drug interaction analysis to assess the different pathways involved in the metabolism of the prescribed drugs and to identify the enzymes’ corresponding drug substrate. The genes eligible for genotyping analysis were identified according to this complex theoretical analysis. In this case, we conducted a molecular analysis of gene variants CYP2B6 (*6 ), CYP2C9 (*2,*3 ), CYP2C19 (*2,*3,*17 ), CYP2D6 (*2, *3,*4,*5,*6,*7,*8,*9,*10,*12,*14,*17,*29,*41, XN ), CYP3A4 (*1B ), CYP3A5 (*3 ) and MDR1 (3435 C>T ) (Table 2). The DNA sample was obtained from peripheral blood extraction and the analysis was performed using a Compaq MagnaPure system. CYP2D6 genotyping was performed using microarrays (Infinity, AutoGenomics, Palex, Spain) after PCR amplification. For other genes, a real-time PCR method was used, alongside fluorescence resonance energy transfer (FRET)-probe assays to define fusion curves.\n\nThe pharmacogenetic study showed a possible decrease in the expression of MDR1 transport protein/multidrug resistance protein (heterozygous genotype carrier of allele T of 3435 C>T of MDR1 gene). A genotype associated with low efficiency of CYP2B6 (G/T), CYP2C9 (*1/*2) and CYP3A5 (G/G) was also identified. By contrast, CYP2D6 (alleles *1/*41), CYP2C19 (*1/*1) and CYP3A4 (A/A) were identified, which gives cause to expect an efficient metabolism of the enzymes encoded by these genes.\n\nAfter several months of near-constant admissions and different drug trials, the lack of clinical response led to a complex polypharmacologic treatment plan (Table 1). Guided by the theoretical interaction assessment and the results yielded by a pharmacogenetic analysis, the treatment regimen was modified:\n\nClonazepam, which can interact with carbamazepine and olanzapine via 2B6 (altered in this patient) and 3A4, was changed to lorazepam, which is not metabolized via the CYP 450 pathway. This was later discontinued.\n\nPaliperidone was then suspended due to low tolerability, partly caused by low expression of the efflux transporter MDR1 alteration, which increase bioavailability and brain levels of paliperidona.19)\n\nOlanzapine was also discontinued due to lack of response and side effects, mainly sedation and weight gain. This could be related to MDR1 and 2C9 alteration in this patient, as well as to interaction with carbamazepine and nicotine via 1A2.\n\nCarbamazepine was stopped because of its adverse effect profile (sedation, liver function impairment) and global induction of hepatic metabolism, in this case olanzapine and clonazepam metabolism induction.\n\nThe lithium dosage was maintained at 1,600 mg/day.\n\nAripiprazole was started at a medium-dose of 15 mg/day.\n\nAfterwards, as the patient started to show signs of a depressive episode, he was started on bupropion, which he took for several months at a dose of 300 mg/day.\n\nThe ultimate goal was to improve the metabolic profile associated to polypharmacy and thereby the efficacy of the treatment, also reducing its side effects, especially weight gain, sedation and apathy.\n\nDuring the two months following modification of the treatment regimen, a progressive overall clinical improvement became apparent, as well as a reduction of side effects.\n\nFive months after starting progressive medication changes based on the pharmacogenetic study, a more simplified treatment (Table 3) was found to be effective in relieving the patient’s symptoms: he regained euthymia, recovered his normal functional behaviour and mental organization, and showed more initiative and an improvement in cognitive performance.\n\nSimilarly, irritability and insomnia disappeared.\n\nIn terms of healthcare resource consumption and overall recovery of functionality, the patient has not required any further hospital admissions; he is living with his parents and has become more involved in both household and social activities.\n\nDISCUSSION\nAntipsychotic treatment efficacy can be influenced by clinical, environmental and social factors, thus explaining the high interindividual variability in drug response and tolerability.\n\nSuch heterogeneity in response can also be associated with genetic factors. Consequently, pharmacogenetic studies should be considered when prescribing drugs that are metabolized via cytochrome P450 or use protein transporter such as MDR1. Similarly, the assessment of the pharmacological effect will depend on whether or not the drug is administered as a prodrug.20)\n\nRegarding the current case, we would like to highlight three elements: 1) a severe and prolonged manic episode with persistent disabling symptoms that required admission for more than five months, and poor therapeutic response; 2) low tolerance to medication with significant side effects and, consequently, poor adherence to treatment21); and 3) large consumption of healthcare resources, with 89 days of hospitalization over the last five months.\n\nP450 CYP1A2 Induction\nPrior to the pharmacogenetic study, we assessed the pattern of theoretical drug interactions in the patient and found two potential stimulators of metabolism: nicotine and carbamazepine, which have been described as inducers of the activity of these enzymes. Specifically, carbamazepine can induce the expression of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP3A4 and CYP3A5. Tobacco consumption, on the other hand, can induce CYP1A1 and CYP1A2. The inductive effect on CYP1A2 by both carbamazepine and nicotine could accelerate the metabolism and, thus, reduce both the efficacy and adverse effects of psychotropic drugs using CYP1A2 (the main metabolism pathway of olanzapine).22) From this point of view, it is also tempting to interpret high tobacco consumption as an attempt to reduce the powerful drug induced side effects suffered by the patient. The potential consequences of this CYP1A2 induction could be: 1) decreased plasma levels of olanzapine, with a reduction of plasma concentration/dose ratio of up to 36%23) that could explain therapeutic resistance; and 2) olanzapine metabolism impairment leading to a variation in the 4-N-desmethylolanzapine-olanzapine ratio that could justify the significant olanzapine related side effects observed in this case. It should be noted that the pharmacokinetics of olanzapine is affected by a wide interindividual variability, resulting in a large variation in plasma concentrations of olanzapine for a same dose, so that an individualized dosage is required to avoid both the occurrence of side effects associated with plasma concentrations (obesity, increased intake, sedation), and therapeutic resistance.24)\n\nLow Efficiency of CYP2C9, CYP2B6 and CYP3A5\nThe pharmacogenetic study revealed that the patient is a carrier of genetic variants that predict low efficiency of CYP2C9, CYP2B6 and CYP3A5. In addition, the inhibitory effect of olanzapine on CYP2C19, CYP2C9 and CYP3A4 could cause phenocopy, which would lead to an accumulation of drug metabolized by these pathways, and thus increase the severity of adverse effects.\n\nMDR1 Genetic Variant\nAnother remarkable result yielded by genetic analysis is the detection of a variation of the Efllux transporter MDR1 pump (heterozygotic genotype carrier of the allele of 3435 C>T polymorphism of MDR1 gene) that could predict significant variation in its efficiency.25) The MDR1 gene encodes P-gp, an ATP-dependent membrane transport protein that regulates the bioavailability of multiple drugs.25) The presence of a T allele suggests an impairment of gene-expression that could increase brain levels of drugs that use this carrier pump. It’s the case of paliperidona which is substrate of MDR1 and its disposition is influenced by the functional status of MDR1.19)\n\nIn fact, this mutation has been found to be related to the severity of symptomatology, indicated by higher scores on the Positive and Negative Syndrome Scale.26) In general, most antipsychotics act as P-gp inhibitors and can thus influence both plasma and brain drug concentrations.27) The existence of polymorphic variations of P-gp modifies the bioavailability of psychoactive drugs27) and the 3435C>T variant has been observed to correlate with raised plasma concentrations of paliperidone.20)\n\nRegarding this, olanzapine, and paliperidone to some extent, could compete with other drugs and effectively block MDR1, causing elevated brain concentrations of drugs whose efflux is inhibited. Nevertheless, paliperidone is not metabolized by P450 cytochrome complex.28) However, the inhibitory effect of olanzapine on CYP3A enzyme, as previously mentioned, combined with MDR1 pump alteration, can cause an increase in drug interactions, as proved by in vitro tests.29) This justifies discontinuation of paliperidone in this patient, since, although it does not interfere with CYP1A2, CYP2C9, and CYP3A5 isoenzymes, it is a substrate for the MDR1 pump, which could make it difficult to control their bioavailability.\n\nAccordingly, it seems that patients with this genotype taking olanzapine have greater needs of social and mental health care.30) Furthermore, dose-related concentrations of olanzapine in plasma and cerebrospinal fluid significantly increase, which would also contribute to the side effects observed in this patient.31)\n\nCYP3A4 and CYP2D6\nFinally, the pharmacogenetic study indicates that CYP3A4 and CYP2D6 have a pattern of efficient metabolism. CYP2D6 is responsible for the oxidative metabolism of up to 25% of drugs, such as antidepressants, antipsychotics, opioids, antiarrhythmic agents and tamoxifen in its prodrug form. Its activity is highly variable, being primarily responsible for defining patients as extensive, deficient, intermediate or ultrarapid metabolizers.32) This great variability is explained, at least partly, because it is an enzyme whose genetic locus can have more than 100 variants and sub-variants.33,34) However, in this case it does not seem to play a significant role, as it has little effect on olanzapine plasma concentrations24) and does not participate in the metabolism of paliperidone. Thus, despite the great importance of this enzyme in the metabolism of psychotropic drugs, it does not play a role in the clinical situation of this patient.\n\nTo summarize, the results of the pharmacogenetic study helped us to redefine a new therapeutic plan in a more rational way.\n\nFirst, we tried to liberate the most compromised enzymes, namely CYP1A2, CYP2C9, CYP2C19 and CYP3A4, by eliminating olanzapine.\n\nSecondly, although paliperidone has a better side effects profile and does not use the P450 pathway, its toxicity may be explained by the MDR1 alteration, which made discontinuation advisable.\n\nThirdly, aripiprazole was selected as the best antipsychotic option because of its good metabolic profile, fewer sedative effects and the fact that it is not affected by MDR1 pump dysfunction.35) Thus, the medication plan was simplified and the daily dose reduced (lithium 1,200 mg/day, and aripiprazole, 15 mg/day).\n\nFinally, the choice of bupropion as an antidepressant was based on its clinical profile, as it has fewer effects on the sexual sphere, can help to reduce nicotine consumption and its interaction potential with antipsychotics is low.22) Bupropion and aripiprazole are both partly metabolized by CYP2D6, which functioned normally in this patient.36) Nonetheless, it is known that when this enzyme is inhibited, bupropion can be metabolized by other routes.37) In addition, bupropion is not affected by CYP2C9 genotypic alterations and can still use CYP2C19 enzyme for its metabolism, so its use in this patient was expected to produce clinical benefits and few tolerance problems.38) Most importantly, bupropion is considered to carry a low risk of inducing mania, especially when it is taken in combination with lithium.39)\n\nOn the other hand, bupropion could inhibit aripiprazole metabolism, raising the latter’s plasma concentrations to up to 45%,40,41) so it would be prudent to use a low-medium dose of aripiprazole while combined with bupropion.\n\nA last important consideration is that none of the psychotropic drugs used in the final prescription plan is influenced by MDR1 dysfunctionality.\n\nThese results highlight the important contribution clinical pharmacogenetic studies make towards predicting responses to psychotropics and understanding individual variation in such clinical response to these drugs.42,43) In addition, this case is an example where pharmacogenetic assessment has a significant impact on reducing costs of mental health care. This has also been observed in other studies, in which cost reduction by the use of pharmacogenetic studies can reach up to 28%44) and, hence, guidelines recommend its use to reduce the high costs associated to mental health care.8,44)\n\nIn our experience, pharmacogenetic analysis proved a very useful guide in choosing an appropriate treatment plan to manage this complex clinical case. Therefore, its use with patients with a history of poor response and extreme or unusual intolerance to standard drug treatment, once plausible explanations are ruled out, is worth considering.20) Incorporating pharmacogenetic assessment to clinical practice would be useful to optimize pharmacological treatment of mental disorders13) and provide a more personalized therapeutic approach, based on the growing knowledge of the function and effect of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of psychotropic drugs.45) Certainly, other genes can be involved and more studies are needed to assess the implications of different factors in the efficacy, tolerability and interindividual variability of response to psychiatric drugs.46) Pharmacogenetics provides a useful tool for further progress towards offering a more personalized medicine, which is particularly necessary in complex clinical cases like the one reported.47)\n\nTable 1 Treatment plan in March 2015, prior to pharmacogenetic analysis\n\nDrug\tCytochrome P450\t\n\n\t\n1A1\t1A2\t1B1\t2A6\t2B6*\t2C8\t2C9*\t2C19\t2D6\t2E1\t3A4\t3A5*\t3A7\t4B1\tNo CYP\tMDR1*\t\nClonazepam\t\t\t\t\tInd\t\t\t\t\t\tS\t\t\t\t\t\t\n\t\t\t\t\tInh\t\t\t\t\t\t\t\t\t\t\t\t\nLithium\t\t\t\t\t\t\t\t\t\t\t\t\t\t\tS\t\t\nCarbamazepine\t\tS\t\tInd\tS\tS\tInd\tInd\t\t\tS\tS\tS\t\t\t\t\n\t\tInb\t\t\tInd\tInd\t\tInh\t\t\tInd\tInd\t\t\t\t\t\n\t\tInd\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nPaliperidone\t\t\t\t\t\t\t\t\t\t\t\t\t\t\tX\tX\t\nOlanzapine\t\tS\t\t\t\t\tInh\tInh\tS\t\tInh\t\t\t\t\tX\t\n\t\t\t\t\t\t\t\t\tInh\t\t\t\t\t\t\t\t\nNo CYP, no use of P450 pathway; Ind, inductor; Inh, inhibitor; S, substrate.\n\n* Enzymes altered in this patient.\n\nTable 2 Pharmacogenetic analysis: genes tested, alleles identified and expected effect on protein function\n\nGene\tAlleles studied\tGenotype\tExpected phenotype\t\nCYP2B6\t*6\tG/T\tDecreased\t\nCYP2C9\t*2,*3\t*1/*2\tDecreased\t\nCYP2C19\t*2,*3,*17\t*1/*1\tNormal\t\nCYP2D6\t*2,*3,*4,*5,*6, *7,*8,*9,*10,*12,*14,*17,*29,*41, XN\t*1/*41\tNormal\t\nCYP3A4\t*1B\tA/A\tNormal\t\nCYP3A5\t*3C\tG/G\tDecreased\t\nMDR1\t3435C>T\tC/T\tDecreased\t\nTable 3 Treatment plan based on pharmacogenetic analysis\n\nDrug\tCytochrome P450\t\n\n\t\n1A1\t1A2\t1B1\t2A6\t2B6*\t2C8\t2C9*\t2C19\t2D6\t2E1\t3A4\t3A5*\t3A7\t4B1\tNo CYP MDR1*\t\nAripiprazole\t\t\t\t\t\t\t\t\tS Ind Inh\t\tS\tS\tS\t\t\t\nLithium\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nBupropion\t\tS\t\t\tS Inh\tS\tS\t\tS Inh\tS\tS\t\t\t\t\t\nInd, inductor; Inh, inhibitor; S, substrate; No CYP, no use of P450 pathway.\n\n* Enzymes altered in this patient.\n==== Refs\nREFERENCES\n1 Kodesh A Goldshtein I Gelkopf M Goren I Chodick G Shalev V Epidemiology and comorbidity of severe mental illnesses in the community: findings from a computerized mental health registry in a large Israeli health organization Soc Psychiatry Psychiatr Epidemiol 2012 47 1775 1782 10.1007/s00127-012-0478-9 22310700 \n2 Angst J Paksarian D Cui L Merikangas KR Hengartner MP Ajdacic-Gross V The epidemiology of common mental disorders from age 20 to 50: results from the prospective Zurich cohort study Epidemiol Psychiatr Sci 2016 25 24 32 10.1017/S204579601500027X 25802979 \n3 Nuss P de Carvalho W Blin P Arnaud R Filipovics A Loze JY Treatment practices in the management of patients with bipolar disorder in France. The TEMPPO study Encephale 2012 38 75 85 French 10.1016/j.encep.2011.11.002 22381727 \n4 Costa e Silva JA Personalized medicine in psychiatry: new technologies and approaches Metabolism 2013 62 Suppl 1 S40 S44 10.1016/j.metabol.2012.08.017 23018148 \n5 Samer CF Lorenzini KI Rollason V Daali Y Desmeules JA Applications of CYP450 testing in the clinical setting Mol Diagn Ther 2013 17 165 184 10.1007/s40291-013-0028-5 23588782 \n6 Nivoli AM Colom F Pacchiarotti I Murru A Scott J Valentí M Treatment strategies according to clinical features in a naturalistic cohort study of bipolar patients: a principal component analysis of lifetime pharmacological and biophysic treatment options Eur Neuropsychopharmacol 2013 23 263 275 10.1016/j.euroneuro.2012.07.015 22939529 \n7 Bernardo M Vieta E Saiz Ruiz J Rico-Villademoros F Alamo C Bobes J Grupo RECAP Recommendations for switching antipsychotics. A position statement of the Spanish Society of Psychiatry and the Spanish Society of Biological Psychiatry Rev Psiquiatr Salud Ment 2011 4 150 168 Spanish 10.1016/j.rpsm.2011.07.003 23446195 \n8 U.S. Food and Drug Administration Table of pharmacogenomic biomarkers in drug labeling [Internet] Silver Spring, MD U.S. Food and Drug Administration 2015 [cited at 2015 Jul 27]. Available from: http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm \n9 Winner J Allen JD Altar CA Spahic-Mihajlovic A Psychiatric pharmacogenomics predicts health resource utilization of outpatients with anxiety and depression Transl Psychiatry 2013 3 e242 10.1038/tp.2013.2 23511609 \n10 Stingl JC Brockmöller J Viviani R Genetic variability of drug-metabolizing enzymes: the dual impact on psychiatric therapy and regulation of brain function Mol Psychiatry 2013 18 273 287 10.1038/mp.2012.42 22565785 \n11 Hiemke C Pfuhlmann B Interactions and monitoring of antipsychotic drugs Handb Exp Pharmacol 2012 212 241 265 10.1007/978-3-642-25761-2_10 23129335 \n12 Ravyn D Ravyn V Lowney R Nasrallah HA CYP450 pharmacogenetic treatment strategies for antipsychotics: a review of the evidence Schizophr Res 2013 149 1 14 10.1016/j.schres.2013.06.035 23870808 \n13 Cacabelos R Martínez-Bouza R Genomics and pharmacogenomics of schizophrenia CNS Neurosci Ther 2011 17 541 565 10.1111/j.1755-5949.2010.00187.x 20718829 \n14 Nakamura A Mihara K Nemoto K Nagai G Kagawa S Suzuki T Lack of correlation between the steady-state plasma concentrations of aripiprazole and haloperidol in Japanese patients with schizophrenia Ther Drug Monit 2014 36 815 818 10.1097/FTD.0000000000000082 24739668 \n15 Eiermann B Engel G Johansson I Zanger UM Bertilsson L The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine Br J Clin Pharmacol 1997 44 439 446 10.1046/j.1365-2125.1997.t01-1-00605.x 9384460 \n16 Trenton A Currier G Zwemer F Fatalities associated with therapeutic use and overdose of atypical antipsychotics CNS Drugs 2003 17 307 324 10.2165/00023210-200317050-00002 12665390 \n17 Zhang JP Malhotra AK Pharmacogenetics and antipsychotics: therapeutic efficacy and side effects prediction Expert Opin Drug Metab Toxicol 2011 7 9 37 10.1517/17425255.2011.532787 21162693 \n18 Ingelman-Sundberg M Sim SC Gomez A Rodriguez-Antona C Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects Pharmacol Ther 2007 116 496 526 10.1016/j.pharmthera.2007.09.004 18001838 \n19 Zhu HJ Wang JS Markowitz JS Donovan JL Gibson BB DeVane CL Risperidone and paliperidone inhibit p-glycoprotein activity in vitro Neuropsychopharmacology 2007 32 757 764 10.1038/sj.npp.1301181 16936711 \n20 Suzuki Y Tsuneyama N Fukui N Sugai T Watanabe J Ono S Impact of the ABCB1 gene polymorphism on plasma 9-hydroxyrisperidone and active moiety levels in Japanese patients with schizophrenia J Clin Psychopharmacol 2013 33 411 414 10.1097/JCP.0b013e31828ecd52 23609388 \n21 Perera V Gross AS Polasek TM Qin Y Rao G Forrest A Considering CYP1A2 phenotype and genotype for optimizing the dose of olanzapine in the management of schizophrenia Expert Opin Drug Metab Toxicol 2013 9 1115 1137 10.1517/17425255.2013.795540 23641727 \n22 Dervaux A Laqueille X Tobacco and schizophrenia: therapeutic aspects Encephale 2007 33 629 632 French 10.1016/S0013-7006(07)92064-3 18033154 \n23 Olesen OV Linnet K Olanzapine serum concentrations in psychiatric patients given standard doses: the influence of comedication Ther Drug Monit 1999 21 87 90 10.1097/00007691-199902000-00013 10051059 \n24 Söderberg MM Dahl ML Pharmacogenetics of olanzapine metabolism Pharmacogenomics 2013 14 1319 1336 10.2217/pgs.13.120 23930678 \n25 Wang D Johnson AD Papp AC Kroetz DL Sadée W Multidrug resistance polypeptide 1 (MDR1, ABCB1) variant 3435C>T affects mRNA stability Pharmacogenet Genomics 2005 15 693 704 10.1097/01.fpc.0000178311.02878.83 16141795 \n26 Almoguera B Riveiro-Alvarez R Lopez-Castroman J Dorado P Vaquero-Lorenzo C Fernandez-Piqueras J CYP2D6 poor metabolizer status might be associated with better response to risperidone treatment Pharmacogenet Genomics 2013 23 627 630 10.1097/FPC.0b013e3283659a94 24026091 \n27 Moons T de Roo M Claes S Dom G Relationship between P-glycoprotein and second-generation antipsychotics Pharmacogenomics 2011 12 1193 1211 10.2217/pgs.11.55 21843066 \n28 de Leon J Wynn G Sandson NB The pharmacokinetics of paliperidone versus risperidone Psychosomatics 2010 51 80 88 10.1016/S0033-3182(10)70664-2 20118446 \n29 Yasuda K Lan LB Sanglard D Furuya K Schuetz JD Schuetz EG Interaction of cytochrome P450 3A inhibitors with P-glycoprotein J Pharmacol Exp Ther 2002 303 323 332 10.1124/jpet.102.037549 12235267 \n30 Alenius M Wadelius M Dahl ML Hartvig P Lindström L Hammarlund-Udenaes M Gene polymorphism influencing treatment response in psychotic patients in a naturalistic setting J Psychiatr Res 2008 42 884 893 10.1016/j.jpsychires.2007.10.007 18086475 \n31 Skogh E Sjödin I Josefsson M Dahl ML High correlation between serum and cerebrospinal fluid olanzapine concentrations in patients with schizophrenia or schizoaffective disorder medicating with oral olanzapine as the only antipsychotic drug J Clin Psychopharmacol 2011 31 4 9 10.1097/JCP.0b013e318204d9e2 21192135 \n32 Gaedigk A Complexities of CYP2D6 gene analysis and interpretation Int Rev Psychiatry 2013 25 534 553 10.3109/09540261.2013.825581 24151800 \n33 Mas S Gassò P Alvarez S Parellada E Bernardo M Lafuente A Intuitive pharmacogenetics: spontaneous risperidone dosage is related to CYP2D6, CYP3A5 and ABCB1 genotypes Pharmacogenomics J 2012 12 255 259 10.1038/tpj.2010.91 21173786 \n34 Gaedigk A Riffel AK Berrocal BG Solaesa VG Dávila I Isidoro-García M Characterization of a complex CYP2D6 genotype that caused an AmpliChip CYP450 Test no-call in the clinical setting Clin Chem Lab Med 2014 52 799 807 10.1515/cclm-2013-0943 24445243 \n35 Suzuki T Mihara K Nakamura A Kagawa S Nagai G Nemoto K Effects of genetic polymorphisms of CYP2D6, CYP3A5, and ABCB1 on the steady-state plasma concentrations of aripiprazole and its active metabolite, dehydroaripiprazole, in Japanese patients with schizophrenia Ther Drug Monit 2014 36 651 655 10.1097/FTD.0000000000000070 24682161 \n36 Sager JE Tripathy S Price LS Nath A Chang J Stephenson-Famy A In vitro to in vivo extrapolation of the complex drug-drug interaction of bupropion and its metabolites with CYP2D6; simultaneous reversible inhibition and CYP2D6 downregulation Biochem Pharmacol 2017 123 85 96 10.1016/j.bcp.2016.11.007 27836670 \n37 Benowitz NL Zhu AZ Tyndale RF Dempsey D Jacob P 3rd Influence of CYP2B6 genetic variants on plasma and urine concentrations of bupropion and metabolites at steady state Pharmacogenet Genomics 2013 23 135 141 10.1097/FPC.0b013e32835d9ab0 23344581 \n38 Zhu AZ Zhou Q Cox LS Ahluwalia JS Benowitz NL Tyndale RF Gene variants in CYP2C19 are associated with altered in vivo bupropion pharmacokinetics but not bupropion-assisted smoking cessation outcomes Drug Metab Dispos 2014 42 1971 1977 10.1124/dmd.114.060285 25187485 \n39 Pacchiarotti I Bond DJ Baldessarini RJ Nolen WA Grunze H Licht RW The International Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders Am J Psychiatry 2013 170 1249 1262 10.1176/appi.ajp.2013.13020185 24030475 \n40 Castberg I Spigset O Effects of comedication on the serum levels of aripiprazole: evidence from a routine therapeutic drug monitoring service Pharmacopsychiatry 2007 40 107 110 10.1055/s-2007-977715 17541885 \n41 Waade RB Christensen H Rudberg I Refsum H Hermann M Influence of comedication on serum concentrations of aripiprazole and dehydroaripiprazole Ther Drug Monit 2009 31 233 238 10.1097/FTD.0b013e3181956726 19142178 \n42 Brandl EJ Chowdhury NI Tiwari AK Lett TA Meltzer HY Kennedy JL Genetic variation in CYP3A43 is associated with response to antipsychotic medication J Neural Transm (Vienna) 2015 122 29 34 10.1007/s00702-014-1298-8 25150845 \n43 Kim KA Joo HJ Lee HM Park JY Influence of ABCB1 and CYP3A5 genetic polymorphisms on the pharmacokinetics of quetiapine in healthy volunteers Pharmacogenet Genomics 2014 24 35 42 10.1097/FPC.0000000000000020 24240480 \n44 Herbild L Andersen SE Werge T Rasmussen HB Jürgens G Does pharmacogenetic testing for CYP450 2D6 and 2C19 among patients with diagnoses within the schizophrenic spectrum reduce treatment costs? Basic Clin Pharmacol Toxicol 2013 113 266 272 10.1111/bcpt.12093 23731498 \n45 Ackenheil M Weber K Differing response to antipsychotic therapy in schizophrenia: pharmacogenomic aspects Dialogues Clin Neurosci 2004 6 71 17 22034253 \n46 Marazziti D Baroni S Picchetti M Piccinni A Carlini M Vatteroni E Pharmacokinetics and pharmacodynamics of psychotropic drugs: effect of sex CNS Spectr 2013 18 118 127 10.1017/S1092852912001010 23374978 \n47 Wilffert B Swen J Mulder H Touw D Maitland-Van der Zee AH Deneer V KNMP working group Pharmacogenetics From evidence based medicine to mechanism based medicine. Reviewing the role of pharmacogenetics Int J Clin Pharm 2011 33 3 9 10.1007/s11096-011-9485-2 21365387\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1738-1088",
"issue": "16(3)",
"journal": "Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology",
"keywords": "Antipsychotic drugs; Bipolar disorder; Cytochrome P450; Individualized medicine.; Pharmacogenetics",
"medline_ta": "Clin Psychopharmacol Neurosci",
"mesh_terms": null,
"nlm_unique_id": "101207332",
"other_id": null,
"pages": "349-357",
"pmc": null,
"pmid": "30121988",
"pubdate": "2018-08-31",
"publication_types": "D002363:Case Reports",
"references": "12665390;10051059;24151800;24030475;22310700;21162693;23018148;22939529;23511609;24739668;23374978;23344581;23641727;16936711;24445243;25802979;22381727;9384460;18033154;18001838;23446195;23129335;21192135;19142178;21365387;22034253;17541885;12235267;21843066;22565785;16141795;25187485;25150845;23588782;18086475;23609388;20718829;24240480;23731498;23870808;24026091;21173786;24682161;27836670;20118446;23930678",
"title": "Usefulness of Pharmacogenetic Analysis in Psychiatric Clinical Practice: A Case Report.",
"title_normalized": "usefulness of pharmacogenetic analysis in psychiatric clinical practice a case report"
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"abstract": "Post-transplant lymphoproliferative disorders are rare but potentially life-threatening complication of HSCT. Although not frequently reported but PTLD can occur as a late post-transplant complication in HSCT recipients. A high index of suspicion should be kept for early diagnosis of these disorders as delay in diagnosis can have catastrophic implications.",
"affiliations": "Armed forces Bone marrow transplant centre Rawalpindi Pakistan.;Armed forces Bone marrow transplant centre Rawalpindi Pakistan.;Armed forces Bone marrow transplant centre Rawalpindi Pakistan.;Armed forces Bone marrow transplant centre Rawalpindi Pakistan.;Armed forces Bone marrow transplant centre Rawalpindi Pakistan.",
"authors": "Iftikhar|Raheel|R|https://orcid.org/0000-0001-8767-3491;Un Nisa Chaudhry|Qamar|Q|;Satti|Tariq Mehmood|TM|;Kamran Mahmood|Syed|S|;Ghafoor|Tariq|T|",
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"doi": "10.1002/ccr3.2095",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.2095CCR32095Case ReportCase ReportsPostallogeneic stem cell transplant Hodgkin lymphoma: Rare presentation of an uncommon occurrence RAHEEL et al.iftikhar Raheel https://orcid.org/0000-0001-8767-3491drraheeliftikhar@gmail.com \n1\nUn nisa Chaudhry Qamar \n1\nSatti Tariq Mehmood \n1\nKamran Mahmood Syed \n1\nGhafoor Tariq \n1\n\n1 \nArmed forces Bone marrow transplant centre\nRawalpindi\nPakistan\n* Correspondence\n\nRaheel Iftikhar, Armed forces Bone marrow transplant centre, Rawalpindi Pakistan.\n\nEmail: drraheeliftikhar@gmail.com\n18 6 2019 7 2019 7 7 10.1002/ccr3.2019.7.issue-71442 1444 28 12 2018 09 2 2019 13 2 2019 © 2019 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\nKey Clinical Message\n\nPost‐transplant lymphoproliferative disorders are rare but potentially life‐threatening complication of HSCT. Although not frequently reported but PTLD can occur as a late post‐transplant complication in HSCT recipients. A high index of suspicion should be kept for early diagnosis of these disorders as delay in diagnosis can have catastrophic implications.\n\naplastic anemiaEpstein‐Barr VirusHodgkin lymphoma source-schema-version-number2.0component-idccr32095cover-dateJuly 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.6.6.1 mode:remove_FC converted:18.07.2019\n\n\nRaheel \nI \n, \nUn nisa Chaudhry \nQ \n, \nSatti \nTM \n, \nKamran Mahmood \nS \n, \nGhafoor \nT \n. Postallogeneic stem cell transplant Hodgkin lymphoma: Rare presentation of an uncommon occurrence . Clin Case Rep . 2019 ;7 :1442 –1444 . 10.1002/ccr3.2095\n==== Body\n1 INTRODUCTION\nPost‐transplant lymphoproliferative disorder (PTLD) is rarely reported in matched sibling donor (MSD) transplants of aplastic anemia (AA), and occurrence of Hodgkin lymphoma in this subgroup is extremely uncommon. Our patient, a 7‐year‐old girl, underwent MSD transplant for AA and developed EBV‐driven Hodgkin lymphoma after tapering of immunosuppression.\n\nPost‐transplant lymphoproliferative disorders (PTLDs) represent heterogenous groups of clonal disorders occurring after solid organ and hematopoietic stem cell transplantation. Most of PTLDs are EBV driven and have a frequency of 3.2% in stem cell transplant recipients and 1.1% in matched sibling donor (MSD) transplants.1 Risk factors of PTLD include unrelated donor and haploidentical transplants, use of T‐cell depleting conditioning and higher recipient age. The underlying mechanism is failure of newly instituted donor immune system to control EBV‐infected host cells due to profound T‐cell immune suppression.\n\nEpstein‐Barr Virus (EBV) DNA monitoring is done in these high‐risk patients to detect reactivation of EBV and institution of pre‐emptive measures like reduction of immunosuppression and treatment with rituximab. There are only few case reports of PTLD in patients of AA undergoing MSD transplant2 but to our knowledge this is first reported case of EBV‐driven Hodgkin lymphoma occurring after tapering of immunosuppression in patient undergoing MSD HSCT for AA.\n\n2 CASE REPORT\nA 7‐year‐old girl presented with 1‐week history of high‐grade fever and gum bleeding. There was no significant past medical history. She was born to consanguineous parents at full term by spontaneous vaginal delivery and was vaccinated as per immunization schedule. There was no family history of bleeding disorder, bone marrow failure, or hematological malignancy. On clinical examination, she had gum bleeding. There was no palpable lymphadenopathy or visceromegaly. Complete blood counts showed pancytopenia with hemoglobin of 6.2 g/dL, absolute neutrophil count (ANC) 0.3 × 109/L, and platelet count of 8 × 109/L. Bone marrow examination showed hypocellular marrow with 10 percent cellularity, absence of abnormal infiltrate or reticulin fibrosis, consistent with severe aplastic anemia. Cytogenetics was normal 46 XX, screening for Fanconi anemia, paroxysmal nocturnal hemoglobinuria, and secondary causes of aplastic anemia including viral serology, autoimmune profile, and thyroid profile were all negative. She underwent allogeneic stem cell transplant with her fully HLA matched brother. There was no ABO mismatch, and both donor and recipient were seropositive for cytomegalovirus (CMV) and Epstein‐Barr Virus (EBV). Conditioning regimen used was cyclophosphamide 200 mg/kg and Thymoglobulin 10 mg/kg, and cyclosporine was given for graft versus host disease (GVHD) prophylaxis. She achieved neutrophil engraftment on day + 14 and had uncomplicated early post‐transplant course except for febrile neutropenia. Her late post‐transplant course was also uneventful, and she had secure trilineage engraftment with complete donor chimerism and adequate B‐cell and T‐cell immune reconstitution by 1 year post‐transplant. Tapering of immunosuppression was started at 1 year and was stopped at 14 months post‐transplant.\n\nFour weeks after stopping immunosuppression, she was seen in outpatient clinic with high‐grade fever and bilateral submandibular and cervical lymphadenopathy. Complete blood counts showed pancytopenia with WBC 0.95 × 109/L, hemoglobin 9.7 g/dL, and platelets 43 × 109/L. Contrast enhanced CT scan showed bilateral cervical, submandibular, mediastinal, and abdominal lymphadenopathy.\n\nBone marrow examination revealed markedly hypocellular marrow consistent with secondary graft rejection and PCR for short tandem repeats showed 50% donor Chimerism. Her PCR for cytomegalovirus (CMV), adenovirus, and human herpes virus‐6 (HHV‐6) were all negative. PCR for Epstein‐Barr virus (EBV) was positive (86 000 copies) demonstrating EBV reactivation. Excisional biopsy of cervical lymph node showed Hodgkin disease (Mixed cellularity type). Immunohistochemistry showed weak positive CD45, strong positivity for CD15, CD30, and PAX 5 in Reed‐Sternberg cells, and CD20 and EBV positivity in background cellular infiltrate. CD10 and BCL‐2 were negative. These findings were consistent with EBV‐associated post‐transplant lymphoproliferative disorder (HD stage III‐B) and secondary graft rejection. Treatment was started with Rituximab and COPDAC chemotherapy for Hodgkin lymphoma. She had an initial response which was documented by regression of lymph nodes but her pancytopenia persisted and repeat STRs after 4 weeks showed only 10 percent donor chimerism. She developed febrile neutropenia and multi‐organ dysfunction syndrome requiring broad‐spectrum parenteral antibiotics, amphotericin B, G‐CSF, granulocyte transfusions, intravenous immunoglobulin, and antiviral treatment. Her repeat PCR for EBV was negative 4 weeks later, and chemotherapy was continued. Despite aggressive management, her multi‐organ dysfunction worsened, and she could not be salvaged and expired.\n\n3 DISCUSSION\nEpstein‐Barr Virus belongs to human herpes‐4 (HHV4) family and is a double‐stranded DNA virus. Seropositivity of more than 90% is documented before adult life. It infects B cells via interaction with surface CD21 and gp350 glycoprotein and assumes latency after primary infection.3 Profound immunosuppression postallogeneic HSCT leads to activation of LMP1‐mediated proliferative signals via nuclear factor kappa B pathway. Moreover, BHFR1 exerts a BCL‐2 like activity and blocks apoptosis giving proliferative advantage and malignant transformation of EBV‐infected cells.4 PTLD post‐HSCT are almost exclusively EBV related and carries high mortality ranging from 35% to 80%.5 Haploidentical and unrelated HSCT, T‐cell depletion, GVHD, and high recipient age are well‐documented risk factors for PTLD in HSCT recipients. As per WHO 2017 classification, PTLD is categorized into six types: three types of nondestructive PTLD (plasmacytic hyperplasia, infectious mononucleosis‐like PTLD, and florid follicular hyperplasia), polymorphic PTLD, monomorphic PTLD, and classic Hodgkin lymphoma‐like PTLD. Most of PTLD in HSCT recipients develop 2‐4 months post‐transplant and only 4% occur after 12 months6 (as seen in our patient).\n\nAs per ECIL‐6 guidelines, risk for EBV‐PTLD can be classified as low risk (auto‐HSCT), standard risk (MSD allo‐HSCT without high risk factors, haplo‐PTCy HSCT), and high risk (MSD with at least one risk factor, MUD, alternative donors including CBT).7 ECIL recommends that EBV seropositivity testing should be done for both donor and recipient before HSCT. Post‐transplant serial monitoring with EBV DNA PCR needs to be done, starting at 4 weeks post‐transplant and continuing weekly till 4 months post‐HSCT. Longer monitoring may be needed for patients with active GVHD, haploidentical HSCT and for patients with poor T‐cell reconstitution post‐transplant. In many institutional guidelines, viral load of more than 10 000 copies/mL is considered for pre‐emptive treatment with rituximab and tapering of immunosuppression.8\n\n\nTherapeutic approaches for EBV‐PTLD includes administration of Rituximab, reduction of immunosuppression, donor lymphocyte infusions, EBV‐specific cytotoxic T‐lymphocytes (CTL) and chemotherapy for specific PTLD. As per ECIL guidelines, patients with standard risk for PTLD do not require pre‐emptive EBV DNA PCR monitoring, and our patient fell in standard risk category, but developed fatal PTLD highlighting variable presentation of PTLD and a need to reconsider high‐risk criteria for PTLD.\n\nOur case is unusual in number of aspects; it is one of few cases of PTLD in AA patients; it developed late post‐transplant, occurred after tapering of immunosuppression, and associated with secondary graft rejection; and histological type was Hodgkin lymphoma, which is least common type of PTLD. EBV reactivation was most likely responsible for malignant transformation of B cells and secondary graft failure as evident by clinical signs and symptoms and high titer EBV viral load.\n\nCONFLICT OF INTEREST\nNone declared.\n\nAUTHOR CONTRIBUTION\nRI: collected data, involved in medical writing, and reference citation. QU nC and TG: collected data and involved in medical writing. TMS and SKM: contributed to reference citation and collected data.\n==== Refs\nREFERENCES\n1 \n\nStyczynski \nJ \n, \nGil \nL \n, \nTridello \nG \n, et al. Response to rituximab‐based therapy and risk factor analysis in Epstein Barr virus related lymphoproliferative disorder after hematopoietic stem cell transplant in children and adults: a study from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation . Clin Infect Dis . 2013 ;57 :794 ‐802 .23771985 \n2 \n\nMashima \nK \n, \nYano \nS \n, \nYokoyama \nH \n, et al. Epstein‐Barr Virus‐associated lymphoproliferative disorder with encephalitis following anti‐thymocyte globulin for aplastic anemia resolved with rituximab therapy: a case report and literature review . Intern Med . 2017 ;56 (6 ):701 ‐706 .28321074 \n3 \n\nDunmire \nSK \n, \nHogquist \nKA \n, \nBalfour \nHH \n. Infectious Mononucleosis . Curr Top Microbiol Immunol . 2015 ;390 :211 .26424648 \n4 \n\nPatriarca \nF \n, \nMedeot \nM \n, \nIsola \nM \n, et al. Prognostic factors and outcome of EpsteinBarr virus DNAemia in high‐risk recipients of allogeneic stem cell transplantation treated with preemptive rituximab . Transpl Infect Dis . 2013 ;15 (3 ):259 ‐267 .23405972 \n5 \n\nvan der Velden \nW \n, \nMori \nT \n, \nStevens \nW \n, et al. Reduced PTLD‐related mortality in patients experiencing EBV infection following Allo‐SCT after the introduction of a protocol incorporating pre‐emptive rituximab . Bone Marrow Transplant . 2013 ;48 (11 ):14651471 .\n6 \n\nFox \nCp \n, \nBurns \nD \n, \nParker \nAn \n, et al. EBV‐associated post‐transplant lymphoproliferative disorder following in vivo T‐cell‐depleted allogeneic transplantation: clinical features, viral load correlates and prognostic factors in the rituximab era . Bone Marrow Transplant . 2014 ;49 (2 ):280 ‐286 .24212561 \n7 \n\nStyczynski \nJ \n, \nvan der Velden \nW \n, \nFox \nCP \n, et al. Management of Epstein‐Barr Virus infections and post‐transplant lymphoproliferative disorders in patients after allogeneic hematopoietic stem cell transplantation: Sixth European Conference on Infections in Leukemia (ECIL‐6) guidelines . Haematologica . 2016 ;101 (7 ):803 ‐811 .27365460 \n8 \n\nGarcía‐Cadenas \nI \n, \nCastillo \nN \n, \nMartino \nR \n, et al. Impact of Epstein Barr virus‐related complications After high‐risk allo‐SCT in The era of pre‐emptive rituximab . Bone Marrow Transplant . 2015 ;50 (4 ):579 ‐584 .25581404\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-0904",
"issue": "7(7)",
"journal": "Clinical case reports",
"keywords": "Epstein‐Barr Virus; Hodgkin lymphoma; aplastic anemia",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "1442-1444",
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"pmid": "31360508",
"pubdate": "2019-07",
"publication_types": "D002363:Case Reports",
"references": "23405972;23749107;23771985;24212561;25581404;26424648;27365460;28321074",
"title": "Postallogeneic stem cell transplant Hodgkin lymphoma: Rare presentation of an uncommon occurrence.",
"title_normalized": "postallogeneic stem cell transplant hodgkin lymphoma rare presentation of an uncommon occurrence"
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"companynumb": "PK-BEH-2019105349",
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"abstract": "Androgen receptor-mediated transcription is directly coupled with the induction of DNA damage, and castration-resistant tumor cells exhibit increased activity of poly (ADP-ribose) polymerase (PARP)-1, a DNA repair enzyme. This study assessed the efficacy and safety of low dose oral PARP inhibitor veliparib (ABT-888) and temozolomide (TMZ) in docetaxel-pretreated patients with metastatic castration-resistant prostate cancer (mCRPC) in a single-arm, open-label, pilot study. Patients with mCRPC progressing on at least one docetaxel-based therapy and prostate specific antigen (PSA) ≥ 2 ng/mL were treated with veliparib 40 mg twice daily on days 1-7 and TMZ once daily (150 mg/m(2)/day cycle 1; if well tolerated then 200 mg/m(2)/day cycle 2 onwards) on days 1-5 q28 days. Patients received 2 (median) treatment cycles (range, 1-9). The primary endpoint was confirmed PSA response rate (decline ≥ 30 %). Twenty-six eligible patients were enrolled, 25 evaluable for PSA response. Median baseline PSA was 170 ng/mL. Two patients had a confirmed PSA response (8.0 %; 95 % CI: 1.0-26.0), 13 stable PSA, and 10 PSA progression. The median progression-free survival was 9 weeks (95 % CI: 7.9-17) and median overall survival 39.6 weeks (95 % CI: 26.6-not estimable). The most frequent treatment-emergent adverse events (AEs) were thrombocytopenia (77 %), anemia (69 %), fatigue (50 %), neutropenia (42 %), nausea (38 %), and constipation (23 %). Grade 3/4 AEs occurring in > 10 % of patients were thrombocytopenia (23 %) and anemia (15 %). Veliparib and TMZ combination was well tolerated but with modest activity. Biomarker analysis supported the proof of concept that this combination has some antitumor activity in mCRPC.",
"affiliations": "Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA, mahahuss@med.umich.edu.",
"authors": "Hussain|Maha|M|;Carducci|Michael A|MA|;Slovin|Susan|S|;Cetnar|Jeremy|J|;Qian|Jiang|J|;McKeegan|Evelyn M|EM|;Refici-Buhr|Marion|M|;Chyla|Brenda|B|;Shepherd|Stacie P|SP|;Giranda|Vincent L|VL|;Alumkal|Joshi J|JJ|",
"chemical_list": "D001562:Benzimidazoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; D003606:Dacarbazine; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen; D000077204:Temozolomide",
"country": "United States",
"delete": false,
"doi": "10.1007/s10637-014-0099-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-6997",
"issue": "32(5)",
"journal": "Investigational new drugs",
"keywords": null,
"medline_ta": "Invest New Drugs",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D001562:Benzimidazoles; D004260:DNA Repair; D003606:Dacarbazine; D006801:Humans; D007610:Kallikreins; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017430:Prostate-Specific Antigen; D064129:Prostatic Neoplasms, Castration-Resistant; D000077204:Temozolomide; D016896:Treatment Outcome",
"nlm_unique_id": "8309330",
"other_id": null,
"pages": "904-12",
"pmc": null,
"pmid": "24764124",
"pubdate": "2014-10",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "17060676;17404082;16622120;17473206;19047122;9207086;11948190;15317891;19934293;20823142;21575865;22496272;20609467;21385925;10854140;21436403;19553641;19081770;19213602;9549229;19035287;21282543;18563191;22307137;21680196;20406929;20609468;1907096;12727891;18456354;19364967;10655437;21571912;16254181;22993403;10858306;19143569;11339428;10767627;20601956",
"title": "Targeting DNA repair with combination veliparib (ABT-888) and temozolomide in patients with metastatic castration-resistant prostate cancer.",
"title_normalized": "targeting dna repair with combination veliparib abt 888 and temozolomide in patients with metastatic castration resistant prostate cancer"
} | [
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"activesubstance": {
"activesubstancename": "VELIPARIB"
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{
"abstract": "BACKGROUND\nNormalization of cortisol concentration by multikinase inhibitors have been reported in three patients with medullary thyroid cancer-related Cushing's syndrome. Aortic dissection has been reported in three patients with Cushing's syndrome. Diabetes insipidus without intrasellar metastasis, intestinal intussusception, and paraneoplastic dysautonomia have not been reported in medullary thyroid cancer.\n\n\nMETHODS\nAn adult male with metastatic medullary thyroid cancer presented with hyperglycemia, hypernatremia, hypokalemia, hypertension, acne-like rash, and diabetes insipidus (urine volume >8 L/d, osmolality 190 mOsm/kg). Serum cortisol, adrenocorticoitropic hormone, dehydroepiandrostenedione sulfate, and urinary free cortisol were elevated 8, 20, 4.4, and 340 folds, respectively. Pituitary imaging was normal. Computed tomography scan revealed jejunal intussusception and incidental abdominal aortic dissection. Sorafenib treatment was associated with Cushing's syndrome remission, elevated progesterone (>10 fold), normalization of dehydroepiandrostenedione sulfate, but persistently elevated cortisol concentration. Newly-developed proximal lower limb weakness and decreased salivation were associated with elevated ganglionic neuronal acetylcholine receptor (alpha-3) and borderline P/Q type calcium channel antibodies.\n\n\nCONCLUSIONS\nExtreme cortisol concentration may have contributed to aortic dissection and suppressed antidiuretic hormone secretion; which combined with hypokalemia due cortisol activation of mineralocorticoid receptors, manifested as diabetes insipidus. This is the first report of paraneoplastic dysautonomia and jejunal intussusception in medullary thyroid cancer, they may be related to medullary thyroid cancer's neuroendocrine origin and metastasis, respectively. Remission of Cushing's syndrome without measurable reduction in cortisol concentration suggests a novel cortisol-independent mechanism of action or assay cross-reactivity. Normalization of dehydroepiandrostenedione sulfate and elevation of progesterone suggest inhibition of 17-hydroxylase and 21-hydroxylase activities by sorafenib.",
"affiliations": "Departments of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. Muhammad@kfshrc.edu.sa.;Departments of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. dr.duaiji@hotmail.com.;Departments of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. almutairighazi@gmail.com.;Departments of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. sabahalaklabi@gmail.com.;Departments of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. alqattan98@gmail.com.;Departments of Radiology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. MAboutaleb@kfshrc.edu.sa.;Departments of Neurosciences, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. msous@kfshrc.edu.sa.",
"authors": "Hammami|Muhammad M|MM|;Duaiji|Najla|N|;Mutairi|Ghazi|G|;Aklabi|Sabah|S|;Qattan|Nasser|N|;Abouzied|Mohei El-Din M|Mel-D|;Sous|Mohamed W|MW|",
"chemical_list": "D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; D006854:Hydrocortisone",
"country": "England",
"delete": false,
"doi": "10.1186/s12885-015-1620-3",
"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 26354794162010.1186/s12885-015-1620-3Case ReportCase report of severe Cushing’s syndrome in medullary thyroid cancer complicated by functional diabetes insipidus, aortic dissection, jejunal intussusception, and paraneoplastic dysautonomia: remission with sorafenib without reduction in cortisol concentration Hammami Muhammad M. +966-1-442-4527Muhammad@kfshrc.edu.sa 12Duaiji Najla dr.duaiji@hotmail.com 1Mutairi Ghazi almutairighazi@gmail.com 1Aklabi Sabah sabahalaklabi@gmail.com 1Qattan Nasser alqattan98@gmail.com 1Abouzied Mohei El-Din M. MAboutaleb@kfshrc.edu.sa 3Sous Mohamed W. msous@kfshrc.edu.sa 41 Departments of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia 2 Departments of Clinical Studies and Empirical Ethics, King Faisal Specialist Hospital and Research Centre, P O Box # 3354 (MBC 03), Riyadh, 11211 Saudi Arabia 3 Departments of Radiology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia 4 Departments of Neurosciences, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia 9 9 2015 9 9 2015 2015 15 6249 3 2015 21 8 2015 © Hammami et al. 2015Open 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\nNormalization of cortisol concentration by multikinase inhibitors have been reported in three patients with medullary thyroid cancer-related Cushing’s syndrome. Aortic dissection has been reported in three patients with Cushing’s syndrome. Diabetes insipidus without intrasellar metastasis, intestinal intussusception, and paraneoplastic dysautonomia have not been reported in medullary thyroid cancer.\n\nCase presentation\nAn adult male with metastatic medullary thyroid cancer presented with hyperglycemia, hypernatremia, hypokalemia, hypertension, acne-like rash, and diabetes insipidus (urine volume >8 L/d, osmolality 190 mOsm/kg). Serum cortisol, adrenocorticoitropic hormone, dehydroepiandrostenedione sulfate, and urinary free cortisol were elevated 8, 20, 4.4, and 340 folds, respectively. Pituitary imaging was normal. Computed tomography scan revealed jejunal intussusception and incidental abdominal aortic dissection. Sorafenib treatment was associated with Cushing’s syndrome remission, elevated progesterone (>10 fold), normalization of dehydroepiandrostenedione sulfate, but persistently elevated cortisol concentration. Newly-developed proximal lower limb weakness and decreased salivation were associated with elevated ganglionic neuronal acetylcholine receptor (alpha-3) and borderline P/Q type calcium channel antibodies.\n\nConclusion\nExtreme cortisol concentration may have contributed to aortic dissection and suppressed antidiuretic hormone secretion; which combined with hypokalemia due cortisol activation of mineralocorticoid receptors, manifested as diabetes insipidus. This is the first report of paraneoplastic dysautonomia and jejunal intussusception in medullary thyroid cancer, they may be related to medullary thyroid cancer’s neuroendocrine origin and metastasis, respectively. Remission of Cushing’s syndrome without measurable reduction in cortisol concentration suggests a novel cortisol-independent mechanism of action or assay cross-reactivity. Normalization of dehydroepiandrostenedione sulfate and elevation of progesterone suggest inhibition of 17-hydroxylase and 21-hydroxylase activities by sorafenib.\n\nissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nCushing’s syndrome (CS) refers to signs and symptoms caused by excessive glucocorticoids action through glucocorticoid and occasionally mineralocorticoid receptors. Ectopic adrenocorticotropic hormone (ACTH) secretion accounts for < 10 % of CS; [1] up to 7.5 % of which are due to medullary thyroid cancer (MTC) [2, 3].\n\nDiabetes insipidus (DI) has been reported in two patients with ectopic CS and sellar metastasis [4, 5]. Although glucocorticoids can suppress antidiuretic hormone (ADH) secretion, DI has not been reported in CS without sellar lesions, possibly due to compensatory renal mechanisms [6].\n\nMTC arises from neuroendocrine calcitonin-producing parafollicular C cells of the thyroid gland; it ectopically secrets ACTH in about 0.6 % of patients [7]. Three case reports described successful treatment of ectopic CS in MTC patients with multikinase inhibitors; in all cases, CS remission was associated with reduction in cortisol concentration [8–10].\n\nCardiovascular complications are rather common in CS; however, aortic dissection has been reported in only three cases [11]. Intestinal intussusception is rare in adults and is secondary to a pathological condition in 90 % of cases [12]. It has not been reported in MTC patients. Paraneoplastic dysautonomia has been associated with neuroendocrine tumors other than MTC [13].\n\nWe report a case of severe CS in a patient with metastatic MTC, which was complicated by DI without sellar lesion, silent aortic dissection, jejunal intussusception, and dysautonomia. Interestingly, sorafenib was associated with remission of CS without measurable reduction in cortisol concentration.\n\nCase presentation\nCase report\nA 30-year old male with MTC presented with 3-week history of severe polyuria, nocturia, polydipsia, salty taste, skin rash, insomnia, and delusion. He denied vomiting, diarrhea, pain, dyspnea, cough, and fever.\n\nHe was referred about 4.5 years earlier after having total thyroidectomy that showed multifocal MTC with cervical lymph nodes metastasis. His past medical and surgical history was otherwise unremarkable. He had no family history of MTC, other tumors, or consanguinity, and negative screening for pheochromocytoma, hyerparathyroidism, and germline RET (rearranged during transfection) oncogene mutation. Calcitonin and carcinoembryonic antigen (CEA) were >5850 pmol/L (normal, <5.5) and 506 μg/L (normal, <4.3), respectively. Over the following year, he underwent bilateral neck dissection for extensive regional lymph node metastasis followed by external radiation. Computed tomography (CT) scan showed normal liver and bilateral pulmonary metastases. Calcitonin and CEA decreased to 1430 pmol/L and 287 μg/L and then increased to 5290 pmol/L and 544 μg/L, respectively, 4 months prior to admission. One year before admission, random glucose was 5.22 mmol/L.\n\nOn admission (day one), he was afebrile and appeared severely dehydrated. Pulse was 125/min, blood pressure 145/90 mmHg (previous readings, 100–110/65–75), and body mass index 20.9 kg/m2. He had multiple facial erythematous papules and few pustules but no moon face, centripetal obesity, supraclavicular fullness, cervical fat pad, striae, easy bruising, or stigmata of chronic liver disease except for non-tender hepatomegaly. He had normal muscle power and deep tendon reflexes. White blood cell (WBC) count was 21.7×109/L (80 % neutrophils), creatinine 52 μmol/L (normal, <115), potassium 2.1 mmol/L (normal, 3.5–5.0), sodium 148 mmol/L (normal, 135–147), CO2 27 mmol/L (normal, 22–31), glucose 25.7 mmol/L, albumin 35 g/L (normal, 32–48), total bilirubin 12 μmol/L (normal, <21), alanine aminotransaminase (ALT) 199 U/L (normal, 10–45), aspartate aminotransferase (AST) 117 U/L (normal, 10–45), alkaline phosphatase 216 U/L (normal, 40–135), venous blood pH 7.49 (normal, 7.30–7.40), CEA 3643 μg/L, calcitonin 1800 pmol/L, and glycated hemoglobin 0.07 (normal, <0.065). Insulin, intravenous fluid and potassium replacement, enoxaparin 40 mg/d, and topical acne treatment were started, and levothyroxine 150 μg, vitamin D3 2000 unit, and calcium carbonate 1200 mg daily were continued.\n\nUrine output was consistently >8 L/d, while plasma and urine osmolality were 296/310 (normal, 275–300) and 189/190 mOsm/kg, respectively; and sodium, potassium, glucose, and urea 154/148, 2.9/2.8, 21.5/14.5, and 2.6/2.3 (normal, 4.2–4.2) mmol/L, respectively. Intranasal desmopressin (DDAVP) 40 μg/d reduced urine output to 4.85 L/d (sodium, potassium, and glucose were 149, 3.5, and 12.1 mmol/L, respectively).\n\nOn day 5, cortisol and ACTH were 3782 nmol/L (normal, 171–536) and 872 ng/L (normal, 5–60; to convert to pmol/L multiply by 0.22), respectively, urinary free cortisol 129,204 nmo (normal, 100–379), dehydroepiandrostenedione sulfate (DHEAS) 50.8 μmol/L (normal, 4.42–11.50), dehydroepiandrostenedione (DHEA) 12 ng/mL (Mayo Medical Laboratories (MML), Mayo Clinic, Rochester, MN; normal, <13; to convert to nmol/L multiply by 3.47), androstendione >35 nmol/L (normal, 2.4-12.6), renin 19.6 mU/L (normal, 4.4–46.1), and aldosterone < 8 ng/dL (MML; normal, < 21; to convert to nmol/L multiply by 0.277). 8-mg dexamethasone suppression test showed a paradoxical increase in cortisol to 4279 nmol/L. Urinary potassium was >100 mmol/d with plasma potassium of 3.3 mmol/L.\n\nCT scan showed 1.8 cm pretracheal lymph node, bilateral hilar lymphadenopathy, 1.4 cm left paracardiac lymph node, progression of lung metastases bilaterally (largest 3 cm), new liver metastases (largest 5x5 cm with central necrosis and hemorrhage), enlarged adrenal glands (Fig. 1a), and short segment of dissection in abdominal aorta with thrombosed false lumen (Fig. 1b). Aortic dissection was managed conservatively by enoxaparin and blood pressure control. Fluorodeoxyglucose (FDG) positron emission tomography (PET)-CT scan showed multiple hypermetabolic liver and lung lesions and diffuse bilateral hypermetabolic adrenal activity (Fig. 1c). Pituitary magnetic resonance imaging (MRI) was normal (Fig. 1d).Fig. 1 Major radiological findings. a Trans axial images of enhanced computed tomography (CT) of the abdomen showing: hypodense liver lesions in both lobes (the largest is located in segment IV adjacent to porta hepatis, white arrow), and bilateral adrenal hyperplasia (black arrows). b Aortic dissection below the level of renal arteries (white arrow head) extending to the left and right common iliac arteries (white arrows). c FDG PET-CT scan showing multiple hyper metabolic liver lesions (white arrow head), lung metastasis involving the left paracardiac area (black arrow), and diffuse bilateral hyper metabolic activity within the adrenal gland (white arrows). d Sagittal and axial (post contrast) T1 weighted MRI images showing normal pituitary gland. e Trans axial image of enhanced computed CT of the abdomen showing jeujenal intussusception\n\n\n\nEscalating doses of insulin (up to 87 U/d), spironolactone (up to 450 mg/d), oral and intravenous potassium (up to 340 mmol/d), amlodipine (up 10 mg/d), and carvedilol (up to 25 mg/d) were required to control CS (Fig. 2a&b). Adrenalectomy was not offered because of aortic dissection/thrombosis necessitating anticoagulation. Ketoconazole and mitotane were not used because of liver dysfunction, and metyrapone because of severe hypokalemia. Sorafinib 400 mg twice daily was started on day 10 (vandetanib and cabozantinib were unavailable). DDAVP was stopped because it may stimulate ectopic ACTH secretion; four days later, urine output increased to 7.8 L/d with ADH of 3.3 pg/mL (MML; normal, 0.0-6.9; to convert to pmol/L multiply by 0.926), plasma and urine osmolality of 311 and 522 mOsm/kg, respectively, and sodium, potassium, and glucose of 149, 3.5, and 14.8 mmol/L, respectively.Fig. 2 Main treatments and clinical and laboratory findings over the course of hospitalization. a Daily doses of spironolactone (mg, open triangles), sorafenib (mg, closed triangles), mifepristone (mg, closed squares), potassium chloride (mmol potassium, open squares), and insulin (units, open circles). b Daily doses of carvedilol (mg, open squares) and amlodipine (mg, closed squares). c Concentrations of cortisol (nmol/L, closed squares), carcinoembryonic antigen (CEA, μg/L, open squares), calcitonin (pmol/L, closed circles), adrenocorticoitropic hormone (ACTH, ng/L, open circles; values greater than 2000 ng/dL are reported as 2000 ng/L; multiply by 0.22 to convert to pmol/L), and renin (mU/L, closed triangles). Aldosterone was < 8 and < 4 ng/L (multiply by 0.277 to convert to nmol/L) on days 5 and 36, respectively. d Mean daily concentration of sodium (mmol/L, closed triangles), mean daily measurements of systolic (mmHg, open triangles) and diastolic blood pressure (mmHg, open squares), and concentration of dehydroepiandrosterone sulfate (DHEAS, closed squares, μmol/L). Dehydroepiandrosterone (DHEA) was 12 and 3.9 ng/mL on days 8 and 25, respectively (multiply by 3.47 to convert to nmol/L). Progesterone was 40.4 and 42.2 nmol/L on days 40 and 43, respectively. 17-hydroxyprogestrone was 6.2 nmol/L on day 40. e Mean daily concentration of glucose (mmol/L, closed squares) and potassium (mmol/L, open squares). f Concentrations of alkaline phosphatase (U/L, closed squares), alanine aminotransaminase (ALT, U/L, open squares), aspartate aminotransferase (AST, U/L, open circles), and total bilirubin (μmol/L, closed circles). Prothrombin time was 15.4, 17.4, 22.1, 31.5, and 37.6 s on days 16, 27, 36, 43, 48, respectively. Albumin was 35, 32, and 19.7 g/L on days 1, 21, and 41, respectively\n\n\n\nOn day 15, he developed dyspnea, cough, mild hemoptysis, and oxygen desaturation without fever. Echocardiography was normal. CT scan showed no evidence of pulmonary embolism and new diffuse bronchial-wall thickening and multiple patchy ground-glass opacities. WBC was 13.6×109 (94 % neutrophils). Sputum culture was positive for streptococcus pneumonia. Procalcitonin concentration was 110 ng/mL (normal, <0.5; severe bacterial infection, >2.0). He was treated vancomycin followed by ceftriaxone (till day 42). 99mTc-Octreotide scan revealed that the liver and lung lesions were not octreotide avid.\n\nOn day 20, because of no measurable changes in ACTH and cortisol concentrations and development of proximal lower limb weakness (could get up from chair unassisted with difficulty), mifepristone 300 mg/d was started. At that time, blood pressure was 141/89 mmHg and sodium, potassium, and glucose 151, 3.6, and 7.8 mmol/L, respectively.\n\nOn day 25, CEA concentration decreased to 3019 μg/L, calcitonin to 1530 pmol/l (Fig. 2c), DHEAS to 23.96 μmol/L (Fig. 2d), and DHEA to 3.9 ng/ml (Fig. 2c). Further, blood pressure normalized to 118/78 mmHg and sodium, potassium, and glucose to 145, 4.3, and 7.5 mmol/L, respectively (Fig. 2d&e). However, cortisol and ACTH did not decrease (3911 nmol/L, 1664 ng/L, respectively) (Fig. 2c), and androstenedione continued to be >35 nmol/L. Renin was 22.1 mU/L.\n\nOn day 27, he complained of intermittent colicky abdominal pain increasing in severity and frequency, loss of appetite, and generalized fatigability in association with low normal blood pressure and glucose despite reducing insulin and amlodipine doses. Procalcitonin concentration was 281 ng/ml. Adrenal insufficiency was suspected, mifepristone discontinued, and intravenous dexamethasone given for 5 days (initially 8 mg/d) without remarkable improvement. The abdominal pain was treated with fentanyl patch supplemented with intravenous morphine. CT scan showed bilateral pleural effusion, reduction in the left paracardiac lymph node to 1 cm with central necrosis, mild reduction in the size of liver metastases, ascites, patent portal vein, no evidence of biliary dilatation, no change in the appearance of aortic dissection or adrenal glands, and jejuno-jejunal intussusception (Fig. 1e) with fecal loading without evidence of bowel obstruction.\n\nOn day 34, proximal lower limb weakness progressed to the degree that he was bed-bound, despite remarkable control of CS manifestations (Fig. 2c-e), and was associated with loss of deep tendon reflexes. There was no muscle pain, tenderness, atrophy, or post-exercise facilitation. Electrolytes were normal. The unexplained weakness together with the development of difficulty in swallowing due to reduced salivation (requiring saliva substitute every four hours, modified barium swallow evaluation was normal), difficulty in urination, constipation, and rather unexplained postural tachycardia prompted investigations for neurological autoimmunity. A paraneoplastic autoantibody screen revealed elevated neuronal ganglionic acetylcholine (alpha-3) autoantibodies of 0.12 nmol/L and borderline P/Q type calcium channel autoantibodies of 0.02 nmol/L (MML; normal, <0.02), consistent with autoimmune dysautonomia. Nerve conduction and repetitive nerve stimulation studies were unremarkable (23 % amplitude increment with 30 stimuli/s). Electromyography of the right anterior tibial and vastus medialis muscles showed reduction in mean amplitude (0.13 and 0.15 mV, normal 0.22 and 0.23 mV, respectively) and duration (8.5 and 8.8 ms, normal 13.1 and 10.9 ms, respectively). 25 Hydroxyvitamin D was 15 nmol/L, free T4 6.4 pmol/L (normal, 12–22), thyroid stimulating hormone (TSH) 1.27 mU/L (normal, 0.27–4.20), and parathyroid hormone (PTH) 20.5 ng/L (normal, 15–65; to convert to pmol/L multiply by 0.1061).\n\nDespite persistently elevated ACTH and cortisol, starting on day 20, insulin and potassium doses had to be tapered off to avoid hypoglycemia and hyperkalemia (Fig. 2a&e). Further, mifepristone which was restarted on day 34 at 200 mg/d had to be decreased to 100 mg/d after 7 days to be stopped 2 days later (Fig. 2a). Similarly, starting on day 30, amlodipine and carvedilol had to be tapered off to avoid hypotension (Fig. 2b). Spironolactone was reduced gradually to 100 mg/d on day 41 (continued for ascites and lower limb edema) (Fig. 2a). By day 31, urine output normalized and he had mild hyponatremia. On day 37, ADH was 3.9 pg/ml, plasma and urine osmolality 284 and 552 mOsm/kg, respectively, and sodium, potassium, glucose, and urea 133, 4.8, 5.33, and 5.7 nmol/L, respectively. Renin increased to 385 and 757 mU/L on days 37 and 46, respectively (Fig. 2c). DHEAS decreased to 9.85 μmol/L on day 46 (Fig. 2d). On day 40, progesterone and 17-hydroxyprogestrone concentrations were 40.4 nmol/L (normal for adult males, 0.7–4.3) and 6.2 nmol/L, respectively. On day 43 progesterone was 42.2 nmol/L. To verify the persistently elevated cortisol, a split sample was sent to another laboratory (competitive binding immunoenzymatic assay, MML). Cortisol was 4170 nmol/L in our laboratory and 114 μg/dL (normal, 7–25; to convert to nmol/L multiply by 27.6) in the other, representing 7.8 vs. 4.6 fold increase over upper limits, respectively.\n\nLiver function tests deteriorated sequentially, starting with an increase in alkaline phosphatase and total (direct) bilirubin followed by a decrease in albumin, prolongation of prothrombin time, and an increase in ALT and AST (Fig. 2f). Screening for hepatitis A, B, and C was negative. Liver US/Doppler showed enlarged liver studded with metastatic disease, patent main portal vein with sluggish flow, flow reversal within the left portal and splenic veins, and no biliary dilatation.\n\nOn day 42, he had desaturation, sputum grew pseudomonas, and procalcitonin was >500 ng/ml. Sorafenib and mifepristone were stopped and intravenous dexamethasone was given. Liver function tests continued to deteriorate and hemoglobin dropped to 87 g/L. He died on day 49 due to cardiopulmonary arrest despite intravenous antibiotics and fresh frozen plasma, red blood cell, and albumin infusions.\n\nLaboratory investigations were performed by our Department of Pathology and Laboratory Medicine except as indicated. Cortisol, ACTH, and DHEAS were measured by electrochemiluminescence immunoassay (Elecsys cortisol, ACTH, DHEAS kits, respectively, Roche Diagnostics, Indianapolis, IN) on cobas e analyzer following manufacturer’s specifications. Androstenedione was measured by solid-phase enzyme-labeled chemiluminescence immunoassay (DPC Immulite andorostenedione kit, Diagnostic Products Corporation, Los Angeles, CA) on DPC automated immunoassay system following manufacturer’s specifications.\n\nDiscussion\nThe unique features of this unfortunate case of sporadic MTC and ectopic ACTH CS include: 1) exceedingly elevated urinary free cortisol, 2) reversible combined neurogenic and nephrogenic DI, 3) CS remission with sorafenib without measurable reduction in cortisol concentration, 4) abdominal aortic dissection, 5) jejuno-jejunal intussusception, 6) development of autoantibodies against neuronal ganglionic acetylcholine receptor, and 7) development of acute liver failure.\n\nCS refers to signs and symptoms caused by excessive glucocorticoids action through glucocorticoid and occasionally mineralocorticoid receptors. Ectopic CS occurs in 0.6 % of MTC patients, usually with advanced disease [7]. As expected, our patient had liver and lung metastasis and markedly elevated tumor markers. However, his exceedingly high serum cortisol and urinary free cortisol were unusual. Further, despite florid derangements related to activation of mineralocorticoid and androgen receptors, hyperglycemia was the only glucocorticoid receptor-related abnormality. Having normoglycemia prior to admission and normal BMI and mildly elevated glycated hemoglobin on admission, indicated that the hyperglycemia was CS-induced and suggested that the other glucocorticoid receptor-related manifestations of CS may take longer time to develop. Severe hypokalemia and hyperkaliuria were likely due to activation of mineralocorticoid receptors by elevated cortisol that evaded inactivation by 11-beta-hydroxysteroid dehydrogenase.\n\nThe polyuria in our patient was not explained by hyperglycemia as it persisted after its correction and was associated with low urine osmolality. Further, the degree and persistence of polyuria were more than expected from the degree of hypokalemia, suggesting a neurogenic DI component. This was confirmed by a partial response to DDAVP, recurrence after stopping DDAVP, and an ADH that was inappropriately in the low normal range. DI was reported in two MTC patients without CS [4, 5] and in two patients with small-cell lung cancer and CS [14, 15]. In all cases there was intrasellar metastasis. Pituitary MRI in our patient was normal, suggesting functional neurogenic DI. As little as 30 mg prednisolone for 5 days inhibited osmotically-stimulated ADH secretion, however, urine osmolar concentration was unaffected; perhaps due to ADH-independent renal compensatory mechanisms [6]. We postulate that elevated cortisol in our patient caused ADH suppression and hypokalemia prevented the proposed compensatory mechanisms. Interestingly, after blocking cortisol action and correction of hypokalemia, urine output normalized and mild hyponatremia developed.\n\nThis is the first reported case of failure of elevated cortisol to decrease in MTC-related CS treated with multikinase inhibitors. In the two cases treated with vandetanib [8, 9] and one case treated with sorafenib [10], cortisol normalized within a week. Nevertheless, CS was reversed in our patient, necessitating discontinuation of the previously-required, large doses of potassium, spironolactone, antihypertensives, and insulin. Although mifepristone may have played a role in diabetes mellitus remission, it could not explain remission of hypertension and hypokalemia, its dose was relatively small, and diabetes mellitus remission persisted despite its withdrawal.\n\nThe mechanisms underlying reduction of cortisol concentration in this setting may be multifactorial. In one case, vandetanib resulted in simultaneous decrease in cortisol and calcitonin and a blunted response of ACTH to DDAVP without reduction in tumor size, suggesting a direct antisecretory action [8]. In another case, sorafenib reduced cortisol and ACTH with modest reduction in calcitonin and CEA, suggesting a selective inhibition of ACTH and cortisol secretion; reduction in POMC mRNA expression through MAPK pathway inhibition, ACTH action down-regulation by downstream signaling pathway inhibition, and adrenal ischemia were postulated [10]. In the third case, vandetanib resulted in sustained (26 months) normalization of cortisol and ACTH. However, a mild re-increase in ACTH without an increase in cortisol occurred while on vandetanib [9]. In our patient, there was a remarkable decrease in DHEAS and elevation in progesterone, suggesting a direct adrenal action of sorafenib, namely, 21-hydroxylase and 17-hydroxylase inhibition. Progesterone exhibits the same affinity as aldosterone for the human mineralocorticoid receptor, acting as antagonist [16]. It has antagonistic activity at the glucocorticoid receptor especially with reduced receptors number [17]. Despite >10 fold increase, progesterone would not effectively compete with prevailing cortisol in our patient, since both are equally protein-bound [16]. Nevertheless, we could not exclude a role of progesterone in CS remission because of the possibility of spuriously high cortisol concentration. For example, 21-deoxycortisol, which is elevated by 21-hydroxylase inhibition, had 45 % cross-reactivity in our cortisol immunoassay [18]. Further, cortisol concentration was increased 7.8 fold over upper normal limit in our immunoassay compared to 4.6 fold in another immunoassay. Much to our regret, we did not measure cortisol concentration by a more specific liquid chromatography assay or 21-deoxycortisol concentration. Finally, sorafenib was shown to down regulate wild type and c-terminally truncated (lacking ligand binding domain) androgen receptors in prostate cancer cells and to inhibit their signaling [19]. We postulate a similar action of sorafenib on mineralocorticoid and glucocorticoid receptors in our patient. It is of note that insulin-independent hypoglycemia was induced by sorafenib in a patient with hemangiopericytoma and was responsive to glucocorticoid treatment [20].\n\nAortic dissection has been reported in 3 men with CS, two with adrenal adenoma and one with pituitary adenoma; all three presented with dissection-related symptoms [11]. In our patient, aortic dissection was discovered accidently. The prevalence of silent aortic dissection in CS is not known as most cases of CS are due to exogenous glucocorticoids or Cushing’s disease and abdominal imaging is not performed. A causal relationship between elevated cortisol and aortic dissection can be postulated; cortisol could increase blood vessels fragility through negative effects on collagen formation and connective tissue strength. Acute elevation in blood pressure is another potentially contributing factor.\n\nIntestinal intussusception in adults is rare accounting for 5 % of all intussusceptions; most cases are secondary to lead lesions requiring surgical intervention; and presenting symptoms are usually chronic and nonspecific [12]. To the best of our knowledge, intestinal intussusception has not been reported in MTC, nor has intestinal metastasis. We postulate that the intussusception was the cause of the intermittent abdominal pain in our patient and that it was likely due to metastasis, however, functional intussusception cannot be excluded as a mass was not visualized.\n\nLambert-Eaton syndrome (LES), a rare neuromuscular transmission disorder, characterized by proximal muscle weakness, depressed deep tendon reflexes, post-tetanic potentiation, and autonomic dysfunction, is caused by autoimmunity against P/Q voltage-gated calcium channel [21, 22]. It is most commonly associated with small-cell lung cancer but has not been reported in MTC [22]. Our patient presented with normal power despite having profound hypokalemia and hypercortisolemia, started to have mild weakness 20 days later when hypokalemia was corrected, and his weakness rapidly progressed to the degree that he became bed-bound despite mifepristone treatment. Electrolytes and TSH were normal. 25- Hydroxyvitamin D concentration was low, however, this was likely due to low binding proteins since PTH and corrected calcium were normal, and he had been on 2000 U of vitamin D daily. Absence of deep tendon reflexes, markedly decreased salivation, and postural tachycardia suggested LES and autoimmune dysautonomia. We could not confirm LES diagnosis since repetitive stimulation testing was negative and P/Q voltage-gated calcium channel antibodies were only upper normal. However, electromyography revealed motor unit potentials of short duration and decreased amplitude as described in LES [23] and neuronal ganglionic acetylcholine receptor autoantibodies, the only proven effector of autoimmune dysautonomia [13], were markedly elevated; which to our knowledge has not been described in MTC.\n\nAnother challenge we encountered in managing the patient was related to using procalcitonin to diagnose bacterial infection. Elevated procalcitonin, in general, indicates bacterial infection [24]. However, procalcitonin was useless in our patient since it is elevated in MTC patients [25] and may be elevated in adrenal crisis [26].\n\nAbout 50 % of sporadic MTC carry RET gene somatic mutations, and RAS mutations are observed in about 50 % of RET-negative tumors [27]. The multikinase inhibitors, vandetanib and cabozantinib, were recently approved to treat symptomatic or progressive MTC [10]. Sorafenib was investigated in Phase II trials [28] and was successfully used to treat CS in MTC [10]. Since vandetanib and cabozantinib were not available in our institution, we treated our patient with sorafenib. There was an initial 15 % decrease in calcitonin and CEA and regression in some of the liver and lymph node metastasis within 17 days of treatment, however, calcitonin and CEA quickly rebounded and liver metastasis progressed.\n\nAcute liver failure, characterized by the development of jaundice, coagulopathy, and hepatic encephalopathy within 8 weeks in the absence of preexisting liver disease, was reported in a patient with liver metastasis from MTC [29]. Liver functions in our patient deteriorated rapidly over 7 weeks, while screening tests for hepatitis A, B, and C were negative. Although iatrogenic liver injury due to sorafenib could not be excluded, it is likely that progression of liver metastasis was the culprit as suggested by the results of hepatic ultrasound/Doppler results. Further, mild liver test abnormalities have been reported in <1 % of sorafenib treated patients, and severe acute hepatitis is very rare, usually of the hepatocellular type, and is associated with high fever and rash; [30] which was not the case in our patient.\n\nConclusions\nExtremely elevated cortisol may have contributed to aortic dissection, due to interference with collagen formation, and suppressed ADH secretion; which combined with hypokalemia due cortisol activation of the mineralocorticoid receptors, manifested as reversible combined neurogenic and nephrogenic DI. Paraneoplastic dysautonomia and jejunal intussusception have not been reported in MTC, they may be related to MTC’s neuroendocrine origin and metastasis, respectively. Remission of CS with sorafenib without measurable reduction in cortisol concentration suggests a novel cortisol-independent mechanism of action, such as down regulation of glucocorticoid and mineralocorticoid receptors or inhibition of their signaling. Alternatively, normalization of DHEAS and elevation of progesterone concentration suggest inhibition of 17-hydroxylase and 21-hydroxylase activities. The later could result in elevated 21-deoxycortisol that may be spuriously measured as cortisol in immunoassays. In addition, progesterone could block glucocorticoid and mineralocorticoid receptors depending on actual cortisol concentration. Further studies are required to explore potential effects of multikinase inhibitors on adrenal steroids synthesis and action, the prevalence of silent aortic dissection in CS, and the prevalence of paraneoplastic dyasautonomia in MTC.\n\nConsent\nWritten informed consent was obtained from the patient 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 of this journal.\n\nAbbreviations\nCSCushing’s syndrome\n\nACTHadrenocorticotropic hormone\n\nMTCMedullary thyroid cancer\n\nDIDiabetes insipidus\n\nADHAntidiuretic hormone\n\nRETRearranged during transfection\n\nCEACarcinoembryonic antigen\n\nCTComputed tomography\n\nWBCWhite blood cell\n\nALTAlanine aminotransaminase\n\nASTAspartate aminotransferase\n\nDDAVPDesmoprssin\n\nDHEASDehydroepiandrostenedione sulfate\n\nMMLMayo Medial Laboratories\n\nDHEADehydroepiandrostenedione\n\nMRIMagnetic resonance imaging\n\nFDGFluorodeoxyglucose\n\nPETPositron emission tomography\n\nTSHThyroid stimulating hormone\n\nPTHParathyroid hormone\n\nDPCDiagnostic products corporation\n\nPOMCProopiomelanocortin\n\nMAPKMitogen-activated protein kinase\n\nLESLambert-Eaton syndrome\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nMMH performed literature review and wrote the manuscript. ND, GM, SA, NQ and MWS participated in literature review. MMA prepared radiological images. All authors were involved in the management of the patient. All authors read and approved the final manuscript.\n\nAcknowledgment\nThis work was supported by King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.\n==== Refs\nReferences\n1. Boscaro M Arnaldi G Approach to the patient with possible Cushing’s syndrome J Clin Endocrinol Metab 2009 94 3121 31 10.1210/jc.2009-0612 19734443 \n2. Isidori AM Kaltsas GA Pozza C Frajese V Newell-Price J Reznek RH Jenkins PJ Monson JP Grossman AB Besser GM The ectopic adrenocorticotropin syndrome: clinical features, diagnosis, management, and long-term follow up J Clin Endocrinol Metab 2006 91 2 371 7 10.1210/jc.2005-1542 16303835 \n3. Ilias I Torpy DJ Pacak K Mullen N Wesley RA Nieman LK Cushing’s syndrome due to ectopic corticotropin secretion: twenty years’ experience at the National Institutes of Health J Clin Endocrinol Metab 2005 90 8 4955 62 10.1210/jc.2004-2527 15914534 \n4. Williams MD Asa SL Fuller GN Medullary thyroid carcinoma metastatic to the pituitary gland: an unusual site of metastasis Ann Diagn Pathol 2008 12 199 203 10.1016/j.anndiagpath.2006.08.007 18486896 \n5. Santarpia L Gagel RF Sherman SI Sarlis NJ Evans DB Hoff AO Diabetes insipidus and panhypopituitarism due to intrasellar metastasis from medullary thyroid cancer Head Neck 2009 31 419 23 10.1002/hed.20911 18798312 \n6. Ba¨hr V Franzen N Oelkers W Pfeiffer AFH Diederich S Effect of exogenous glucocorticoid on osmotically stimulated antidiuretic hormone secretion and on water reabsorption in man Eur J Endocrinol 2006 155 845 8 10.1530/eje.1.02299 17132754 \n7. Barbosa SL Rodien P Leboulleux S Niccoli-Sire P Kraimps JL Caron P Archambeaud-Mouveroux F Conte-Devolx B Rohmer V Groupe d’Etude des Tumeurs Endocrines Ectopic adrenocorticotropic hormone –syndrome in medullary carcinoma of the thyroid: a retrospective analysis and review of the literature Thyroid 2005 15 6 618 23 10.1089/thy.2005.15.618 16029131 \n8. Baudry C Paepegaey AC Groussin L Reversal of Cushing’s syndrome by vandetanib in medullary thyroid carcinoma N Engl J Med 2013 369 584 6 10.1056/NEJMc1301428 23924025 \n9. Nella AA Lodish MB Fox E Balis FM Quezado MM Whitcomb PO Derak J Kebebew E Widemann BC Stratakis CA Vandetanib successfully controls medullary thyroid cancer-related Cushing syndrome in an adolescent patient J Clin Endocrinol Metab 2014 99 3055 9 10.1210/jc.2013-4340 24617713 \n10. Barroso-Sousa R Lerario AM Evangelista J Papadia C Lourenc DM Jr Lin CS Kulcsar MA Fragoso MC Hoff AO Complete resolution of hypercortisolism with sorafenibin a patient with advanced medullary thyroid carcinoma and ectopic ACTH (adrenocorticotropic hormone) syndrome Thyroid 2014 24 6 1062 6 10.1089/thy.2013.0571 24499195 \n11. Petramala L Cotesta D Sapienza P Zinnamosca L Moroni E di Marzio L De Toma G Letizia C A case of acute aortic dissection type B associated with Cushing’s syndrome J Clin Med Res 2009 1 50 2 22505966 \n12. Marinis A Yiallourou A Samanides L Dafnios N Anastasopoulos G Vassiliou I Theodosopoulos T Intussusception of the bowel in adults: A review World J Gastroenterol 2009 15 4 407 11 10.3748/wjg.15.407 19152443 \n13. Vernino S Low PA Fealey RD Stewart JD Farrugia G Lennon VA Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies N Eng J Med 2000 343 847 55 10.1056/NEJM200009213431204 \n14. Castro Cabezas M Vrinten DH Burgers JA Croughs RJM Central diabetes insipidus and Cushing’s syndrome due to ectopic ACTH production by disseminated small cell lung cancer: A case report Neth J Med 1998 53 32 6 10.1016/S0300-2977(98)00051-5 9718940 \n15. Agha A Brennan S Moore KB Grogan L Thompson CJ Small-Cell lung cancer presenting as diabetes insipidus and Cushing’s syndrome Pituitary 2005 8 2 105 7 10.1007/s11102-005-3308-1 16195775 \n16. Quinkler M Meyer B Bumke-Vogt C Grossmann C Gruber U Oelkers W Diederich S Ba¨hr V Agonistic and antagonistic properties of progesterone metabolites at the human mineralocorticoid receptor Eur J Endocrinol 2002 146 789 800 10.1530/eje.0.1460789 12039699 \n17. Zhang S Jonklaas J Danielsen M The glucocorticoid agonist activities of mifepristone (RU486) and progesterone are dependent on glucocorticoid receptor concentrations but not on EC50 values Steroids 2007 72 6–7 600 8 10.1016/j.steroids.2007.03.012 17509631 \n18. Krasowski MD Drees D Morris CS Maakestad J Blau JL Ekins S Cross-reactivity of steroid hormone immunoassays: clinical significance and two-dimentional molecular similarity prediction BMC Clin Pathol 2014 14 33 10.1186/1472-6890-14-33 25071417 \n19. Zengerling F Streicher W Schrader AJ Schrader M Nitzsche B Cronauer MV Hopfner M Effects of sorafenib on C-terminally truncated androgen receptor variants in human prostate cancer cells Int J Mol Sci 2012 13 11530 42 10.3390/ijms130911530 23109869 \n20. Lee SW Lee EK Yun T Won YW Ko EJ Choi M Choi SI Park SS Hong EK Recurrent hypoglycemia triggered by sorafenib therapy in a patient with hemangiopericytoma Endocrinol Metab 2014 29 202 5 10.3803/EnM.2014.29.2.202 \n21. Lennon VA Kryzer GE Calcium-channel antibodies in the Lambert-Eaton syndrome and other paraneoplastic syndromes N Engl J Med 1995 332 1467 74 10.1056/NEJM199506013322203 7739683 \n22. Titulaer MJ Wirtz PW Kuks JB Schelhaas HJ van der Kooi AJ Faber CG van der Pol WL de Visser M Sillevis Smitt PA Verschuuren JJ The Lambert-Eaton myasthenic syndrome 1988–2008: A clinical picture in 97 patients J Neuroimmunol 2008 201–202 153 8 10.1016/j.jneuroim.2008.05.025 18644631 \n23. Crone C Christiansen I Vissing J Myopathic EMG findings and type II muscle fiber atrophy in patients with Lambert-Eaton myasthenic syndrome Clin Neurophysiol 2013 124 1889 92 10.1016/j.clinph.2013.02.115 23643575 \n24. Jin M Khan AI Procalcitonin: Uses in the clinical laboratory for the diagnosis of sepsis Labmed 2020 41 3 173 7 \n25. Kaczka K Mikosinski S Fendker W Celnik A Pomorski L Calcitonin and procalcitonin in patients with medullary thyroid cancer or bacterial infection Adv Cli Exp Med 2012 21 2 169 78 \n26. Schumm J Pfeifer R Ferrari M Kuethe F Figulla HR An unusual case of progressive shock and highly elevated procalcitonin concentration Am J Crit Care 2010 1 19 96 93 10.4037/ajcc2009805 19304564 \n27. Moura MM Cavaco BM Pinto AE Leite V High prevalence of RAS mutations in RET-negative sporadic medullary thyroid carcinomas J Clin Endocrinol Metab 2011 96 E863 8 10.1210/jc.2010-1921 21325462 \n28. Lam ET Ringel MD Kloos RT Prior TW Knopp MV Liang J Phase II clinical trial of sorafenib in metastatic medullary thyroid cancer J Clin Oncol 2010 28 2323 30 10.1200/JCO.2009.25.0068 20368568 \n29. Gorospe EC and Badamas J. Acute liver failure secondary to metastaic medullary thyroid cancer. Case Report in Hepatology. Volume 2011, Article ID 603757, 4 pages. Doi:10.1155/2011/603757.\n30. Van Hootegem A, Verslype C, Van Steenbergen W. Sorafenib-induced liver failure: A case report and review of the literature. Case Reports in Hepatology Volume 2011, Article ID 941395, 4 pages.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2407",
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"medline_ta": "BMC Cancer",
"mesh_terms": "D000328:Adult; D000784:Aneurysm, Dissecting; D000970:Antineoplastic Agents; D001014:Aortic Aneurysm; D018276:Carcinoma, Medullary; D003480:Cushing Syndrome; D003919:Diabetes Insipidus; D017809:Fatal Outcome; D006801:Humans; D006854:Hydrocortisone; D007443:Intussusception; D007579:Jejunal Diseases; D008297:Male; D009536:Niacinamide; D020364:Paraneoplastic Polyneuropathy; D010671:Phenylurea Compounds; D054969:Primary Dysautonomias; D000077157:Sorafenib; D013964:Thyroid Neoplasms",
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"references": "19304564;23643575;24499195;23109869;16029131;23924025;25071417;19152443;10995864;25954549;7739683;19734443;20368568;17509631;16195775;23214280;22505966;18798312;21325462;25031894;12039699;16303835;24617713;18486896;15914534;9718940;25954546;18644631;17132754",
"title": "Case report of severe Cushing's syndrome in medullary thyroid cancer complicated by functional diabetes insipidus, aortic dissection, jejunal intussusception, and paraneoplastic dysautonomia: remission with sorafenib without reduction in cortisol concentration.",
"title_normalized": "case report of severe cushing s syndrome in medullary thyroid cancer complicated by functional diabetes insipidus aortic dissection jejunal intussusception and paraneoplastic dysautonomia remission with sorafenib without reduction in cortisol concentration"
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"abstract": "Immune checkpoint inhibitors (ICIs) can produce specific immune-related adverse events including pneumonitis. The impact of ICI therapy on the severity of acute coronavirus infection symptomatology warrants further exploration.\n\n\n\nWe report a 65-year-old man diagnosed with stage IV melanoma who developed pulmonary and brain metastases and was treated with bilateral craniotomies followed by combined nivolumab and ipilimumab immunotherapy. He developed early-onset severe dyspnea associated with acute coronavirus HKU1 (non-COVID-19) infection, with diffuse pneumonitis evidenced by ground glass opacification on CT scan. He was treated with steroids leading to resolution of pneumonitis on repeat imaging, suggesting an exacerbated immune-mediated toxicity.\n\n\n\nWe report the first case of a patient with melanoma with severe and reversible diffuse pneumonitis in association with coronavirus HKU1 following combined nivolumab and ipilimumab immunotherapy. Although we do not have data on the impact of ICI therapy on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) symptomatology, a possible interaction should be considered when deciding on dosing in patients with possible SARS-CoV-2 exposure or when evaluating patients with presumed ICI-related pneumonitis during the COVID-19 pandemic.",
"affiliations": "Oncology, Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA michael.t.serzan@gunet.georgetown.edu.;Infectious Diseases, Georgetown University Medical Center, Washington, DC, USA.;Oncology, Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA.",
"authors": "Serzan|Michael T|MT|0000-0001-6453-8035;Kumar|Princy N|PN|;Atkins|Michael B|MB|0000-0003-3901-9924",
"chemical_list": "D000074324:Ipilimumab; D013256:Steroids; D000077594:Nivolumab",
"country": "England",
"delete": false,
"doi": "10.1136/jitc-2020-000898",
"fulltext": "\n==== Front\nJ Immunother Cancer\nJ Immunother Cancer\njitc\njitc\nJournal for Immunotherapy of Cancer\n2051-1426 BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR \n\n32434789\njitc-2020-000898\n10.1136/jitc-2020-000898\nCase Report\n1506\n2474\nDiffuse pneumonitis from coronavirus HKU1 on checkpoint inhibitor therapy\nhttp://orcid.org/0000-0001-6453-8035Serzan Michael T 1 Kumar Princy N 2 http://orcid.org/0000-0003-3901-9924Atkins Michael B 1 \n1 \nOncology, Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA\n\n\n2 \nInfectious Diseases, Georgetown University Medical Center, Washington, DC, USA\n\nCorrespondence to Dr Michael T Serzan; michael.t.serzan@gunet.georgetown.edu\n2020 \n19 5 2020 \n8 1 e00089809 5 2020 © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.2020https://creativecommons.org/licenses/by/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See https://creativecommons.org/licenses/by/4.0/.Background\nImmune checkpoint inhibitors (ICIs) can produce specific immune-related adverse events including pneumonitis. The impact of ICI therapy on the severity of acute coronavirus infection symptomatology warrants further exploration.\n\nCase presentation\nWe report a 65-year-old man diagnosed with stage IV melanoma who developed pulmonary and brain metastases and was treated with bilateral craniotomies followed by combined nivolumab and ipilimumab immunotherapy. He developed early-onset severe dyspnea associated with acute coronavirus HKU1 (non-COVID-19) infection, with diffuse pneumonitis evidenced by ground glass opacification on CT scan. He was treated with steroids leading to resolution of pneumonitis on repeat imaging, suggesting an exacerbated immune-mediated toxicity.\n\nConclusion\nWe report the first case of a patient with melanoma with severe and reversible diffuse pneumonitis in association with coronavirus HKU1 following combined nivolumab and ipilimumab immunotherapy. Although we do not have data on the impact of ICI therapy on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) symptomatology, a possible interaction should be considered when deciding on dosing in patients with possible SARS-CoV-2 exposure or when evaluating patients with presumed ICI-related pneumonitis during the COVID-19 pandemic.\n\nmelanomaimmunotherapyimmunomodulationcase reportsspecial-featureunlocked\n==== Body\nBackground\nIpilimumab and nivolumab are recombinant human monoclonal antibodies which target cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed death-1 (PD-1) receptor, respectively. Immune checkpoint inhibitors (ICIs) enable the restoration of endogenous antitumor immunity and have revolutionized treatment of advanced melanoma among other malignancies.1–3 Blockade of immune checkpoints has been associated with immune-related adverse events (irAEs) resulting from excessive inflammation in various organs.4 Checkpoint inhibitor pneumonitis (CIP) is characterized by dyspnea and/or other respiratory symptoms coupled with inflammatory changes on chest imaging after exclusion of infection and tumor progression. The incidence of all-grade CIP in clinical trials was estimated at 3%–5% with up to 70%–80% of cases responsive to glucocorticoid therapy.5 Patients who do not show improvement at 48–72 hours are typically treated with further immunosuppressive medications, such as infliximab, mycophenolate mofetil, intravenous immunoglobulins, or cyclophosphamide.6 Here, we present a case of a patient with melanoma with symptomatic and reversible diffuse pneumonitis associated with acute coronavirus HKU1 infection within days following the initiation of nivolumab and ipilimumab immunotherapy.\n\nCase presentation\nA 65-year-old Caucasian man was diagnosed in February 2017 with a stage IVD BRAF wild-type cutaneous melanoma of the scalp with six intracranial metastases, innumerable bilateral lung metastases, and a peritoneal metastasis. He underwent bilateral craniotomies for excision of left temporal and right frontal lobe lesions with pathology showing melanoma with spindle cell and clear cell features. The day after corticosteroids were weaned off, combination nivolumab 1 mg/kg and ipilimumab 3 mg/kg was initiated.\n\nIn April 2017, 2 days after the first dose of nivolumab and ipilimumab, he developed cough productive of yellow sputum and dyspnea that persisted over the next 5 days. One week into ICI therapy, physical examination was notable for bilateral upper lung crackles without fever, hypotension, tachycardia, or hypoxia on room air. CT of the chest confirmed known pulmonary metastases superimposed by new diffuse ground glass opacification with slight central and upper lobe predominance (figure 1A, B). On hospital day 2, evaluation of respiratory viral pathogens with nasopharyngeal swab revealed the presence of coronavirus HKU1 (non-COVID-19). Complete blood count showed white cell count (WCC) 7.2 (109/L), hemoglobin 12.9 (g/L), and platelets 252 (109). Blood and sputum cultures revealed no growth and normal respiratory flora, respectively. The patient was initially diagnosed with CIP and treated with high-dose corticosteroids. Due to the patient’s rapid symptomatic benefit and our inability to exclude a role for the ICIs in exacerbating the newly diagnosed coronavirus infection, steroids were tapered off over a week rather than immediately discontinued.\n\nFigure 1 Comparison of the appearance of pulmonary metastasis and diffuse pneumonitis on CT scans. (A, B) In April 2017, multiple bilateral pulmonary metastases with superimposed ground glass opacities in the mid and upper lung fields. (C, D) In May 2017, resolution of diffuse pneumonitis and partial regression of lung nodules. (E, F) In February 2020, near-complete resolution of lung nodules.\n\nIn May 2017, a follow-up chest CT demonstrated resolution of ground glass opacification (figure 1C, D) at which time nivolumab 3 mg/kg monotherapy was initiated and continued for 25 doses until April 2018 without recurrence of pneumonitis. In April 2018, brain MRI showed postsurgical changes without evidence of metastases and chest and abdominal CT scans showed interval additional decrease in size and number of pulmonary nodules and right peritoneal nodule (figure 1E, F). 18F-fluorodeoxyglucose (FDG) positron emission tomography/CT scan showed no evidence of FDG-avid disease, supporting the likelihood of a metabolic complete systemic and cerebral response. Nivolumab monotherapy was discontinued after informed discussion of the known risks and benefits of both continuing and stopping therapy.\n\nHe was followed with clinical evaluation, brain MRI and torso CT scans every 3 months. At most recent follow-up in February 2020, 3 years after initial diagnosis and nearly 2 years of treatment he remains free of disease progression.\n\nDiscussion and conclusions\nCIP is uncommon; however, it can be life-threatening, necessitating early diagnosis and prompt intervention. This case study provides the first description of symptomatic pneumonitis in association with coronavirus HKU1 after combined anti-CTLA and anti-PD-1 blockade with ipilimumab and nivolumab in a patient with metastatic melanoma.\n\nCoronavirus HKU1 was first discovered as a pathogenic cause for community-acquired pneumonia in 2005.7 A majority of patients experienced a monophasic infection leading to rapid recovery with median duration of hospitalization of only 5.5 days.8 Despite many patients having relatively mild infections, a minority of patients with comorbidities including malignancy, diabetes, and cardiovascular disease experienced severe infections leading to death. These patients died from early pneumonitis within approximately 1 week of hospital admission and there were no reports of late hyperinflammatory syndromes. Although there is a paucity of evidence for the use of corticosteroids in coronavirus HKU1 infections, steroids have been used to mitigate the secondary inflammatory response in severe coronavirus pneumonias caused by severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV).9 10 Several retrospective studies and meta-analyses have consistently shown no clinical benefit from corticosteroid treatment and suggest impaired viral clearance of SARS-CoV and MERS-CoV.10 11 Despite the lack of benefit in phylogenetically similar coronavirus infections, this patient’s unique presentation of severe coronavirus HKU1 shortly after ICI therapy, and his clinical response to an initial corticosteroid dose, raised the possibility of synergistic pulmonary toxicity and led the authors to continue a short-course corticosteroids following viral detection.\n\nPulmonary adverse events of ICIs remain a complex diagnosis of exclusion. In a previous report, the median time to onset of pulmonary irAEs following ICI therapy was approximately 2.8 months (range: 0.3 to 19.2 months).5 Among patients treated with oral steroids, the median starting dose was prednisone 50 mg daily (range 20 to 80 mg) and median duration of treatment was 68 days (range 2 to 154 days). A number of factors distinguish our patient’s case from the typical ICI-related pneumonitis. First, the short interval of 1 week between dosing of ipilimumab and nivolumab and the occurrence of diffuse pneumonitis suggests an exacerbated immune response to a viral infection rather than a reaction solely to the ICI therapy. Furthermore, the rapid improvement in symptoms and radiographic pneumonitis with prompt short-course steroids is distinct from the usual case of ICI pneumonitis. Lastly, the absence of recurrent pneumonitis after re-challenging with anti-PD1 monotherapy supports the viral infection an inciting factor. Remarkably, the patient experienced a metabolic complete systemic and cerebral response to therapy that has been sustained for 3 years including 2 years after stopping therapy.\n\nThe novel COVID-19 has been confirmed in over 3 500 000 patients worldwide as of May 6, 2020 with a mortality rate of approximately 6.8%.12 In contrast to the monophasic coronavirus HKU1 and similar to SARS-CoV and MERS-CoV infections, COVID-19 has demonstrated a biphasic course. A recent cluster of 41 patients with SARS-CoV-2 infection demonstrated initial symptoms of fever (98%), cough (76%), and fatigue (44%) followed by development of dyspnea (55%) at a median 8 days, acute respiratory distress syndrome (27%) at median 9 days, and intensive care unit admission (39%) at median 10.5 days.13 Additionally, a recent retrospective study of 150 patients with confirmed COVID-19 discovered significantly elevated inflammatory markers in 68 deceased patients compared with 82 survivors with elevations in WCC (mean 10.6 vs 6.7; p<0.001), C reactive protein (mean 126.6 ng/mL vs 34.1 ng/mL; p<0.001), serum ferritin (mean 1297.6 ng/mL vs 614 ng/mL; p<0.001), and interleukin 6 (IL-6; mean 11.4 ng/mL vs 6.8 ng/mL).14 Together these clinical and laboratory findings suggest that COVID-19 mortality may be due to a late-phase virus-induced hyperinflammatory syndrome, rather than the direct effects of the virus itself and that this syndrome could be potentially exacerbated by ICI administration.\n\nSeveral immune-modulating strategies have shown anecdotal efficacy for severe COVID-19 including biological therapies targeting inflammatory pathways with anti-IL-6 antibodies tocilizumab and sarilumab.15 Tocilizumab is a humanized monoclonal antibody to the IL-6 receptor that is Food and Drug Administration (FDA) approved for the management of cytokine release syndrome (CRS) for patients receiving chimeric antigen receptor (CAR) T-cell therapy and used for steroid-refractory irAEs from ICI therapy.16 17 The FDA has recently approved COVACTA, a randomized, double-blind, placebo-controlled phase III trial of tocilizumab plus standard of care (SOC) compared with placebo plus SOC.18 A trial of the anti-IL-6-receptor sarilumab for patients with severe COVID-19 infections is also ongoing.19 Due to the limited access to such specific anticytokine agents, many institutions are substituting high-dose steroids for patients with elevated inflammatory marker profiles with anecdotal evidence of benefit (Charles Drake, personal communication, 2020). Given this pathophysiology, corticosteroid use might be particularly appropriate for patients with COVID-19 pneumonitis in the setting of ICI therapy.\n\nThis case report highlights a potential interaction between coronavirus infection and ICI therapy that could lead to exacerbation of pneumonitis. In patients with suspected CIP, several irAE guidelines recommend evaluation of alternative etiologies including nasopharyngeal testing for viral infections, which may facilitate more accurate diagnosis and appropriate therapy.20–22 While this case was related to coronavirus HKU1 and was readily treated, it highlights a potential concern regarding the impact of ICI therapy on the effects of both common coronaviruses and the more virulent SARS-CoV-2 infection. Considering the prevalence COVID-19 worldwide, we recommend SARS-CoV-2 testing for patients on ICIs with symptoms (fever, dyspnea, or cough) regardless of the presence or absence of infiltrates on imaging. In patients under investigation for COVID-19, we further recommend that ICI treatment should be withheld until SARS-CoV-2 infection is excluded. Due to the potential risk of exacerbating an asymptomatic infection, we also recommend that for patients with a potential exposure to a person with COVID-19, ICI therapy be withheld until SARS-CoV-2 infection can be ruled out.\n\nThe case sheds some light on the potential biology of the lethal pulmonary toxicity associated COVID-19. The elevated inflammatory markers seen in severe SARS-CoV-2 infections are reminiscent of a low level of the CRS seen with CAR T-cell therapy, a condition where selective immunosuppressive treatment can be effective. These observations support the ongoing study of immunosuppressive therapies including high-dose corticosteroids and anti-IL-6 receptor antibodies in patients with severe COVID-19.\n\nThe authors thank the patient and his family for entrusting us with his care.\n\nContributors: MTS analyzed and interpreted the patient case, wrote and edited the manuscript, performed radiological interpretation, provided the imaging figures. PNK interpreted the case and reviewed the manuscript. MBA was the main treating physician, analyzed and interpreted the patient case, wrote and edited the manuscript, and supervised this case report. All authors read and approved 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: MBA has received honoraria or fees for serving on advisory boards for Bristol-Meyers Squibb (BMS), Merck, Novartis, Arrowhead, Pfizer, Galactone, Werewolf, Fathom, Pneuma, and Leads; consulting fees from BMS, Merck, Novartis, Pfizer, Genentech/Roche, Exelixis, Eisai, Aveo, Array, AstraZeneca, Ideera, Aduro, ImmunoCore, Boehringer-Ingelheim, Iovance, Newlink, Pharma, Surface, Alexion, Acceleron, Cota, and Amgen; institutional support from BMS, Merck, Pfizer, and Genentech; and owns stock options in Werewolf and Pyxis Oncology. PNK has received honoraria or fees from Theratechnologies: consultant and investigator, consulting fee and research grant. ViiV: consultant, investigator, and shareholder; research grant; and speaker honorarium. MTS: investigator and shareholder; research grant. Gilead: consultant, investigator, and shareholder; consulting fee; and research grant.\n\nPatient consent for publication: Obtained.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n1 \nLarkin J , Chiarion-Sileni V , Gonzalez R , et al \nCombined nivolumab and ipilimumab or monotherapy in untreated melanoma\n. N Engl J Med \n2015 ;373 :23 –34\n. 10.1056/NEJMoa1504030 \n26027431 \n2 \nWolchok JD , Kluger H , Callahan MK , et al \nNivolumab plus ipilimumab in advanced melanoma\n. N Engl J Med \n2013 ;369 :122 –33\n. 10.1056/NEJMoa1302369 \n23724867 \n3 \nTopalian SL , Sznol M , McDermott DF , et al \nSurvival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab\n. J Clin Oncol \n2014 ;32 :1020 –30\n. 10.1200/JCO.2013.53.0105 \n24590637 \n4 \nPostow MA , Sidlow R , Hellmann MD \nImmune-Related adverse events associated with immune checkpoint blockade\n. N Engl J Med \n2018 ;378 :158 –68\n. 10.1056/NEJMra1703481 \n29320654 \n5 \nNaidoo J , Wang X , Woo KM , et al \nPneumonitis in patients treated with Anti-Programmed Death-1/Programmed death ligand 1 therapy\n. J Clin Oncol \n2017 ;35 :709 –17\n. 10.1200/JCO.2016.68.2005 \n27646942 \n6 \nBrahmer JR , Lacchetti C , Schneider BJ , et al \nManagement of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of clinical oncology clinical practice guideline\n. J Clin Oncol \n2018 ;36 :1714 –68\n. 10.1200/JCO.2017.77.6385 \n29442540 \n7 \nWoo PCY , Lau SKP , Chu C-ming , et al \nCharacterization and complete genome sequence of a novel coronavirus, coronavirus HKU1, from patients with pneumonia\n. J Virol \n2005 ;79 :884 –95\n. 10.1128/JVI.79.2.884-895.2005 \n15613317 \n8 \nWoo PCY , Lau SKP , Tsoi H-W , et al \nClinical and molecular epidemiological features of coronavirus HKU1-associated community-acquired pneumonia\n. J Infect Dis \n2005 ;192 :1898 –907\n. 10.1086/497151 \n16267760 \n9 \nStockman LJ , Bellamy R , Garner P \nSars: systematic review of treatment effects\n. PLoS Med \n2006 ;3 :e343. 10.1371/journal.pmed.0030343 \n16968120 \n10 \nArabi YM , Mandourah Y , Al-Hameed F , et al \nCorticosteroid therapy for critically ill patients with Middle East respiratory syndrome\n. Am J Respir Crit Care Med \n2018 ;197 :757 –67\n. 10.1164/rccm.201706-1172OC \n29161116 \n11 \nLee N , Allen Chan KC , Hui DS , et al \nEffects of early corticosteroid treatment on plasma SARS-associated coronavirus RNA concentrations in adult patients\n. J Clin Virol \n2004 ;31 :304 –9\n. 10.1016/j.jcv.2004.07.006 \n15494274 \n12 \nWHO Coronavirus disease 2019 (COVID-19)situation report – 52\n. Available: https://www.who.int/docs/default-source/coronaviruse/20200312-sitrep-52-covid-19.pdf?sfvrsn=e2bfc9c0_2 [Accessed 6 May 2020 ].\n13 \nHuang C , Wang Y , Li X , et al \nClinical features of patients infected with 2019 novel coronavirus in Wuhan, China\n. The Lancet \n2020 ;395 :497 –506\n. 10.1016/S0140-6736(20)30183-5 \n\n14 \nRuan Q , Yang K , Wang W , et al \nClinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China\n. Intensive Care Med \n2020 ;46 :846 –8\n. 10.1007/s00134-020-05991-x \n32125452 \n15 \nXu X , Han M , Li T , et al \nEffective treatment of severe COVID-19 patients with tocilizumab\n. Proc Natl Acad Sci U S A \n2020 .\n16 \nMaude SL , Barrett D , Teachey DT , et al \nManaging cytokine release syndrome associated with novel T cell-engaging therapies\n. Cancer J \n2014 ;20 :119 –22\n. 10.1097/PPO.0000000000000035 \n24667956 \n17 \nStroud CR , Hegde A , Cherry C , et al \nTocilizumab for the management of immune mediated adverse events secondary to PD-1 blockade\n. J Oncol Pharm Pract \n2019 ;25 :551 –7\n. 10.1177/1078155217745144 \n29207939 \n18 \nGenentech Announces FDA approval of clinical trial for Actemra to treat hospitalized patients with severe COVID-19 pneumonia\n. Available: https://www.gene.com/media/press-releases/14843/2020-03-23/genentech-announces-fda-approval-of-clin\n\n19 \nSanofi and Regeneron begin global Kevzara® (sarilumab) clinical trial program in patients with severe COVID-19\n. Available: http://www.news.sanofi.us/2020-03-16-Sanofi-and-Regeneron-begin-global-Kevzara-R-sarilumab-clinical-trial-program-in-patients-with-severe-COVID-19\n\n20 \nBrahmer JR , Lacchetti C , Schneider BJ , et al \nManagement of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of clinical oncology clinical practice guideline\n. JCO \n2018 ;36 :1714 –68\n. 10.1200/JCO.2017.77.6385 \n\n21 \nThompson JA , Schneider BJ , Brahmer J , et al \nManagement of Immunotherapy-Related toxicities, version 1.2019, NCCN clinical practice guidelines in oncology\n. J Nat Comp Can Net \n2019 ;17 :255 –89\n. 10.6004/jnccn.2019.0013 \n\n22 \nHaanen JBAG , Carbonnel F , Robert C , et al \nManagement of toxicities from immunotherapy: ESMO clinical practice guidelines for diagnosis, treatment and follow-up\n. Ann Oncol \n2017 ;28 :iv119 –42\n. 10.1093/annonc/mdx225\n\n",
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"issue": "8(1)",
"journal": "Journal for immunotherapy of cancer",
"keywords": "case reports; immunomodulation; immunotherapy; melanoma",
"medline_ta": "J Immunother Cancer",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D017934:Coronavirus; D018352:Coronavirus Infections; D006801:Humans; D007167:Immunotherapy; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma; D000077594:Nivolumab; D011024:Pneumonia, Viral; D013256:Steroids",
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"title": "Diffuse pneumonitis from coronavirus HKU1 on checkpoint inhibitor therapy.",
"title_normalized": "diffuse pneumonitis from coronavirus hku1 on checkpoint inhibitor therapy"
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"abstract": "BACKGROUND\nSouth Africa (SA) is known to have a high disease burden of tuberculosis (TB). Extraspinal osteoarticular multidrug-resistant tuberculosis (ESOA MDR-TB) in children has only been described in a few case reports worldwide.\n\n\nOBJECTIVE\nTo describe the epidemiology and highlight the potential problem of ESOA MDR-TB infections as seen in children from a single academic hospital in SA.\n\n\nMETHODS\nA retrospective record review was performed on all children diagnosed with ESOA TB infection at Chris Hani Baragwanath Academic Hospital, Johannesburg, between 1 January 2006 and 31 December 2015. All patients with a positive TB culture (fluid or tissue) from the surgical site of biopsy (bone or joint) and who were hospitalised were included. Organism culture and drug sensitivity testing were performed.\n\n\nRESULTS\nOverall 19 cases of ESOA TB were identified. Areas involved included the shoulder (2 cases), elbow (2 cases), hip (7 cases), knee (4 cases), ankle (3 cases) and humerus (1 case). The mean age of the population was 7.7 (range 2.0 - 14.0) years. The mean white cell count was 11.3 (range 5 - 28.9) × 109/L, the mean C-reactive protein level 53.8 (range 1.0 - 364.0) mg/L and the mean erythrocyte sedimentation rate 35.5 (range 4.0 - 85.0) mm/h. Two cases (10.5%) were MDR, and a further case (5.3%) was resistant to isoniazid only. Four of 12 patients tested positive for HIV. One of the HIV-positive patients was isoniazid resistant. The two positive ESOA MDR-TB cases are discussed in detail.\n\n\nCONCLUSIONS\nThese findings indicate that ESOA MDR-TB is a reality in this paediatric population (10.5%) and a high index of suspicion should be maintained, especially when cultures are negative in children with signs and symptoms of ESOA TB. The effect of HIV infection on the incidence of ESOA MDR-TB requires further study.",
"affiliations": "Division of Orthopaedic Surgery, Chris Hani Baragwanath Academic Hospital and Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. greg.firth@gmail.com.",
"authors": "Firth|G B|GB|;Lescheid|J|J|;Camacho|M|M|;Esteves|M|M|;Beylis|N|N|;Groome|M J|MJ|;Madhi|S A|SA|",
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"title": "Extraspinal osteoarticular multidrug-resistant tuberculosis in children: A case series.",
"title_normalized": "extraspinal osteoarticular multidrug resistant tuberculosis in children a case series"
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"abstract": "Autoimmune hepatitis (AIH) is an inflammatory disorder of the liver with a wide spectrum of disease presentation, from asymptomatic elevations in liver-associated enzymes to acute liver failure. AIH is classically associated with elevated immunoglobulins and autoantibodies, although approximately 20% of patients with features of AIH lack circulating antibodies. Recently, tumour necrosis factor alpha inhibitors have been implicated in several cases of drug-induced AIH which impact treatment regimens for patients with inflammatory bowel disease (IBD). We present a case of infliximab-induced seronegative AIH responding to budesonide therapy with successful alteration of IBD treatment regimen to vedolizumab.",
"affiliations": "Internal Medicine, Walter Reed National Military Medical Center, Bethesda, Maryland, USA arj3030@gmail.com.;Pathology, Walter Reed National Military Medical Center, Bethesda, Maryland, USA.;Internal Medicine, Naval Medical Center San Diego, San Diego, California, USA.;Gastroenterology, Naval Medical Center Portsmouth, Portsmouth, Virginia, USA.;Gastroenterology, Naval Medical Center Portsmouth, Portsmouth, Virginia, USA.",
"authors": "Jenkins|Alexander|A|;Austin|Amy|A|;Hughes|Kathryn|K|;Sadowski|Brett|B|;Torres|Dawn|D|",
"chemical_list": "D001323:Autoantibodies; D000069285:Infliximab",
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"mesh_terms": "D001323:Autoantibodies; D056486:Chemical and Drug Induced Liver Injury; D019693:Hepatitis, Autoimmune; D006801:Humans; D000069285:Infliximab",
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"title": "Infliximab-induced autoimmune hepatitis.",
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"abstract": "Issues regarding food safety are seen increasingly in the news; outbreaks of foodborne illness have been associated with public health concerns ranging from mild illness to death. For the solid organ transplant patient, immunosuppressive and antibacterial drugs, which maintain transplant organ function, can expose the transplant patient to increased risk of foodborne illness from bacteria, viruses, fungi, and parasites. This review article describes the clinical consequences, sources of foodborne illness, and food safety practices needed to minimize risks to the solid organ transplant patient who must take lifelong immunosuppressive drugs. All members of the transplant team share responsibility for education of the solid organ transplant patient in preventing infections. The registered dietitian, as part of the transplant team, is the recognized expert in providing food safety education in the context of medical nutrition therapy to solid organ transplant patients, the patients' caregivers, and other healthcare providers.",
"affiliations": "Department of Clinical Nutrition, Stanford Hospital and Clinics, 300 Pasteur Drive, H1207, M/C 5226, Stanford, CA 94305-5226, USA. pobayashi@stanfordmed.org",
"authors": "Obayashi|Patricia A C|PA|",
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"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Food safety for the solid organ transplant patient: preventing foodborne illness while on chronic immunosuppressive drugs.",
"title_normalized": "food safety for the solid organ transplant patient preventing foodborne illness while on chronic immunosuppressive drugs"
} | [
{
"companynumb": "US-ROCHE-1162795",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "1",
... |
{
"abstract": "Although the outcomes of patients with mantle cell lymphoma (MCL) have improved, there is still no cure. Bortezomib has a 33% response rate in relapsed/refractory MCL and has shown additive and/or synergistic effects in preclinical trials with known effective agents.\n\n\n\nThis is a report of a prospective phase 2 trial of bortezomib added to rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (BzR-hyperCVAD)/rituximab, high-dose methotrexate, and high-dose cytarabine (BzR-MA) for 95 patients with newly diagnosed MCL.\n\n\n\nThe overall and complete response rates were 100% and 82%, respectively. Hematologic toxicity was high but expected and did not lead to an increased incidence of neutropenic fever or dose reductions in comparison with a similar reported regimen without bortezomib. After a median follow-up of 44 months, the median overall survival had not been reached, and the time to treatment failure (TTF) was 55 months, which is not different from that of historical controls.\n\n\n\nBzR-hyperCVAD/BzR-MA at the dose and schedule studied produced high rates of response and a TTF similar to that of historical reports without bortezomib. Cancer 2018;124:2561-9. © 2018 American Cancer Society.",
"affiliations": "Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Lymphoma Center, City of Hope, Duarte, California.;Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Lymphoma Division, John Theurer Cancer Hackensack University Medical Center, Hackensack, New Jersey.;Lymphoma Division, John Theurer Cancer Hackensack University Medical Center, Hackensack, New Jersey.;Lymphoma Division, John Theurer Cancer Hackensack University Medical Center, Hackensack, New Jersey.;Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Lymphoma Division, John Theurer Cancer Hackensack University Medical Center, Hackensack, New Jersey.",
"authors": "Romaguera|Jorge E|JE|0000-0003-4830-9173;Wang|Michael|M|0000-0001-9748-5486;Feng|Lei|L|;Fayad|Luis E|LE|;Hagemeister|Frederick|F|;McLaughlin|Peter|P|;Rodriguez|M Alma|MA|;Fanale|Michelle|M|;Orlowski|Robert|R|;Kwak|Larry W|LW|;Neelapu|Sattva|S|;Oki|Yasuhiro|Y|;Pro|Barbara|B|;Younes|Anas|A|;Samaniego|Felipe|F|;Fowler|Nathan|N|;Hartig|Kimberly|K|;Valentinetti|Marisa|M|;Smith|Judy|J|;Ford|Peggy|P|;Naig|Adam|A|;Medeiros|L Jeffrey|LJ|;Kantarjian|Hagop M|HM|0000-0002-1908-3307;Goy|Andre|A|",
"chemical_list": "D003561:Cytarabine; D000069283:Rituximab; D014750:Vincristine; D000069286:Bortezomib; D003907:Dexamethasone; D004317:Doxorubicin; D003520:Cyclophosphamide; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1002/cncr.31361",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0008-543X",
"issue": "124(12)",
"journal": "Cancer",
"keywords": "and dexamethasone (R-hyperCVAD); bortezomib; doxorubicin; mantle cell lymphoma; rituximab plus hyperfractionated cyclophosphamide; vincristine",
"medline_ta": "Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069286:Bortezomib; D064146:Chemotherapy-Induced Febrile Neutropenia; D003520:Cyclophosphamide; D003561:Cytarabine; D003907:Dexamethasone; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D053208:Kaplan-Meier Estimate; D020522:Lymphoma, Mantle-Cell; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011446:Prospective Studies; D000069283:Rituximab; D015996:Survival Rate; D013997:Time Factors; D017211:Treatment Failure; D014750:Vincristine",
"nlm_unique_id": "0374236",
"other_id": null,
"pages": "2561-2569",
"pmc": null,
"pmid": "29723393",
"pubdate": "2018-06-15",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Phase 2 trial of bortezomib in combination with rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with bortezomib, rituximab, methotrexate, and cytarabine for untreated mantle cell lymphoma.",
"title_normalized": "phase 2 trial of bortezomib in combination with rituximab plus hyperfractionated cyclophosphamide vincristine doxorubicin and dexamethasone alternating with bortezomib rituximab methotrexate and cytarabine for untreated mantle cell lymphoma"
} | [
{
"companynumb": "US-TAKEDA-2018MPI009381",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BORTEZOMIB"
},
"drugadditional": "3",
... |
{
"abstract": "Bezold-Jarisch reflex is a reflex that may occur during regional anesthesia, upper-extremity blocks and sometimes in general anesthesia, resulting in hypotension, bradycardia, apnea or cardiac arrest elicited by chemical or mechanical receptor stimulations. This reflex mostly occurs in the sitting position during upper-extremity nerve blocks can be forgotten in other complications. The complications that occurred after this reflex can be overcome by taking necessary precautions and providing sufficient cardiac monitorization. In our cases to be presented, we want to remind you of Bezold-Jarisch reflex, which may cause severe complications when forgotten.",
"affiliations": "Department of Anesthesia and Reanimation, Erzincan University Faculty of Medicine, Training and Research Hospital, Erzincan, Turkey.;Department of Anesthesia and Reanimation, Harran University Faculty of Medicine, Research and Practice Hospital, Şanlıurfa, Turkey.;Department of Anesthesia and Reanimation, Erzincan University Faculty of Medicine, Training and Research Hospital, Erzincan, Turkey.;Department of Anesthesia and Reanimation, Harran University Faculty of Medicine, Research and Practice Hospital, Şanlıurfa, Turkey.;Department of Anesthesia and Reanimation, Harran University Faculty of Medicine, Research and Practice Hospital, Şanlıurfa, Turkey.;Department of Anesthesia and Reanimation, Harran University Faculty of Medicine, Research and Practice Hospital, Şanlıurfa, Turkey.",
"authors": "Akyol|Fethi|F|;Binici|Orhan|O|;Özmen|Özgür|Ö|;Büyükfırat|Evren|E|;Erol|Mehmet Kenan|MK|;Karahan|Mahmut Alp|MA|",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.5505/agri.2018.62687",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1300-0012",
"issue": "32(3)",
"journal": "Agri : Agri (Algoloji) Dernegi'nin Yayin organidir = The journal of the Turkish Society of Algology",
"keywords": null,
"medline_ta": "Agri",
"mesh_terms": "D001132:Arm; D001919:Bradycardia; D005260:Female; D006801:Humans; D008875:Middle Aged; D009407:Nerve Block; D012018:Reflex; D000077708:Sitting Position",
"nlm_unique_id": "9426197",
"other_id": null,
"pages": "168-170",
"pmc": null,
"pmid": "32789827",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Rare reflex in regional anesthesia which have a high-risk in case of forgotten: Bezold-Jarisch reflex.",
"title_normalized": "rare reflex in regional anesthesia which have a high risk in case of forgotten bezold jarisch reflex"
} | [
{
"companynumb": "TR-FRESENIUS KABI-FK202107840",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BUPIVACAINE"
},
"drugadditional": null,
... |
{
"abstract": "We present management strategies utilised for the first case of an urgent live-donor ABO incompatible B blood group renal transplant, in a patient with a prior A blood group lung transplant for cystic fibrosis. Three years on, renal function is excellent and stable, whilst lung function has improved.",
"affiliations": "Lung Transplant Service, Alfred Hospital and Monash University, Melbourne, Australia. Electronic address: g.snell@alfred.org.au.;Department of Haematology, Alfred Hospital and Monash University, Melbourne, Australia.;Department of Renal Medicine, Alfred Hospital and Monash University, Melbourne, Australia.;Lung Transplant Service, Alfred Hospital and Monash University, Melbourne, Australia.;Lung Transplant Service, Alfred Hospital and Monash University, Melbourne, Australia.;Lung Transplant Service, Alfred Hospital and Monash University, Melbourne, Australia.;Lung Transplant Service, Alfred Hospital and Monash University, Melbourne, Australia.;Department of Haematology, Alfred Hospital and Monash University, Melbourne, Australia.;Lung Transplant Service, Alfred Hospital and Monash University, Melbourne, Australia.;Department of Renal Medicine, Alfred Hospital and Monash University, Melbourne, Australia.",
"authors": "Snell|G I|GI|;Davis|A K|AK|;Menahem|S|S|;Kotecha|S|S|;Whitford|H M|HM|;Levvey|B J|BJ|;Paraskeva|M|M|;Webb|A|A|;Westall|G W|GW|;Walker|R G|RG|",
"chemical_list": "D000017:ABO Blood-Group System; D006680:HLA Antigens; D007519:Isoantigens; D011239:Prednisolone; D009173:Mycophenolic Acid; D016559:Tacrolimus",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.trim.2016.09.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0966-3274",
"issue": "39()",
"journal": "Transplant immunology",
"keywords": "ABO blood group incompatibility; End-stage kidney disease; Lung transplantation; Renal transplantation",
"medline_ta": "Transpl Immunol",
"mesh_terms": "D000017:ABO Blood-Group System; D000208:Acute Disease; D000328:Adult; D003550:Cystic Fibrosis; D018572:Disease-Free Survival; D005260:Female; D006084:Graft Rejection; D006680:HLA Antigens; D006801:Humans; D007519:Isoantigens; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D019520:Living Donors; D016040:Lung Transplantation; D008875:Middle Aged; D009035:Mothers; D009173:Mycophenolic Acid; D010956:Plasmapheresis; D011239:Prednisolone; D018805:Sepsis; D016559:Tacrolimus; D028761:Withholding Treatment",
"nlm_unique_id": "9309923",
"other_id": null,
"pages": "30-33",
"pmc": null,
"pmid": "27663090",
"pubdate": "2016-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "ABO incompatible renal transplantation following lung transplantation.",
"title_normalized": "abo incompatible renal transplantation following lung transplantation"
} | [
{
"companynumb": "PHHY2016AU181413",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "Hydromorphone, unlike other opioids associated with histamine release, has never been reported to cause angioedema. We report a rare case of hydromorphone-induced angioedema in a 34-year-old woman with history of deep venous thrombosis and pulmonary embolism who presented with leg swelling and pain after trauma. Hydromorphone was administered with subsequent rapid development of stridor and edematous changes of the tongue, uvula, and surrounding mucosa. The difficult airway response team was activated, and the airway was secured by emergent awake fiberoptic intubation in the operating room. After being treated with antihistamines and steroids for 24 hours, the airway edema had resolved, leading to a successful extubation.",
"affiliations": "From the Departments of *Anesthesiology and †Pulmonary and Critical Care Medicine, Oakland University William Beaumont Hospital, Royal Oak, Michigan.",
"authors": "Masson|Scott|S|;Villerot|Matthew|M|;Dalal|Bhavinkumar|B|",
"chemical_list": "D000701:Analgesics, Opioid; D004091:Hydromorphone",
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000000379",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2325-7237",
"issue": "7(9)",
"journal": "A & A case reports",
"keywords": null,
"medline_ta": "A A Case Rep",
"mesh_terms": "D000328:Adult; D058109:Airway Management; D000701:Analgesics, Opioid; D000799:Angioedema; D019468:Disease Management; D005260:Female; D006801:Humans; D004091:Hydromorphone; D007442:Intubation, Intratracheal; D010348:Patient Care Team",
"nlm_unique_id": "101637720",
"other_id": null,
"pages": "188-189",
"pmc": null,
"pmid": "27552239",
"pubdate": "2016-11-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Rare Case of Hydromorphone-Induced Angioedema Effectively Managed by a Difficult Airway Response Team.",
"title_normalized": "a rare case of hydromorphone induced angioedema effectively managed by a difficult airway response team"
} | [
{
"companynumb": "US-ELITE LABORATORIES INC.-2017ELT00002",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HYDROMORPHONE HYDROCHLORIDE"
},
... |
{
"abstract": "Pyometra is an uncommon condition with an incidence of less than 1% in gynaecologic patients. Spontaneous rupture of pyometra in cervical cancer presenting as generalized peritonitis is very rare. Only four cases have been described in the English literature to the best of our knowledge and from a PubMed search. The index case is an elderly postmenopausal female who was diagnosed with cervical cancer, started on radiotherapy and presented with features of generalized peritonitis. Contrast-enhanced CT revealed uterine perforation at the fundus with multiple abdominal and pelvic collections. A brief review of all the cases of ruptured pyometra in cervical cancer in the literature and a discussion of the role of imaging is presented.",
"affiliations": "Postgraduate Institute of Medical Education and Research PGIMER, Chandigarh, India. sameer574@yahoo.co.in",
"authors": "Vyas|Sameer|S|;Kumar|Ajay|A|;Prakash|Mahesh|M|;Kapoor|Rakesh|R|;Kumar|Pankaj|P|;Khandelwal|Niranjan|N|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1102/1470-7330.2009.0002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1470-7330",
"issue": "9()",
"journal": "Cancer imaging : the official publication of the International Cancer Imaging Society",
"keywords": null,
"medline_ta": "Cancer Imaging",
"mesh_terms": "D000368:Aged; D005260:Female; D006801:Humans; D010538:Peritonitis; D017698:Postmenopause; D055112:Pyometra; D012422:Rupture, Spontaneous; D002583:Uterine Cervical Neoplasms; D014595:Uterine Perforation",
"nlm_unique_id": "101172931",
"other_id": null,
"pages": "12-4",
"pmc": null,
"pmid": "19419914",
"pubdate": "2009-03-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16604973;8406207;18324325;11077640;17093350;18182356;17485806;16325818",
"title": "Spontaneous perforation of pyometra in a cervical cancer patient: a case report and literature review.",
"title_normalized": "spontaneous perforation of pyometra in a cervical cancer patient a case report and literature review"
} | [
{
"companynumb": "IN-PFIZER INC-2019014574",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CEFOPERAZONE SODIUM"
},
"drugadditional": "3",... |
{
"abstract": "The outcomes of COVID-19 in patients treated with biologic agents are a subject of intense investigation. Recent data indicated that patients under rituximab (RTX) may carry an increased risk of serious disease. We performed an electronic search in Medline and Scopus using the keywords rituximab and COVID-19. We present a rare case of severe, protracted COVID-19 pneumonia in a patient with mixed connective tissue disease (MCTD) who was infected a few days following RTX treatment. In a relevant literature search, we identified 18 cases of patients with rheumatic diseases (6 RA, 8 ANCA vasculitis, 3 systemic sclerosis and 1 polymyositis) treated with RTX who experienced an atypical and/or prolonged course of COVID-19 pneumonia with no evidence of cytokine storm. Our case indicates that RTX may unfavorably affect outcomes following SARS-CoV-2 infection. B cell depletion may dampen the humoral response against the virus; we may hypothesize that B cell-depleted patients may be protected from cytokine storm but on the other hand may have difficulties in virus clearance leading to a protracted course. Taking into account that COVID-19 vaccines are available we may consider delaying RTX infusions at least in patients without life threatening disease, until vaccination is completed.",
"affiliations": "Division of Rheumatology, Department of Internal Medicine, Patras University Hospital, University of Patras Medical School, Rion, 26504, Patras, Greece. jimdaoussis@hotmail.com.;Department of Infectious Diseases, Patras University Hospital, University of Patras Medical School, Patras, Greece.;Department of Radiology, Patras University Hospital, University of Patras Medical School, Patras, Greece.;Department of Microbiology, Patras University Hospital, University of Patras Medical School, Patras, Greece.;Department of Pneumonology, Patras University Hospital, University of Patras Medical School, Patras, Greece.",
"authors": "Daoussis|Dimitrios|D|http://orcid.org/0000-0001-8027-3655;Leonidou|Lydia|L|http://orcid.org/0000-0003-4167-2746;Kalogeropoulou|Christina|C|http://orcid.org/0000-0002-9725-1791;Paliogianni|Fotini|F|http://orcid.org/0000-0001-5112-1724;Tzouvelekis|Argyrios|A|http://orcid.org/0000-0002-6295-1384",
"chemical_list": "D018501:Antirheumatic Agents; D000069283:Rituximab",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00296-021-04969-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0172-8172",
"issue": "41(10)",
"journal": "Rheumatology international",
"keywords": "COVID-19; Rituximab; SARS-Cov-2",
"medline_ta": "Rheumatol Int",
"mesh_terms": "D000368:Aged; D018501:Antirheumatic Agents; D000086382:COVID-19; D000075203:Contraindications, Drug; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008947:Mixed Connective Tissue Disease; D000069283:Rituximab; D000086402:SARS-CoV-2",
"nlm_unique_id": "8206885",
"other_id": null,
"pages": "1839-1843",
"pmc": null,
"pmid": "34409510",
"pubdate": "2021-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Protracted severe COVID-19 pneumonia following rituximab treatment: caution needed.",
"title_normalized": "protracted severe covid 19 pneumonia following rituximab treatment caution needed"
} | [
{
"companynumb": "GR-PFIZER INC-202101100905",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Clinical and radiological diagnosis of infantile fibrosarcoma (IFS) is challenging because of its similarity to vascular origin tumors. Treatment involves complete resection. Although chemotherapy may allow more conservative resection, treatment guidelines are not strictly defined. One IFS patient with an unresectable tumor had disease progression during chemotherapy. A primary tumor sample showed high VEGFR-1/2/3 and PDGFR-α/β expression. After pazopanib therapy, most tumor showed necrosis within 29 days and could be removed completely, with no relapse in 8 months post-resection. When IFS features hypervascularity, VEGFR and PDGFR expression may be high, thus allowing consideration of VEGFR inhibitors such as pazopanib.",
"affiliations": "Department of Hematology/Oncology, Nagano Children's Hospital, Azumino, Japan.;Department of Plastic and Reconstructive Surgery, Nagano Children's Hospital, Azumino, Japan.;Department of Plastic and Reconstructive Surgery, Nagano Children's Hospital, Azumino, Japan.;Department of Hematology/Oncology, Nagano Children's Hospital, Azumino, Japan.;Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan.;Department of Clinical Pathology, Nagano Children's Hospital, Azumino, Japan.;Department of Pharmacy, Shinshu University Hospital, Matsumoto, Japan.;Department of Radiology, Nagano Children's Hospital, Azumino, Japan.;Department of Hematology/Oncology, Nagano Children's Hospital, Azumino, Japan.;Department of Hematology/Oncology, Nagano Children's Hospital, Azumino, Japan.;Division of Neonatology, Nagano Children's Hospital, Azumino, Japan.;Division of Neonatology, Nagano Children's Hospital, Azumino, Japan.;Department of Hematology/Oncology, Nagano Children's Hospital, Azumino, Japan.",
"authors": "Yanagisawa|Ryu|R|;Noguchi|Masahiko|M|;Fujita|Kenya|K|;Sakashita|Kazuo|K|;Sano|Kenji|K|;Ogiso|Yoshifumi|Y|;Katsuyama|Yoshihiko|Y|;Kondo|Yoshiaki|Y|;Komori|Kazutoshi|K|;Fujihara|Ikuko|I|;Kitamura|Rei|R|;Hiroma|Takehiko|T|;Nakamura|Tomohiko|T|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.25733",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "63(2)",
"journal": "Pediatric blood & cancer",
"keywords": "infantile fibrosarcoma; pazopanib; platelet-derived growth factor receptor; vascular endothelial growth factor receptor",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D020533:Angiogenesis Inhibitors; D001365:Axilla; D019008:Drug Resistance, Neoplasm; D005354:Fibrosarcoma; D006801:Humans; D007191:Indazoles; D007223:Infant; D008297:Male; D020360:Neoadjuvant Therapy; D011743:Pyrimidines; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "348-51",
"pmc": null,
"pmid": "26375879",
"pubdate": "2016-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Preoperative Treatment With Pazopanib in a Case of Chemotherapy-Resistant Infantile Fibrosarcoma.",
"title_normalized": "preoperative treatment with pazopanib in a case of chemotherapy resistant infantile fibrosarcoma"
} | [
{
"companynumb": "JP-ACCORD-050660",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "Circulating tumor cells (CTCs) are a rare population of cells found in the bloodstream and represent key players in the metastatic cascade. Their analysis has proved to provide further core information concerning the tumor. Herein, we aim at investigating CTCs isolated from a 32-year-old patient diagnosed with triple negative spindle-shaped metaplastic breast cancer (MpBC), a rare tumor poorly responsive to therapies and with a dismal prognosis. The molecular analysis performed on the primary tumor failed to underline effective actionable targets to address the therapeutic strategy. Besides the presence of round-shaped CTCs, cells with a spindle shape were present as well, and through molecular analysis, we confirmed their malignant nature. This aspect was coherent with the primary tumor histology, proving that CTCs are released regardless of their morphology. Copy number aberration (CNA) profiling and variant analysis using next-generation sequencing (NGS) showed that these cells did not harbor the alterations exhibited by the primary tumor (PIK3CA G1049A mutation, MYC copy number gain). However, despite the great heterogeneity observed, the amplification of regions involved in metastasis emerged (8q24.22-8q24.23). Our findings support the investigation of CTCs to identify alterations that could have a role in the metastatic process. To the best of our knowledge, this is the first examination of CTCs in an MpBC patient.",
"affiliations": "Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy.;Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy.;Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy.;Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy.;Scientific Directorate, IRCCS Istituto Scientifico Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy.;Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy.;Azienda Unità Sanitaria Locale Imola, Imola, Italy.;Pathology Unit, Morgagni-Pierantoni Hospital, Forlì, Italy.;Healthcare Administration, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy.;Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy.;Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy.",
"authors": "Rossi|Tania|T|;Palleschi|Michela|M|;Angeli|Davide|D|;Tebaldi|Michela|M|;Martinelli|Giovanni|G|;Vannini|Ivan|I|;Puccetti|Maurizio|M|;Limarzi|Francesco|F|;Maltoni|Roberta|R|;Gallerani|Giulia|G|;Fabbri|Francesco|F|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fmed.2021.689895",
"fulltext": "\n==== Front\nFront Med (Lausanne)\nFront Med (Lausanne)\nFront. Med.\nFrontiers in Medicine\n2296-858X\nFrontiers Media S.A.\n\n10.3389/fmed.2021.689895\nMedicine\nCase Report\nCase Report: Analysis of Circulating Tumor Cells in a Triple Negative Spindle-Cell Metaplastic Breast Cancer Patient\nRossi Tania 1*\n\nPalleschi Michela 2\n\nAngeli Davide 3\n\nTebaldi Michela 3\n\nMartinelli Giovanni 4\n\nVannini Ivan 1\n\nPuccetti Maurizio 5\nLimarzi Francesco 6\nMaltoni Roberta 7\nGallerani Giulia 1†\n\nFabbri Francesco 1†\n\n1Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy\n2Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy\n3Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy\n4Scientific Directorate, IRCCS Istituto Scientifico Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy\n5Azienda Unità Sanitaria Locale Imola, Imola, Italy\n6Pathology Unit, Morgagni-Pierantoni Hospital, Forlì, Italy\n7Healthcare Administration, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy\nEdited by: Dario de Biase, University of Bologna, Italy\n\nReviewed by: Ivonne Nel, Leipzig University, Germany; Liubov A. Tashireva, Tomsk Cancer Research Institute (RAS), Russia\n\n*Correspondence: Tania Rossi tania.rossi@irst.emr.it\nThis article was submitted to Pathology, a section of the journal Frontiers in Medicine\n\n†These authors have contributed equally to this work and share last authorship\n\n24 6 2021\n2021\n8 68989501 4 2021\n17 5 2021\nCopyright © 2021 Rossi, Palleschi, Angeli, Tebaldi, Martinelli, Vannini, Puccetti, Limarzi, Maltoni, Gallerani and Fabbri.\n2021\nRossi, Palleschi, Angeli, Tebaldi, Martinelli, Vannini, Puccetti, Limarzi, Maltoni, Gallerani and Fabbri\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nCirculating tumor cells (CTCs) are a rare population of cells found in the bloodstream and represent key players in the metastatic cascade. Their analysis has proved to provide further core information concerning the tumor. Herein, we aim at investigating CTCs isolated from a 32-year-old patient diagnosed with triple negative spindle-shaped metaplastic breast cancer (MpBC), a rare tumor poorly responsive to therapies and with a dismal prognosis. The molecular analysis performed on the primary tumor failed to underline effective actionable targets to address the therapeutic strategy. Besides the presence of round-shaped CTCs, cells with a spindle shape were present as well, and through molecular analysis, we confirmed their malignant nature. This aspect was coherent with the primary tumor histology, proving that CTCs are released regardless of their morphology. Copy number aberration (CNA) profiling and variant analysis using next-generation sequencing (NGS) showed that these cells did not harbor the alterations exhibited by the primary tumor (PIK3CA G1049A mutation, MYC copy number gain). However, despite the great heterogeneity observed, the amplification of regions involved in metastasis emerged (8q24.22–8q24.23). Our findings support the investigation of CTCs to identify alterations that could have a role in the metastatic process. To the best of our knowledge, this is the first examination of CTCs in an MpBC patient.\n\nmetaplastic breast cancer\ncirculating tumor cells\nnext generation sequencing\ncopy number aberration\nmetastasis\nliquid biopsy\n==== Body\nIntroduction\n\nAmong all the breast malignancies, metaplastic breast cancer (MpBC) accounts for <1% and has a dismal prognosis, worse than the other BC types. Pathologically, MpBCs are ductal carcinomas composed by one or more cell populations that have undergone metaplastic transformation into a non-glandular pattern, leading to the presence of epithelial (e.g., squamous cells) and sarcomatous (e.g., chondroid, spindle cell, and osseous) elements. The World Health Organization (WHO) further divides MpBCs in subgroups, resulting in a plethora of chemorefractory and aggressive MpBC variants (1–3).\n\nDespite the paucity of MpBC cases, some studies in literature have detected epithelial-to-mesenchymal transition (EMT), phosphoinositide 3-kinase (PI3K) signaling, epidermal growth factor receptor (EGFR) signaling, and others as the major altered pathways in this disease (3). Nevertheless, the lack of actionable targets remains a matter of concern, and conventional regimens of chemotherapy mainstay are the gold standards for treatment together with surgery and radiation therapy (4, 5). However, the poor survival and the high recurrence rates further emphasize the inadequacy of the available treatment options and the imperative need to individuate appropriate therapeutic strategies.\n\nGenetic and phenotypic heterogeneity is a hallmark of MpBC and has important reflections for cancer treatment as the presence of multiple clones may hide cells responsible for relapse (6, 7). In this context, the characterization of circulating tumor cells (CTCs), a rare population of cells considered as pro-metastasis precursors (8), may be helpful in the unraveling of tumor heterogeneity (9).\n\nWe report a case of a patient diagnosed with triple negative spindle-cell MpBC for which molecular analysis of the primary tumor failed to highlight valid actionable alterations. We decided to characterize CTCs at both morphological and molecular levels, as they may bring out new alterations to be explored. To the best of our knowledge, this is the first examination of CTCs in a MpBC patient.\n\nCase Presentation\n\nHere we report the case of a 32-year-old patient (Figure 1) who presented, on December 20, 2018, during breastfeeding, a clinical onset of a right breast lump. Ultrasound-guided core biopsy of this right breast mass was performed with histological diagnosis of metaplastic spindle-cell infiltrating carcinoma of the breast, estrogen receptor (ER) = 0%, progesterone receptor (PgR) = 0%, HER2-neu negative (score 0), and Ki-67 = 90%. She had a past history of Crohn's disease, at the time of MpBC diagnosis during treatment with mesalamine. Positron emission tomography-computed tomography (PET-CT) revealed a 40-mm lesion in the right breast without bone or visceral involvement. In January 2019, treatment began with neoadjuvant chemotherapy (NAC) with adryamicin (60 mg/m2) and cyclophosphamide (600 mg/m2) intravenous for one cycle. Due to local progression, NAC was switched to docetaxel for one cycle (January 23, 2019), but the patient experienced further local progression.\n\nFigure 1 Patient's timeline. At the top, we reported the milestones of her clinical course, while on the bottom the treatment regimens administered to the patient. PET-CT, positron emission tomography-computed tomography; AC, adryamicin-cyclophosphamide; DTX, docetaxel; PTX, paclitaxel; CIS, cisplatin; VRL, vinorelbine; CAP, capecitabine; ERI, eribulin; DXR, doxorubicin; EVE, everolimus; BEV, bevacizumab; CTC, circulating tumor cell.\n\nIn February 2019, she underwent right mastectomy with axillary node dissection; the histopathology exam describes a lesion of 65-mm maximum diameter, ypT3 ypN0 M0, ER = 0%, PgR = 0%, HER2-neu negative (score 0), and Ki-67 = 90%. The microscopic photograph (10 × magnification) of hematoxylin and eosin staining of the resected tumor is reported in Figure 2. On immunostains, the tumor cells were strongly positive for vimentin and showed weak positivity for p63. Cytokeratins (AE1/AE3 clone) and E-cadherin were positive in scattered cells. Moreover, CAM5.2, calponin, SMA, GATA-3, ALK, ER, PR, and Her2-neu were negative. Expression of programmed death-ligand 1 (PD-L1) was <1%.\n\nFigure 2 Microscopic hematoxylin and eosin photograph of metaplastic breast carcinoma (MpBC) with coexisting spindled (green arrows) and oval (black arrows) cells. Scale bar: 50 μm.\n\nFrom March to June 2019, she received adjuvant weekly paclitaxel (80 mg/m2) for 12 cycles. From July to August 2019 right chest radiotherapy (total dose 50 Gy) was performed.\n\nIn November 2019, PET-CT scan revealed the presence of a 40 × 37-mm lung lesion and other sub-centimeter bilateral lung nodules. Further analyses on primary tumor revealed no BRCA1/BRCA2 alterations.\n\nFrom November to December 2019, she received two cycles of cisplatin (60 mg/m2; day 1), vinorelbine (20 mg/m2; days 1 and 3), and capecitabine (500 mg thrice a day).\n\nIn January 2020, PET-CT showed lung, bone, and bilateral ovarian progression. The NGS Oncomine Focus Assay (Thermo Fisher Scientific) on the primary tumor exposed the G1049A PIK3CA mutation and amplification of the MYC locus (copy number: 26 copies).\n\nIn January 2020, she received two cycles of eribulin (1.23 mg/m2), and in February, she underwent bilateral ovariectomy and wedge liver resection. The histopathology exam described triple negative metaplastic BC metastases. Moreover, several subcutaneous metastases on the scalp, neck, and chest arise, other than bilateral lung nodules. After multidisciplinary meeting, in consideration of the absence of valid therapeutic alternatives, physicians decided to start an “off-label” treatment regimen: doxorubicin (30 mg/m2) plus bevacizumab (15 mg/kg every 3 weeks) plus everolimus (7.5 mg daily) (10).\n\nIn February 2020, she started the first cycle (without bevacizumab due to recent surgery), with a clinically stable disease, improvement on pain, and reduction of all subcutaneous nodules. Before chemotherapy administration, CTC investigation was performed.\n\nIn March 2020, she received the second cycle (including bevacizumab). She had a clinical benefit in terms of the disappearance of most subcutaneous metastases, no pain, and a good quality of life until April 2020 when she complained of fever, cough, and low blood pressure. Therefore, she was hospitalized for the appropriate treatment with antibiotics and steroids without benefit, and she died on April 21, 2020 due to respiratory failure.\n\nIsolation of Circulating Tumor Cells and Analyses\n\nTo investigate the features of CTCs, approximately 9 ml of peripheral blood was collected in a PAXGene Blood ccfDNA tube before the administration of the off-label therapy. CTCs were enriched from whole blood by immunomagnetic negative selection. In order to identify the highest number of CTCs, we opted for antibody cocktails for the detection of each phenotype, instead of a single target for each channel. EpCAM, CKs, and E-cadherin antibodies were used to identify epithelial phenotype (phycoerythrin, PE channel), and N-cadherin, ABCG2, CD44v6, and CD133 were used to identify stem/mesenchymal phenotype (allophycocyanin, APC channel). Hoechst 33342 (DAPI channel) was used for nuclear staining and anti-CD45 Alexafluor488 antibody (FITC channel) as leukocyte marker for CTC negative selection. CTC identification and analysis were performed by DEPArray NxT platform (Figure 3A). To set up the auto-fluorescence signal detected in FITC channel, we used MCF7 cell line (CD45–) and leukocytes (CD45+) (Supplementary Figure 1).\n\nFigure 3 (A) DEPArray images of the most representative single circulating tumor cells (CTCs) of the patient based on their shape (round- and spindle-shaped). The DAPI channel was used for nuclear staining using Hoechst 33342, PE channel for epithelial tag [anti-EPCAM, anti-cytokeratins (CKs) and anti-E-cadherin antibodies], and APC channel for mesenchymal tag (anti-N-cadherin, anti-CD44v6, anti-ABCG2, and anti-CD133 antibodies). Anti-CD45 (FITC channel) was used for CTC negative selection (Supplementary Figure 1). Scale bar: 30 μm. (B) Profiling of the CTC ID: 793 reveals the presence of aberrant regions, consistent with tumor nature. Chromosomes (Chr) and number of copies are reported along the x- and y-axis, respectively. Black dots in the figure represent chromosome regions with a normal diploid copy number. Conversely, red dots and blue dots indicate, respectively, significant copy number gains (copies > 2) and losses (copies <2), called by Control-FREEC (11).\n\nWe identified non-canonical cells positive for both epithelial and stem/mesenchymal targets with a spindle-shaped morphology (n = 14) and CTCs with a round-shaped morphology (n = 184). CTC clusters (n = 5) were present as well (Supplementary Figure 2). Due to the high amount of debris into the sample, we successfully sorted one single spindle-shaped cell (ID: 793) and two 10-CTC pools (Pool 1 and Pool 2).\n\nNext, we aimed at assessing the molecular characteristics of the MpBC patient's CTCs isolated through DEPArray and to establish the nature of the spindle-shaped cell. To do this, we massively amplified the genome of the samples using Ampli1 WGA kit (Menarini-Silicon Biosystems) to obtain evaluable genetic material, then we proceeded with library construction and sequencing for copy number aberrations (CNAs) and single nucleotide variant (SNV) analyses.\n\nFor CNAs, libraries were prepared using the Ampli1 LowPass kit for Ion Torrent (Menarini-Silicon Biosystems).\n\nAfter Ion 520 chip loading was performed on Ion Torrent Chef (Thermo Fisher Scientific), sequencing was carried out on an Ion S5 System (Thermo Fisher Sc.), and CNAs were called with Control-FREEC (11). Through this technique, we were able to unequivocally establish the tumor nature of the unconventional spindle-shaped CTC (ID: 793), since it was characterized by an aneuploid genome with an altered CNA profile (Figure 3B). Through intersection bioinformatic analysis, we observed that the greatest part of the entire genome was not comparable among the three samples, suggesting high heterogeneity levels. We detected only three mutual aberrant regions (4p16.1, 8q24.22–8q24.23, and 22q12.3) shared among the samples, which were always in gain. The genes within the mentioned regions are reported in Supplementary Table 1. We did not observe the gain of MYC gene, which was observed in the primary tumor molecular characterization. Moreover, after whole genome amplification, we assessed the mutational status of 60 cancer-related genes. Libraries were prepared using the Ampli1 OncoSeek kit (Menarini Silicon Biosystems) and run on a 300-cycle V2 cartridge on the miSeq instrument (Illumina Inc.). We did not observe the PIK3CA mutation G1049A, which emerged at primary tumor NGS analysis. The single CTC 793 harbored the homozygous RET I602V and heterozygous M249V variant of gene MAP2K1. Interestingly, we also found a heterozygous synonymous C50C variant of TP53 that, although not responsible for the amino acid change in protein structure, may be associated with gene expression regulation as it occurs in the noncoding exon 1 (12). Concerning the 10-CTC pools, in Pool 1, we found the variants KRAS S17I (frequency 80%), PIK3CA W498C (20%), PTEN A34T (16%), MET T835N (14%), PIK3CA L1026I (14%), SMAD4 Q249R (10%), KIT G534V (10%), MAP2K1 G131A and N122K (10%), and PTEN M35T (10%). Pool 2 harbored the HRAS frameshift deletion I46fs (20%) and the non-synonymous SNV of RB1 R556G (10%). None of the detected variants were already described as pathogenic in literature, and no variants were identified in common among the samples. However, frequencies of some alterations found in samples Pool 1 and Pool 2 reveal that more than one cell within each pool harbor certain mutations.\n\nDiscussion\n\nHere, we report a case of a 32-year-old patient diagnosed with triple-negative spindle-cell MpBC, a rare disease with marked tendency to metastasize to secondary organs. Because of the paucity of cases, few is known about the molecular mechanisms underlying its aggressiveness, and no druggable targets have been identified yet.\n\nInvestigation of the primary tumor performed through an NGS-based approach detected alterations that are not uniquely ascribable to MpBC and failed to underline effective actionable targets to address the therapeutic strategy. Indeed, MYC copy number gain (13, 14) and PIK3CA mutation (15, 16) are widely described in the literature to be involved in many cancer types, including BC (17, 18). Herein, by exploiting a liquid biopsy approach, we emphasize that the characterization of CTCs, rare cells with a crucial role in the metastatic cascade, could be worthwhile to guide the investigation of the molecular mechanisms underlying rare tumors. However, this study has some weaknesses. First, due to the high amount of debris in the sample, it was not possible for us to recover, for downstream analysis, all the CTCs found. Moreover, the primary tumor and metastatic tissue specimens were not available, making impossible the comparison with CTCs, except for clinical reports. Conversely, to the best of our knowledge, this is the first investigation of CTCs in an MpBC case and could have a strong impact in the improvement of personalized medicine in the future. In fact, the investigation of CTCs has the potential to unmask the intra-tumor heterogeneity of MpBC, revealing the presence of under-represented clones from the primary tumor. Simultaneously, longitudinal molecular profiling of CTCs could reveal acquired resistance mechanism, helping to address the therapeutic strategy (19).\n\nOur analysis revealed a high count of CTCs expressing both epithelial and mesenchymal markers in the peripheral blood of the MpBC patient. CTC enumeration and evaluation have been performed in a delayed period after removal of the primary tumor. Therefore, in the absence of their major source, CTCs are likely to come from secondary homing sites such as bone marrow or other occult niches (9, 20).\n\nThe first criterion concerned the different morphology of CTCs retrieved in the bloodstream of the patient. Along with the canonical round CTCs, we found unconventional cells characterized by a spindle morphology, whose nature was confirmed to be cancerous due to the presence of CNAs along the genome. A study by Yu et al., conducted on non-metaplastic BC patients, demonstrates that besides the presence of round-shaped CTCs with unconventional morphology associated with EMT initiation, therapy failure and tumor progression were present as well (21). However, it is not clear whether the presence of both round- and spindle-shaped CTCs in this MpBC case assumes the same meaning as in non-metaplastic BC, or is consistent with tumor histology solely. Indeed, the cytopathology of CTCs detected in this MpBC case is coherent with primary tumor histology, in which oval and spindle-shaped cells were shown to coexist. Thorough analysis on the metastatic site specimens would provide further information about the role of CTC morphology in MpBC tumor progression.\n\nConcerning molecular analyses, we found that CTCs did not harbor primary tumor-specific alterations (MYC copy number gain and G1049A PIK3CA mutation). In addition, CTC samples had discordant CNAs and SNVs compared with each other, suggesting molecular heterogeneity as well. These results are consistent with the presence of circulating heterogeneous subclones with a potential role in tumor progression and resistance to therapies. Accordingly, in the HR-positive metastatic BC patient, CTCs could circulate as heterogeneous subclones and harbor molecular alterations that could drive to different mechanisms of resistance to endocrine therapies (22). Together with our data, these findings support the need to increase the application of CTCs in the clinical practice to gain further complementary information concerning the tumor evolution, including therapy resistance.\n\nCNA profiling revealed the existence of three amplified genomic regions (4p16.1, 8q24.22–8q24.23, and 22q12.3) shared among the CTC samples. Among these, region 8q24.22–8q24.23 turned out to be highly attractive.\n\nAmplification of chromosome 8q regions has been described in numerous cancer types, such as hepatocellular carcinoma (23), gastric cancer (24), clear cell renal carcinoma (25), and BC (26). In particular, in BC, 8q is considered a hotspot site of amplification associated with unfavorable prognosis (27) and, accordingly in our study, poor response to NAC (28), in part due to the location of c-myc locus in 8q24.1, near 8q24.22–8q24.23. However, the tendency to drive metastasis is not only imputable to MYC solely, but other genes have been hypothesized to enhance the metastatic process, as reported by Han and collaborators (28). Accordingly, investigation of CTCs revealed that several cancer-associated genes were found altered, but not MYC.\n\nFor instance, WISP1 codifies for WNT1-inducible signaling pathway protein 1 (WISP1/CCN4), a member of the CCN family that acts as an oncogene in BC. It has been shown to stimulate EMT and metastasis, and to modulate the expression of the tumor suppressor N-myc downstream-regulated gene 1 (NDRG1) in BC cell lines. This modulation occurs through the NDGR1 gene promoter, which is located within the 8q24.23 site (29). However, the role of this tumor-suppressor protein is controversial, as recent data highlighted that NDRG1 expression is a predictor of worse prognosis in inflammatory BC patients receiving adjuvant radiotherapy (30). Both WISP1 and NDGR1 loci are included within the regions that we found in gain in all the CTC samples.\n\nAnother gene located in the 8q22.2 locus that recently emerged as a metastasis driver is the Otoconin 90 (OC90) gene. Although it is normally expressed in the cochlea for appropriate otolith development, its expression and gene amplification were observed in different cancer types, such as breast, prostate, and lung cancer. In TNBC cell lines, OC90 overexpression was shown to increase invasion, and knockdown reduced cellular viability and invasiveness (31).\n\nTaken together, despite high levels of heterogeneity, we observed that the analysis of CTCs at the molecular level can potentially drive to the discovery of chromosomal regions that may have a role in the metastatic cascade. In the future, this aspect could be helpful to deepen the knowledge regarding MpBC and to address new therapeutic strategies.\n\nData Availability Statement\n\nThe datasets presented in this article are not readily available for ethical and privacy reasons. Requests to access the datasets should be directed to the corresponding author.\n\nEthics Statement\n\nEthical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nTR, MPa, GM, IV, GG, and FF contributed to the conceptualization and design of the study. TR and MPa wrote the first draft. DA and MT performed bioinformatic analysis. TR, MPa, MPu, FL, RM, and GG contributed to data collection. GG and FF reviewed the final draft before submission. All authors contributed to the manuscript revision, and read and approved the submitted version.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmed.2021.689895/full#supplementary-material\n\nClick here for additional data file.\n\nClick here for additional data file.\n\nClick here for additional data file.\n==== Refs\nReferences\n\n1. Pezzi CM Patel-Parekh L Cole K Franko J Klimberg VS Bland K . Characteristics and treatment of metaplastic breast cancer: analysis of 892 cases from the national cancer data base. Ann Surg Oncol. (2006) 14 :166–73. 10.1245/s10434-006-9124-7 17066230\n2. Tray N Taff J Adams S . Therapeutic landscape of metaplastic breast cancer. Cancer Treat Rev. 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Cancer Discov. (2016) 6 :479–91. 10.1158/2159-8290.CD-15-1483 26969689\n20. Banys M Krawczyk N Becker S Jakubowska J Staebler A Wallwiener D . The influence of removal of primary tumor on incidence and phenotype of circulating tumor cells in primary breast cancer. Breast Cancer Res Treat. (2012) 132 :121–9. 10.1007/s10549-011-1569-0 21562707\n21. Yu M Bardia A Wittner BS Stott SL Smas ME Ting DT . Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science. (2013) 339 :580–4. 10.1126/science.1228522 23372014\n22. Paoletti C Cani AK Larios JM Hovelson DH Aung K Darga EP . Comprehensive mutation and copy number profiling in archived circulating breast cancer tumor cells documents heterogeneous resistance mechanisms. Cancer Res. (2018) 78 :1110–22. 10.1158/0008-5472.CAN-17-2686 29233927\n23. Zhao K Zhao Y Zhu J-Y Dong H Cong W-M Yu Y . A panel of genes identified as targets for 8q24.13-24.3 gain contributing to unfavorable overall survival in patients with hepatocellular carcinoma. Curr Med Sci. (2018) 38 :590–6. 10.1007/s11596-018-1918-x 30128866\n24. Kang JU . Chromosome 8q as the most frequent target for amplification in early gastric carcinoma. Oncol Lett. (2014) 7 :1139–43. 10.3892/ol.2014.1849 24944681\n25. Klatte T Kroeger N Rampersaud EN Birkhäuser FD Logan JE Sonn G . Gain of chromosome 8q is associated with metastases and poor survival of patients with clear cell renal cell carcinoma. Cancer. (2012) 118 :5777–82. 10.1002/cncr.27607 22605478\n26. Ching HC Naidu R Seong MK Har YC Taib NAM . Integrated analysis of copy number and loss of heterozygosity in primary breast carcinomas using high-density SNP array. Int J Oncol. (2011) 39 :621–33. 10.3892/ijo.2011.1081 21687935\n27. Zhang Y Martens JWM Yu JX Jiang J Sieuwerts AM Smid M . Copy number alterations that predict metastatic capability of human breast cancer. Cancer Res. (2009) 69 :3795–801. 10.1158/0008-5472.CAN-08-4596 19336569\n28. Han S Park K Shin E Kim H-J Kim JY Kim JY . Genomic change of chromosome 8 predicts the response to taxane-based neoadjuvant chemotherapy in node-positive breast cancer. Oncol Rep. (2010) 24 :121–8. 10.3892/or_00000836 20514452\n29. Chiang K-C Yeh C-N Chung L-C Feng T-H Sun C-C Chen M-F . WNT-1 inducible signaling pathway protein-1 enhances growth and tumorigenesis in human breast cancer. Sci Rep. (2015) 5 :8686. 10.1038/srep08686 25732125\n30. Villodre ES Gong Y Hu X Huo L Yoon EC Ueno NT . NDRG1 expression is an independent prognostic factor in inflammatory breast cancer. Cancers. (2020) 12 :3711. 10.3390/cancers12123711 33321961\n31. Pearlman A Rahman MT Upadhyay K Loke J Ostrer H . Ectopic Otoconin 90 expression in triple negative breast cancer cell lines is associated with metastasis functions. PLoS ONE. 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"abstract": "Diabetic ketoacidosis (DKA) is a life-threatening acute metabolic complication occurring in patients with diabetes, especially in patients with type 1 diabetes (T1D), due to an insulin deficiency. Moderate hypertriglyceridemia is commonly observed in DKA but severe hypertriglyceridemia with a triglyceride level exceeding 10g/L is very rarely reported. We report a case of a 14-year-old boy who had type 1 diabetes for 4 years treated with insulin therapy, also having adrenal insufficiency treated with hydrocortisone who presented with ketoacidosis and excruciating abdominal pain. Investigations revealed hypertriglyceridemia at 64g/L, lipasemia at 1000 U/L, and stage E pancreatitis on abdominal CT. The patient was treated with intravenous insulin, rehydration, and fenofibrate with good clinical and biological evolution. Severe hypertriglyceridemia causing pancreatitis in type 1 diabetes mellitus is a rare but very serious complication of DKA in children.",
"affiliations": "Department of Endocrinology, Diabetes, Metabolic Diseases and Nutrition, Mohammed VI University Hospital, Marrakech, Morocco.;Department of Endocrinology, Diabetes, Metabolic Diseases and Nutrition, Mohammed VI University Hospital, Marrakech, Morocco.;Department of Endocrinology, Diabetes, Metabolic Diseases and Nutrition, Mohammed VI University Hospital, Marrakech, Morocco.;Department of Endocrinology, Diabetes, Metabolic Diseases and Nutrition, Mohammed VI University Hospital, Marrakech, Morocco.;Department of Endocrinology, Diabetes, Metabolic Diseases and Nutrition, Mohammed VI University Hospital, Marrakech, Morocco.",
"authors": "Zaher|Fatima Zahra|FZ|0000-0002-9480-1663;Boubagura|Imane|I|;Rafi|Sana|S|;Elmghari|Ghizlane|G|;Elansari|Nawal|N|",
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"fulltext": "\n==== Front\nCase Rep EndocrinolCase Rep EndocrinolCRIECase Reports in Endocrinology2090-65012090-651XHindawi 10.1155/2019/8974619Case ReportDiabetic Ketoacidosis Revealing a Severe Hypertriglyceridemia and Acute Pancreatitis in Type 1 Diabetes Mellitus http://orcid.org/0000-0002-9480-1663Zaher Fatima Zahra drzaherfz@gmail.comBoubagura Imane Rafi Sana Elmghari Ghizlane Elansari Nawal Department of Endocrinology, Diabetes, Metabolic Diseases and Nutrition, Mohammed VI University Hospital, Marrakech, MoroccoAcademic Editor: John Broom\n\n2019 6 1 2019 2019 897461911 10 2018 1 12 2018 26 12 2018 Copyright © 2019 Fatima Zahra Zaher et al.2019This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Diabetic ketoacidosis (DKA) is a life-threatening acute metabolic complication occurring in patients with diabetes, especially in patients with type 1 diabetes (T1D), due to an insulin deficiency. Moderate hypertriglyceridemia is commonly observed in DKA but severe hypertriglyceridemia with a triglyceride level exceeding 10g/L is very rarely reported. We report a case of a 14-year-old boy who had type 1 diabetes for 4 years treated with insulin therapy, also having adrenal insufficiency treated with hydrocortisone who presented with ketoacidosis and excruciating abdominal pain. Investigations revealed hypertriglyceridemia at 64g/L, lipasemia at 1000 U/L, and stage E pancreatitis on abdominal CT. The patient was treated with intravenous insulin, rehydration, and fenofibrate with good clinical and biological evolution. Severe hypertriglyceridemia causing pancreatitis in type 1 diabetes mellitus is a rare but very serious complication of DKA in children.\n==== Body\n1. Introduction\nDiabetes ketoacidosis (DKA) is the association of hyperglycemia with serum glucose ≥200 mg/dL or 11 mmol/L, the presence of ketonemia or ketonuria and acidosis with serum bicarbonate <15 mEq/L, or venous pH < 7.3 [1]. DKA represents a common complication of T1D due to an absolute insulin deficiency; it can be the mode of revelation of type 1 diabetes in 25% of cases [2], as it can complicate the evolution of a known T1D. Severe hypertriglyceridemia is an uncommon T1D complication which is also due to insulin deficiency and which can trigger acute pancreatitis. The triad of DKA, severe hypertriglyceridemia, and acute pancreatitis have been rarely described in children, especially in those with new onset T1D. We report only the tenth observation of this triad in a child known to be diabetic for 4 years with poor glycemic control.\n\n2. Case Report\nWe report a case of a 14-year-old boy with type 1 diabetes from the age of 9 years treated with insulin 4 injections per day and followed up one year ago for adrenal insufficiency treated with hydrocortisone 25mg per day. His maternal uncle had a type 2 diabetes and his sister has been diagnosed with corticoid-induced diabetes; no family history of dislipidemia was reported. This child presented to the emergency room with severe abdominal pain and vomiting and he was found to have DKA, with an elevated lipase of 1000 U/L, and his abdominal ultrasound was suggestive of acute pancreatitis associated with moderate peritoneal effusion. His abdominal computed tomography (CT) showed pancreatitis grade E with antropyloric parietal thickening extended to the 2nd part of the duodenum associated with peritoneal effusion and a moderate hepatomegaly; the imaging did not show any other anomaly causing acute pancreatitis (Figures 1, 2 and 3). His plasma triglyceride (TG) level at admission was very high 64 g/L, and C- reactive protein was elevated at 358 mg/L, and other biochemical values were at the normal range. Fluid resuscitation and insulin therapy have been started and, on arrival to the pediatric intensive care unit, he was treated with the continuous insulin infusion, fenofibrate 160mg per day, antibiotic (third-generation cephalosporins 2g per day), and hydrocortisone 50mg four times per day intravenously. The indication of plasmapheresis was not retained in the light of the reduction in triglyceride levels.\n\nHe was transferred to our department one week after stabilization. History revealed steatorrhea 15 days before admission and a glycemic imbalance with hemoglobin A1c level of 11.5% (2 months before his admission). Our patient had a Glasgow score of 15/15, pulse rate 80/min, respiratory rate 16/min, and blood pressure 90/61mmHg. Anthropometric measurements showed weight of 44 kg, height 155 cm, body mass index 18.3 kg/m2, and a capillary glycemia of 3.38 g/L with presence of urine ketone; there was no eruptive or tuberous xanthoma or xanthelasma at the skin.\n\nThe therapeutic management was continued by correction of diabetic ketosis, fenofibrates, and the use of unsaturated oils: omega 3.6.9. The evolution was favorable: clinical improvement marked by disappearance of pain and a biological improvement (Table 1).\n\nAt the follow-up, the monitoring was favorable, the level of triglycerides gradually decreases until normalization, and the last rate is 1.56 g/L.\n\n3. Discussion\nDiabetic ketoacidosis (DKA) is associated with an increase in triglycerides (TG) level, which is observed in approximately 30-50% of cases [3]; however severe hypertriglyceridemia (HTG), defined by a triglyceride level above 2000 mg/dL [4], is a rare complication of ketoacidosis which increases the risk of acute pancreatitis.\n\nIn many case reports, severe HTG is observed during DKA associated with newly diagnosed T1D [5, 6] or attributed to poor diabetes control [7] with severe insulin deficiency. In our case, the fact that his HbA1c was 11.5% signifies insulin deficiency for months, even if he did not report discontinuing his insulin therapy.\n\nThe mechanism of hypertriglyceridemia in DKA involves insulin deficiency which activate lipolysis in adipose tissue and increase the release of free fatty acid, which accelerate formation of very low-density lipoprotein by the liver [5]. Insulin deficiency is also associated with decreased activity of lipoprotein lipase (LPL), the enzyme responsible for TG metabolism, which reduces the clearance of VLDL and chylomicrons from the plasma, causing hypertriglyceridemia [8, 9].\n\nHowever, in severe hypertriglyceridemia, the pathogenesis cannot be only explained by insulin deficiency, but may be aggravated by a coexisting genetic predisposition to hypertriglyceridemia, especially mutations in the gene coding for LPL which is located in chromosome 8 [10]. In the literature, more than 100 mutations of that gene with autosomal recessive inheritance were reported [11]. Young patients with homozygous mutation present with severe hypertriglyceridemia with abdominal pain, recurrent episodes of acute pancreatitis, and xanthomas [12] and those symptoms occur during the first year of life in approximately 25% of cases. However, in patients with a heterozygous mutation with normal health condition otherwise, blood lipid level is slightly increased or normal and disease symptoms occur during periods of insulin deficiency, stressful situation, or pregnancy [9, 11, 13].\n\nAlthough severe hypertriglyceridemia is a rare condition, it may have devastating consequences such as lipidemia retinalis or acute pancreatitis [7]. Acute pancreatitis secondary to hypertriglyceridemia was reported in only 4% of DKA episodes in adults [14], and only nine cases are reported in children [5]. A triglyceride level more than 10g/L is associated with a risk of 5% for the development of acute pancreatitis; this risk is increased to 10%–20% when the triglyceride level is more than 20g/L [14]; DKA itself can cause pancreatic injury with false elevation of amylase and lipase. In our patient, the initial TG level was 64g/L. The mechanisms of this acute pancreatitis are composed of intrapancreatic release of free fatty acids resulting in cell injury, edema, and ischemia, as well as pancreatic ischemia caused directly by capillary hyperviscosity due to hyperchylomicronemia [15].\n\nManagement of DKA with HTG includes continuous insulin administration and intravenous fluid and according to diabetic ketoacidosis guidelines because the major mechanism of hypertriglyceridemia is insulin deficiency. However, some patients may require plasmapheresis, especially those with organ failure, which is the case of the patient reported by Lutfi who had extremely high TG level (163 g/L) with renal insufficiency, who failed with conservative treatment, but was successfully treated by plasmapheresis [16]. Heparin was also reported as a treatment for hypertriglyceridemia in adult with DKA, associated with fluid and insulin administration [17]. The use of lipid-lowering agents, such as fibrates, can be useful in most conditions accompanied by HTG but not beneficial in patients with lipoprotein lipase deficiency [18]. Omega oils are essential fatty acid naturally present in fish, algae, and other seafood; their use as a TG-lowering drug in the management of severe HTG is recommended by both the National Lipid Association [19] and the American Heart Association [20]. The EVOLVE study found a statistically significant reduction in serum TG in patients with severe HTG treated with omega 3 oil 2 g daily in comparison with those treated with olive oil 2 g daily, with a greater treatment effect in patients with very high baseline TG concentrations [21]. The proposed mechanisms to explain these finding include decreased VLDL synthesis by altering transcription factors such as sterol regulatory element-binding proteins involved in triglyceride synthesis and increased triglyceride clearance from the serum by increased lipoprotein lipase activity [22]. In our case, TG level was reduced from 64g/l to 3.37 g/L in 5 days, under insulin, fluid administration, fibrates, and omega oils.\n\nThe weakness of our case was that we could not perform appropriate genetic testing in our patient as well as his first-degree relatives. The genetic testing would have had an impact on the management of our patient since the majority of TG-lowering drugs, other than omega oils, decrease the plasma TG levels by the stimulation LPL activity, which makes them less effective in the case of a severely dysfunctional LPL protein. Surendran et al. have shown that a molecular diagnosis is effective in patients with severe HTG, and, by diagnosing the underlying genetic defect, different therapeutic strategies can be proposed [23]. For example, in the case of a genetic defect in GPIHBP1, where LPL itself is unaffected, Surendran et al. successfully used heparin infusion to facilitate activating LPL in the absence of GPIHBP1. On the other hand, in the case of patients with genetic LPL gene deficiency, LPL gene therapy has been used successfully. However, in the case of APOC2 or LMF1 deficiency, no clear treatment options are currently available, beyond strict dietary restrictions [23].\n\n4. Conclusion\nIn patients with diabetic ketoacidosis and acute pancreatitis, clinicians should be aware of the possibility of associated hypertriglyceridemia caused by the severe insulin deficiency, recognition of this triad has important implications in the management of the patient as insulin requirements, and recovery period can be changed.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 Abdominal CT showing a stage E pancreatitis.\n\nFigure 2 Abdominal CT showing a stage E pancreatitis.\n\nFigure 3 Abdominal CT showing a stage E pancreatitis.\n\nTable 1 Evolution of biological parameters.\n\n\nDAYS\n\t\nTG (g/l)\n\t\nLIPASE (U/l)\n\t\nCRP (mg/l)\n\t\n\n1st day\n\t64\t1000\t358\t\n\n2nd day\n\t20\t410\t350\t\n\n3rd day\n\t12\t285\t169\t\n\n4th day\n\t4.31\t-\t76\t\n\n5th day\n\t3.37\t159\t20\t\n\n6th day\n\t4.20\t-\t5.38\t\n\n7th day\n\t3.32\t65\t5.25\n==== Refs\n1 Wolfsdorf J. I. The International Society of Pediatric and Adolescent Diabetes guidelines for management of diabetic ketoacidosis: do the guidelines need to be modified? Pediatric Diabetes 2014 15 4 277 286 10.1111/pedi.12154 2-s2.0-84901458833 24866064 \n2 Rewers A. Klingensmith G. Davis C. Presence of diabetic ketoacidosis at diagnosis of diabetes mellitus in youth: The search for diabetes in youth study Pediatrics 2008 121 5 e1258 e1266 2-s2.0-44449178931 10.1542/peds.2007-1105 18450868 \n3 Blackett P. R. Holcombe J. H. Alaupovic P. Fesmire J. D. Plasma lipids and apolipoproteins in a 13-year-old boy with diabetic ketoacidosis and extreme hyperlipidemia The American Journal of the Medical Sciences 1986 291 5 342 346 10.1097/00000441-198605000-00010 2-s2.0-0022720924 3085497 \n4 Fulop M. Eder H. Severe hypertriglyceridemia in diabetic ketosis The American Journal of the Medical Sciences 1990 300 6 361 365 10.1097/00000441-199012000-00004 2-s2.0-0025648269 2124781 \n5 Sharma P. K. Kumar M. Yadav D. K. Severe hypertriglyceridemia causing pancreatitis in a child with new-onset type-i diabetes mellitus presenting with diabetic ketoacidosis Indian Journal of Critical Care Medicine 2017 21 3 176 178 2-s2.0-85015416551 10.4103/ijccm.IJCCM_281_16 28400692 \n6 Wolfgram P. M. MacDonald M. J. Severe hypertriglyceridemia causing acute pancreatitis in a child with new onset type I diabetes mellitus presenting in ketoacidosis Journal of Pediatric Intensive Care 2013 2 2 77 80 2-s2.0-85013616532 24455446 \n7 Saengkaew T. Sahakitrungruang T. Wacharasindhu S. Supornsilchai V. DKA with Severe Hypertriglyceridemia and Cerebral Edema in an Adolescent Boy: A Case Study and Review of the Literature Case Reports in Endocrinology 2016 2016 4 7515721 10.1155/2016/7515721 \n8 Radhakutty A. Shen J. Hooper A. J. Quantification and genotyping of lipoprotein lipase in patients with diabetic lipaemia Diabetic Medicine 2014 31 12 1702 1707 2-s2.0-84910606148 10.1111/dme.12565 25131724 \n9 Nocoń-Bohusz J. Wikiera B. Basiak A. Śmigiel R. Noczyńska A. LPL gene mutation as the cause of severe hypertriglyceridemia in the course of ketoacidosis in a patient with newly diagnosed type 1 diabetes mellitus Pediatric Endocrinology, Diabetes and Metabolism 2015 21 2 89 92 2-s2.0-84988227785 10.18544/PEDM-21.02.0029 26901141 \n10 Fulop M. Eder H. A. Plasma triglycerides and cholesterol in diabetic ketosis JAMA Internal Medicine 1989 149 9 1997 2002 2-s2.0-0024438612 10.1001/archinte.1989.00390090063013 2505705 \n11 McLean A. G. Petersons C. J. Hooper A. J. Burnett J. R. Burt M. G. Doogue M. P. Extreme diabetic lipaemia associated with a novel lipoprotein lipase gene mutation Clinica Chimica Acta 2009 406 1-2 167 169 2-s2.0-67650224046 10.1016/j.cca.2009.05.003 19447100 \n12 Karagianni C. Stabouli S. Roumeliotou K. Severe hypertriglyceridaemia in diabetic ketoacidosis: Clinical and genetic study Diabetic Medicine 2004 21 4 380 382 2-s2.0-1942455238 10.1111/j.1464-5491.2004.1111.x 15049943 \n13 Rip J. Nierman M. C. Wareham N. J. Serum lipoprotein lipase concentration and risk for future coronary artery disease: The EPIC-Norfolk prospective population study Arteriosclerosis, Thrombosis, and Vascular Biology 2006 26 3 637 642 2-s2.0-33646590329 10.1161/01.ATV.0000201038.47949.56 16373616 \n14 Nair S. Yadav D. Pitchumoni C. S. Association of diabetic ketoacidosis and acute pancreatitis: observations in 100 consecutive episodes of DKA American Journal of Gastroenterology 2000 95 10 2795 2800 10.1016/s0002-9270(00)01981-x 2-s2.0-0033792658 11051350 \n15 Tsuang W. Navaneethan U. Ruiz L. Palascak J. B. Gelrud A. Hypertriglyceridemic pancreatitis: presentation and management American Journal of Gastroenterology 2009 104 4 984 991 10.1038/ajg.2009.27 2-s2.0-65449169275 19293788 \n16 Lutfi R. Huang J. Wong H. R. Plasmapheresis to treat hypertriglyceridemia in a child with diabetic ketoacidosis and pancreatitis Pediatrics 2012 129 1 e195 e198 10.1542/peds.2011-0217 2-s2.0-84855271582 22201145 \n17 Cole R. P. Heparin treatment for severe hypertriglyceridemia in diabetic ketoacidosis JAMA Internal Medicine 2009 169 15 1439 1441 10.1001/archinternmed.2009.221 2-s2.0-68849104376 \n18 Rahalkar A. R. Giffen F. Har B. Novel LPL mutations associated with lipoprotein lipase deficiency: Two case reports and a literature review Canadian Journal of Physiology and Pharmacology 2009 87 3 151 160 2-s2.0-65249109805 10.1139/Y09-005 19295657 \n19 Jacobson T. A. Ito M. K. Maki K. C. National Lipid Association recommendations for patient-centered management of dyslipidemia: Part 1 - Executive summary Journal of Clinical Lipidology 2014 8 5 473 488 2-s2.0-84908397421 10.1016/j.jacl.2014.07.007 25234560 \n20 Miller M. Stone N. J. Ballantyne C. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association Circulation 2011 123 20 2292 2333 10.1161/CIR.0b013e3182160726 2-s2.0-79958098706 21502576 \n21 Stroes E. S. G. Susekov A. V. de Bruin T. W. A. Kvarnström M. Yang H. Davidson M. H. Omega-3 carboxylic acids in patients with severe hypertriglyceridemia: EVOLVE II, a randomized, placebo-controlled trial Journal of Clinical Lipidology 2018 12 2 321 330 2-s2.0-85039159925 10.1016/j.jacl.2017.10.012 29289538 \n22 Harris W. S. Miller M. Tighe A. P. Davidson M. H. Schaefer E. J. Omega-3 fatty acids and coronary heart disease risk: clinical and mechanistic perspectives Atherosclerosis 2008 197 1 12 24 10.1016/j.atherosclerosis.2007.11.008 2-s2.0-39649111988 18160071 \n23 Surendran R. P. Visser M. E. Heemelaar S. Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients with severe hypertriglyceridaemia Journal of Internal Medicine 2012 272 2 185 196 2-s2.0-84863986988 10.1111/j.1365-2796.2012.02516.x 22239554\n\n",
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"title": "Mediastinal syndrome: A report of three cases.",
"title_normalized": "mediastinal syndrome a report of three cases"
} | [
{
"companynumb": "IT-MUNDIPHARMA DS AND PHARMACOVIGILANCE-DEU-2016-0018320",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MORPHINE SULFATE"
},
... |
{
"abstract": "BACKGROUND\nAs with other types of dementia, the behavioral and psychological symptoms of dementia (BPSD) can make caregiving difficult for patients with dementia with Lewy bodies (DLB). We hypothesized that administration of donepezil at an increased dose of 10 mg/day might dose-dependently improve BPSD in DLB patients with relapse, after their symptoms had been controlled initially by donepezil therapy at the standard dose.\n\n\nMETHODS\nThe present study was as an open-label trial. We enrolled 24 patients with DLB (diagnosed according to the Consortium on Dementia with Lewy Bodies Guideline-Revised) who experienced a relapse of BPSD despite treatment with donepezil at the standard dose (5 mg/day). The donepezil dose for these patients was increased to 10 mg/day, and we evaluated the efficacy and safety of this dose escalation strategy.\n\n\nRESULTS\nThe Neuropsychiatric Inventory (NPI) scores for BPSD showed statistically significant improvements as a result of the increased dosage, except those for anxiety and euphoria, disinhibition, irritability/lability. High-dose donepezil therapy caused gastrointestinal symptoms in 4 patients, but there were no life-threatening adverse events, such as arrhythmias, or no exacerbation of parkinsonian symptoms.\n\n\nCONCLUSIONS\nWe found that donepezil dose-dependently improved relapsing BPSD in these patients. Therefore, increasing the dosage of donepezil is a safe and effective treatment for patients with DLB who experience a relapse of BPSD.",
"affiliations": "Dementia Diagnosis Center, Department of Internal Medicine, Yokohama Shintoshi Neurosurgical Hospital, Yokohama, Japan.;Department of Emergency and General Internal Medicine, Fujita Health University, School of Medicine, Toyoake, Japan.;Department of Emergency and General Internal Medicine, Fujita Health University, School of Medicine, Toyoake, Japan.;Medical Care Court Clinic, Yokohama, Japan.",
"authors": "Manabe|Yuta|Y|;Ino|Teruo|T|;Yamanaka|Katsuo|K|;Kosaka|Kenji|K|",
"chemical_list": "D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D000077265:Donepezil",
"country": "England",
"delete": false,
"doi": "10.1111/psyg.12140",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1346-3500",
"issue": "16(3)",
"journal": "Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society",
"keywords": "Alzheimer's disease; Lewy bodies; Neuropsychiatric Inventory; behavioral and psychological symptoms of dementia; cholinesterase inhibitors; hallucination",
"medline_ta": "Psychogeriatrics",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D001519:Behavior; D001526:Behavioral Symptoms; D002800:Cholinesterase Inhibitors; D003071:Cognition; D003704:Dementia; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007189:Indans; D020961:Lewy Body Disease; D008297:Male; D008875:Middle Aged; D010880:Piperidines; D012720:Severity of Illness Index; D016896:Treatment Outcome",
"nlm_unique_id": "101230058",
"other_id": null,
"pages": "202-8",
"pmc": null,
"pmid": "26179411",
"pubdate": "2016-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Increased dosage of donepezil for the management of behavioural and psychological symptoms of dementia in dementia with Lewy bodies.",
"title_normalized": "increased dosage of donepezil for the management of behavioural and psychological symptoms of dementia in dementia with lewy bodies"
} | [
{
"companynumb": "JP-CIPLA LTD.-2015JP06142",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVODOPA\\UNSPECIFIED INGREDIENT"
},
"drugadd... |
{
"abstract": "We describe a case of dose-related periorbital edema in a patient with FLT3-mutated acute myeloid leukemia taking sorafenib and voriconazole that resolved following sorafenib dose reduction. We hypothesize that the mechanism of this adverse event may be related to the inhibition of platelet-derived growth factor receptor (PDGFR) by sorafenib. Clinicians should be aware of this possible dose-related adverse event and the potential role of sorafenib dose reduction when on concurrent voriconazole.",
"affiliations": "Department of Pharmacy Services, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.;Division of Hematology-Oncology, Department of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.",
"authors": "Freyer|Craig W|CW|https://orcid.org/0000-0002-6526-8134;Mangan|James K|JK|",
"chemical_list": "D000970:Antineoplastic Agents; D000077157:Sorafenib; D051941:fms-Like Tyrosine Kinase 3; D065819:Voriconazole",
"country": "England",
"delete": false,
"doi": "10.1177/1078155218818719",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "25(8)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "FLT3; Sorafenib; acute myeloid leukemia; edema; periorbital",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D004487:Edema; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D009154:Mutation; D000077157:Sorafenib; D065819:Voriconazole; D051941:fms-Like Tyrosine Kinase 3",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "2035-2037",
"pmc": null,
"pmid": "30537918",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Dose-related periorbital edema following sorafenib in a patient with acute myeloid leukemia.",
"title_normalized": "dose related periorbital edema following sorafenib in a patient with acute myeloid leukemia"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/20/0119608",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AZACITIDINE"
},
"drugadditional": null,
... |
{
"abstract": "Collagenofibrotic glomerulopathy (CG) is a rare disease characterized by the deposition of collagen type 3 fibrils in the glomeruli. Patients may have proteinuria, hematuria, and/or renal dysfunction. CG is considered a progressive disease with variable rates of progression. The definitive diagnosis is made by electron microscopy with the presence of characteristic subendothelial and mesangial curved, comma-like, banded collagen type 3 fibers of 40-65 nm periodicity. We are reporting the first case of CG in a kidney transplant recipient with kidney disease of unknown cause.",
"affiliations": "Division of Nephrology and Hypertension, Department of Internal Medicine, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.;Division of Renal Pathology and Electron Microscopy, Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.;Division of Anatomic Pathology, Department of Pathology and Laboratory Medicine, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.;Division of Nephrology and Hypertension, Department of Internal Medicine, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.;Division of Nephrology and Hypertension, Department of Internal Medicine, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.",
"authors": "Jdiaa|Sara S|SS|0000-0003-0726-7931;Moeckel|Gilbert W|GW|0000-0002-6059-0837;Kfoury|Hala M|HM|;Medawar|Walid A|WA|;Abu-Alfa|Ali K|AK|0000-0001-8122-0221",
"chemical_list": "D024061:Collagen Type III",
"country": "United States",
"delete": false,
"doi": "10.1111/ajt.16399",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1600-6135",
"issue": "21(5)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "clinical research/practice; genetics; kidney transplantation/nephrology; recurrent disease",
"medline_ta": "Am J Transplant",
"mesh_terms": "D024061:Collagen Type III; D006801:Humans; D007674:Kidney Diseases; D007678:Kidney Glomerulus; D016030:Kidney Transplantation; D011507:Proteinuria",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "1948-1952",
"pmc": null,
"pmid": "33206467",
"pubdate": "2021-05",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Collagenofibrotic glomerulopathy in a kidney transplant recipient: A first report.",
"title_normalized": "collagenofibrotic glomerulopathy in a kidney transplant recipient a first report"
} | [
{
"companynumb": "LB-ACCORD-226828",
"fulfillexpeditecriteria": "1",
"occurcountry": "LB",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
"drug... |
{
"abstract": "The intrathecal administration of hyperbaric morphine 1 mg for pain relief during labour was followed, 7 h after injection, and 1 h after delivery, by respiratory depression. Pulseoximetry was helpful in alerting the medical personnel. After an initial 1 mg of naloxone i.v. in increments of 0.1-0.2 mg, a continuous infusion of naloxone 0.4 mg h-1 i.v. was used to prevent a recurrence of the respiratory depression. The total dose of naloxone over an 8-h period was 3.6 mg.",
"affiliations": "University of Texas Health Science Center, Medical School, Department of Anesthesiology, Houston 77030.",
"authors": "Abouleish|E|E|",
"chemical_list": "D009020:Morphine",
"country": "England",
"delete": false,
"doi": "10.1093/bja/60.5.592",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-0912",
"issue": "60(5)",
"journal": "British journal of anaesthesia",
"keywords": null,
"medline_ta": "Br J Anaesth",
"mesh_terms": "D000328:Adult; D000773:Anesthesia, Obstetrical; D001049:Apnea; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007278:Injections, Spinal; D008297:Male; D009020:Morphine; D011247:Pregnancy; D011644:Puerperal Disorders; D012131:Respiratory Insufficiency",
"nlm_unique_id": "0372541",
"other_id": null,
"pages": "592-4",
"pmc": null,
"pmid": "3377935",
"pubdate": "1988-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Apnoea associated with the intrathecal administration of morphine in obstetrics. A case report.",
"title_normalized": "apnoea associated with the intrathecal administration of morphine in obstetrics a case report"
} | [
{
"companynumb": "US-PFIZER INC-2020269192",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BUPIVACAINE"
},
"drugadditional": null,
... |
{
"abstract": "Type B lactic acidosis is rare among patients with malignant diseases. To date only one case report has documented lactic acidosis occurring in a patient with multiple myeloma (MM). Our patient, a 55-year-old black man, was diagnosed with stage IIIA immunoglobulin G-kappa (IgG-kappa) MM in September 1995. He was found to have severe lactic acidosis at the time of second relapse. During the terminal phase of his disease, he required multiple hospitalizations for management of lactic acidosis and other complications of his MM. No other cause of his elevated lactate levels was identified. Although type B lactic acidosis may more commonly occur in patients with leukemia or lymphoma, it may rarely present in patients with rapidly progressive and refractory MM.",
"affiliations": "Department of Internal Medicine, Medical College of Georgia, Veterans Affairs Medical Center, 1 Freedom Way, Augusta, GA 30904, USA.",
"authors": "Ustun|Celalettin|C|;Fall|Pamela|P|;Szerlip|Harold M|HM|;Jillella|Anand|A|;Hendricks|Linda|L|;Burgess|Russell|R|;Dainer|Paul|P|",
"chemical_list": "D007074:Immunoglobulin G; D007145:Immunoglobulin kappa-Chains; D019344:Lactic Acid",
"country": "United States",
"delete": false,
"doi": "10.1080/1042819021000040116",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "43(12)",
"journal": "Leukemia & lymphoma",
"keywords": null,
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000140:Acidosis, Lactic; D018450:Disease Progression; D006801:Humans; D007074:Immunoglobulin G; D007145:Immunoglobulin kappa-Chains; D019344:Lactic Acid; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D012008:Recurrence",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "2395-7",
"pmc": null,
"pmid": "12613530",
"pubdate": "2002-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Multiple myeloma associated with lactic acidosis.",
"title_normalized": "multiple myeloma associated with lactic acidosis"
} | [
{
"companynumb": "US-BAXTER-2015BAX016914",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nNonsteroidal anti-inflammatory drugs (NSAIDs) are the most frequent triggers of drug hypersensitivity with NSAIDs-induced urticaria/angioedema (NIUA) the most common phenotype. Loss of hypersensitivity has been reported for IgE-mediated reactions; however, it has not been assessed in nonimmunological reactions such as NIUA. We evaluated NSAID-hypersensitivity over time in NIUA patients.\n\n\nMETHODS\nPatients confirmed as NIUA by positive drug provocation test (DPT) with acetylsalicylic acid (ASA) during 2005-2012 (V1) were included (n=38). Subjects were prospectively re-evaluated by DPT with ASA/other NSAIDs at two time points between 2013 and 2015 (V2 and V3). Atopy was assessed by skin prick test (SPT) using inhalant and food allergens.\n\n\nRESULTS\nPatients were evaluated at V1 and re-evaluated after 60 months (V2; IR:48-81) and a further 18 months (V3; IR:14-24). At V2, the majority (24; 63.15%) tolerated ASA and other NSAIDs (Group A) while 14 (36.84%) still reacted (Group B). At V3, all Group A patients remained tolerant; all Group B patients remained hypersensitive. The number of previous episodes reported at V1 and the percentage of reactions induced by ASA/ibuprofen were significantly lower in Group A (P=.005 and P=.006, respectively). Group A patients developed tolerance 72 months (IR:45-87) after their last evaluated reaction (V1); this interval was shorter in nonatopics (P=.003), patients who experienced reactions over 1 hour after NSAIDs administration (P=.001), and those who experienced isolated urticaria after NSAID intake (P=.024).\n\n\nCONCLUSIONS\nNIUA patients may develop tolerance to NSAIDs over time, a process that seems to be influenced by atopy and type of clinical reaction.",
"affiliations": "Allergy Unit, Regional University Hospital of Malaga-IBIMA, Malaga, Spain.;Allergy Unit, Regional University Hospital of Malaga-IBIMA, Malaga, Spain.;Allergy Unit, Regional University Hospital of Malaga-IBIMA, Malaga, Spain.;Research Laboratory, IBIMA-Regional University Hospital of Malaga-UMA, Malaga, Spain.;Research Laboratory, IBIMA-Regional University Hospital of Malaga-UMA, Malaga, Spain.;Allergy Unit, Regional University Hospital of Malaga-IBIMA, Malaga, Spain.;Allergy Unit, Regional University Hospital of Malaga-IBIMA, Malaga, Spain.;Allergy Unit, Regional University Hospital of Malaga-IBIMA, Malaga, Spain.",
"authors": "Doña|I|I|http://orcid.org/0000-0002-5309-4878;Barrionuevo|E|E|;Salas|M|M|;Cornejo-García|J A|JA|;Perkins|J R|JR|;Bogas|G|G|;Prieto|A|A|;Torres|M J|MJ|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D001241:Aspirin",
"country": "Denmark",
"delete": false,
"doi": "10.1111/all.13147",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0105-4538",
"issue": "72(9)",
"journal": "Allergy",
"keywords": "NSAID-induced urticaria/angioedema; Nonsteroidal anti-inflammatory drugs; atopy; hypersensitivity; urticaria",
"medline_ta": "Allergy",
"mesh_terms": "D000328:Adult; D000799:Angioedema; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001241:Aspirin; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D008297:Male; D011446:Prospective Studies; D012882:Skin Tests; D013997:Time Factors; D014581:Urticaria",
"nlm_unique_id": "7804028",
"other_id": null,
"pages": "1346-1355",
"pmc": null,
"pmid": "28226401",
"pubdate": "2017-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Natural evolution in patients with nonsteroidal anti-inflammatory drug-induced urticaria/angioedema.",
"title_normalized": "natural evolution in patients with nonsteroidal anti inflammatory drug induced urticaria angioedema"
} | [
{
"companynumb": "ES-JNJFOC-20170820755",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": "3",
... |
{
"abstract": "Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare and potentially life-threatening idiosyncratic drug reaction. It presents with extensive rash, fever, lymphadenopathy, hematologic abnormalities (eosinophilia and/or atypical lymphocytosis) and internal organ involvement. It has been described in association with more than 50 drugs. To the best of our knowledge neither cefotaxime nor clindamycin has been previously reported to induce DRESS syndrome in children. Clindamycin was reported only in adults as a cause of DRESS syndrome in the literature. In this report, we aimed to present a child with DRESS syndrome that developed after cefotaxime and clindamycin treatment. A 6-year-old boy was diagnosed with the left lower lobe pneumonia and pleural effusion. Parenteral cefotaxime and clindamycin were then started, after which the patient improved clinically and was discharged 7 days later with oral amoxicillin clavulanate treatment. After four days he was readmitted to the hospital with fever and cough. Chest X-ray revealed left lower lobe pneumonia and pleural effusion. We considered that the pneumonia was unresponsive to oral antibiotic treatment, and therefore parenteral cefotaxime and clindamycin were re-administered. As a result, his clinical and radiological findings were improved within 10 days. On the 12th of day of hospitalization, the body temperature has risen to 39°C, which we considered to be caused by antibiotics and stopped antibiotic treatment. At the same day he developed generalized maculopapular erythematous rash, which was considered an allergic reaction secondary to antibiotics. Despite the antihistaminic drug administration, the clinical status quickly deteriorated with generalized edema, lymphadenopathies and hepatosplenomegaly. Laboratory tests revealed a white blood cell count of 4300/μl, a lymphocyte count of 1300/μl, a hemoglobin level of 11.2 gr/dl, a platelet count of 120.000/μl, an eosinophilia ratio of 10% on peripheral blood smear, a C-reactive protein level of 20 mg/dl, a procalcitonin level of 23.94 ng/ml and an erythrocyte sedimentation rate of 48 mm/h. Anti nuclear antibody, anti-double stranded DNA, the serologic tests for Epstein Bar virus, herpes simplex virus, parvovirus, mycoplasma, toxoplasmosis, rubella, cytomegalovirus were all found negative. Bone marrow aspiration was consistent with an autoimmune reaction. An echocardiographic examination was normal. Thoracic tomography revealed multiple enlarged axillary, supraclavicular and anterior mediastinal lymph nodes. As the patient met 8 out of 9 RegiSCAR criteria for the diagnosis of DRESS, we started pulse methyl prednisolone (30 mg/kg/day) for three days followed by 2 mg/kg/day. On the 2nd day fever resolved and cutaneous rash and edema improved. Ten days after developing eruptions the patient was discharged. To our knowledge, we report the first pediatric case of DRESS syndrome following treatment with cefotaxime and clindamycin. Pediatricians should be aware of this potential complication associated with these commonly prescribed antibiotics.",
"affiliations": "Healthy Sciences University, Umraniye Training and Research Hospital, Department of Pediatrics, Istanbul, Turkey.;Healthy Sciences University, Umraniye Training and Research Hospital, Department of Pediatrics, Istanbul, Turkey.;Healthy Sciences University, Umraniye Training and Research Hospital, Department of Pediatrics, Istanbul, Turkey.;Healthy Sciences University, Umraniye Training and Research Hospital, Department of Pediatrics, Istanbul, Turkey.;Healthy Sciences University, Umraniye Training and Research Hospital, Department of Pediatrics, Istanbul, Turkey.;Healthy Sciences University, Umraniye Training and Research Hospital, Department of Pediatrics, Istanbul, Turkey.;Healthy Sciences University, Umraniye Training and Research Hospital, Department of Pediatrics, Istanbul, Turkey.;Healthy Sciences University, Umraniye Training and Research Hospital, Department of Pediatrics, Istanbul, Turkey.",
"authors": "Karakayalı|Burcu|B|;Yazar|Ahmet Sami|AS|;Çakir|Deniz|D|;Cetemen|Aysen|A|;Kariminikoo|Mandana|M|;Deliloglu|Burak|B|;Guven|Sirin|S|;Islek|Ismail|I|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002981:Clindamycin; D002097:C-Reactive Protein; D002439:Cefotaxime; D008775:Methylprednisolone",
"country": "Uganda",
"delete": false,
"doi": "10.11604/pamj.2017.28.218.10828",
"fulltext": "\n==== Front\nPan Afr Med JPan Afr Med JPAMJThe Pan African Medical Journal1937-8688The African Field Epidemiology Network PAMJ-28-21810.11604/pamj.2017.28.218.10828Case ReportDrug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome associated with cefotaxime and clindamycin use in a 6 year-old boy: a case report Karakayalı Burcu 1Yazar Ahmet Sami 1Çakir Deniz 1Cetemen Aysen 1Kariminikoo Mandana 1Deliloglu Burak 1Guven Sirin 1Islek Ismail 1&\n1 Healthy Sciences University, Umraniye Training and Research Hospital, Department of Pediatrics, Istanbul, Turkey& Corresponding author: Ismail Islek, Healthy Sciences University, Umraniye Training and Research Hospital, Department of Pediatrics, Istanbul, Turkey09 11 2017 2017 28 21829 9 2016 06 11 2017 © Burcu Karakayali et al.2017The Pan African Medical Journal - ISSN 1937-8688. This is an Open Access article distributed under the terms of the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare and potentially life-threatening idiosyncratic drug reaction. It presents with extensive rash, fever, lymphadenopathy, hematologic abnormalities (eosinophilia and/or atypical lymphocytosis) and internal organ involvement. It has been described in association with more than 50 drugs. To the best of our knowledge neither cefotaxime nor clindamycin has been previously reported to induce DRESS syndrome in children. Clindamycin was reported only in adults as a cause of DRESS syndrome in the literature. In this report, we aimed to present a child with DRESS syndrome that developed after cefotaxime and clindamycin treatment. A 6-year-old boy was diagnosed with the left lower lobe pneumonia and pleural effusion. Parenteral cefotaxime and clindamycin were then started, after which the patient improved clinically and was discharged 7 days later with oral amoxicillin clavulanate treatment. After four days he was readmitted to the hospital with fever and cough. Chest X-ray revealed left lower lobe pneumonia and pleural effusion. We considered that the pneumonia was unresponsive to oral antibiotic treatment, and therefore parenteral cefotaxime and clindamycin were re-administered. As a result, his clinical and radiological findings were improved within 10 days. On the 12th of day of hospitalization, the body temperature has risen to 39°C, which we considered to be caused by antibiotics and stopped antibiotic treatment. At the same day he developed generalized maculopapular erythematous rash, which was considered an allergic reaction secondary to antibiotics. Despite the antihistaminic drug administration, the clinical status quickly deteriorated with generalized edema, lymphadenopathies and hepatosplenomegaly. Laboratory tests revealed a white blood cell count of 4300/μl, a lymphocyte count of 1300/μl, a hemoglobin level of 11.2 gr/dl, a platelet count of 120.000/μl, an eosinophilia ratio of 10% on peripheral blood smear, a C-reactive protein level of 20 mg/dl, a procalcitonin level of 23.94 ng/ml and an erythrocyte sedimentation rate of 48 mm/h. Anti nuclear antibody, anti-double stranded DNA, the serologic tests for Epstein Bar virus, herpes simplex virus, parvovirus, mycoplasma, toxoplasmosis, rubella, cytomegalovirus were all found negative. Bone marrow aspiration was consistent with an autoimmune reaction. An echocardiographic examination was normal. Thoracic tomography revealed multiple enlarged axillary, supraclavicular and anterior mediastinal lymph nodes. As the patient met 8 out of 9 RegiSCAR criteria for the diagnosis of DRESS, we started pulse methyl prednisolone (30 mg/kg/day) for three days followed by 2 mg/kg/day. On the 2nd day fever resolved and cutaneous rash and edema improved. Ten days after developing eruptions the patient was discharged. To our knowledge, we report the first pediatric case of DRESS syndrome following treatment with cefotaxime and clindamycin. Pediatricians should be aware of this potential complication associated with these commonly prescribed antibiotics.\n\nDRESS syndromecefotaximeclindamycinchildren\n==== Body\nIntroduction\nDrug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare and potentially life-threatening idiosyncratic drug reaction. It presents with extensive rash, fever, lymphadenopathy, hematologic abnormalities (eosinophilia and/or atypical lymphocytosis) and internal organ involvement. The incidence of this syndrome ranges from 1/1,000 to 1/10,000 after drug exposure. Adults are more commonly affected than children [1]. Approximately 50 drugs (sulfa derivates, antidepressants, nonsteroidal anti-inflammatory drugs) may induce DRESS syndrome, but it is most commonly induced by anticonvulsants (phenytoin, phenobarbital, carbamazepine) and antibiotics [1,2]. It has been described in association with more than 50 drugs. To the best of our knowledge neither cefotaxime nor clindamycin have been previously reported to cause DRESS syndrome in children. Clindamycin was reported only in adults as an agent causing DRESS syndrome in the literature [1-4]. We present a child with DRESS syndrome presenting 21 days after starting cefotaxime and clindamycin treatment.\n\nPatient and observation\nA 6-year-old boy was diagnosed with the left lower lobe pneumonia and pleural effusion and was put on parenteral cefotaxime and clindamycin treatment. He then improved clinically and was discharged 7 days later with oral amoxicillin clavulanate treatment. After four days, however, he was readmitted to the hospital with fever and cough. A chest X-ray revealed left lower lobe pneumonia and pleural effusion. As a case of complicated pneumonia was considered, we started parenteral cefotaxime and clindamycin treatment, 10 days after which his clinical and radiological findings were improved. At the 12th of day of hospitalization, however, he developed at 39°C, which we considered as a side effect of antibiotics. Therefore, antibiotic treatment was stopped. At the same day, he also developed a generalized maculopapular erythematous rash, which was considered an allergic reaction secondary to antibiotics (Figure 1).\n\nFigure 1 Severe cutaneous rashes and edema\n\nDespite the administration of antihistaminic drugs, his clinical status quickly deteriorated with generalized edema, lymphadenopathies and hepatosplenomegaly. Laboratory tests showed a white blood cell count of 4,300/mm3, a lymphocyte count of 1,300/μl, a hemoglobin level of 11.2 gr/dl, a platelet count of 120,000/μl, an eosinophil ratio of 10% on peripheral blood smear, a C-reactive protein level of 20 mg/dl, a procalcitonin level of 23.94 ng/ml and an erythrocyte sedimentation rate of 48 mm/h. Anti-nuclear antibody, anti-double strain DNA, the serologic tests for Epstein Bar virus, herpes simplex virus, parvovirus, mycoplasma, toxoplasmosis, rubella, cytomegalovirus were all found negative. Bone marrow aspiration was consistent with an autoimmune reaction. An echocardiographic examination was found normal. A Thoracic computerized tomography revealed multiple enlarged axillary, supraclavicular and anterior mediastinal lymph nodes. As the patient met 8 out of 9 RegiSCAR criteria for the diagnosis of DRESS, pulse methyl prednisolone (30 mg/kg/day) was administered for three days followed by 2mg/kg/day. On the 2nd day fever resolved and cutaneous rash and edema improved. He was discharged ten days after the appearance of eruptions. The patient’s father gave consent for publication of his son’s pictures.\n\nDiscussion\nDRESS syndrome was first defined in 1996 by Bocquet et al [5]. It is characterized by fever, cutaneous eruption, internal organ involvement and hematologic abnormalities within 1-8 weeks after the exposure of the suspected drug [5,6]. Anticonvulsants such as carbamazepine, lamotrigine, phenobarbital, phenytoin and allopurinol are the most common causes of DRESS syndrome [1]. In a series of 172 cases of DRESS syndrome carbamazepine accounted for the greatest percentage of cases (27%), followed by allopurinol (11%), lamotrigine (6%), phenobarbital (6%), sulfasalazine (6%) [1].\n\nThe pathogenesis of DRESS syndrome has not been elucidated. Different mechanisms have been proposed, including detoxification defects leading to reactive metabolite formation and subsequent immunological reactions, slow acetylation and reactivation of Human Herpes Virus (HHV-6-7) and EBV [1]. Severe DRESS syndrome has also been reported following infection with or reactivation of HHV-6 [7]. CMV and paramyxovirus have been reported as the other viral agents associated with DRESS syndrome. Although it is thought that there is a genetic predisposition to adverse reactions, no genetic factor responsible for the syndrome has been identified yet [1].\n\nThree different sets of criteria are used to diagnose of DRESS syndrome: RegiSCAR criteria, Bocquet’s criteria and Japanese consensus group to diagnose DIHS [5,6]. RegiSCAR criteria include at least 3 of the following 7 characteristics: 1) skin eruption; 2) fever > 38°C; 3) lymphadenopathy involving at least 2 sites; 4) involvement of at least 1 internal organ; 5) lymphocytosis (> 4000/mm3) or lymphocytopenia (< 1500/mm3); 6) blood eosinophilia (> %10 or 700/mm3) and 7) thrombocytopenia (< 120.000/mm3 ) [8]. Three of the four main criteria (fever > 38°C, lymphadenopathy at least 2 sites, involvement of at least 1 internal organ and blood abnormalities) are required for the diagnosis of DRESS syndrome. Additional criteria are hospitalization and drug induced reaction [6, 8, 9]. Our patient met 6 of 7 RegiSCAR criteria and he also had two additional criterias ( hospitalization and drug induced reaction).\n\nThe reported mortality of the syndrome ranges between 10% and 40%. Liver damage secondary to eosinophilic infiltration is the most important cause of mortality. There are no consensus guidelines for the management of patients with DRESS syndrome. The most important steps for a proper management include the recognition of the syndrome and immediate discontinuation of the offending drug. The French Society of Dermatology recommends the use of systemic corticosteroids (prednisone 1 mg/kg/day) and intravenous immunoglobulin (2 gr/kg) for five days especially in patients with life threatening internal organ involvement, such as in renal or respiratory failure [10]. Pulse methyl prednisolone treatment was also reportedly administered in a pediatric case of DRESS syndrome secondary to anticonvulsant use [11,12]. Gancyclovir has been suggested in patients with severe signs and the confirmation of a major viral reactivation of HHV-6 [10].\n\nConclusion\nThe diagnosis of the DRESS syndrome should be highly suspected in patients with fever, skin rash, liver involvement, hypereosinophilia and lymphadenopathy that develop during the use of a culprit drug. We report the first case of DRESS syndrome associated with cefotaxime and clindamycin exposure in a 6-year-old boy. Early recognition of the signs of the DRESS syndrome and immediate cessation of the suspected drug are the most important steps for an appropriate management of the syndrome. Pediatricians should be careful about this potential complication associated with these commonly prescribed antibiotics in pediatric practice.\n\nCompeting interests\nThe authors declare no competing interests.\n\nAuthors’ contributions\nAll authors have read and agreed to the final manuscript.\n==== Refs\nReferences\n1 Cacoub P Musette P Descamps V Meyer O Speirs C Finzi L Roujeau JC The DRESS syndrome: a literature review Am J Med. 2011 7 124 7 588 597 Epub 2011 May 17 21592453 \n2 Walsh SA Creamer D Drug reaction with eosinophilia and systemic symptoms (DRESS): a clinical update and review of current thinking Clin Exp Dermatol. 2011 1 36 1 6 11 21143513 \n3 Miller Quidley A Bookstaver PB Gainey AB Gainey MD Fatal clindamycin-induced drug rash with eosinophilia and systemic symptoms (DRESS) syndrome Pharmacotherapy. 2012 12 32 12 e387 92 23165860 \n4 Tian D Mohan RJ Stallings G Drug rash with eosinophilia and systemic symptoms syndrome associated with clindamycin Am J Med. 2010 11 123 11 e7 8 Epub 2010 Sep 16 \n5 Bocquet H Bagot M Roujeau JC Drug-induced pseudolymphoma and drug hypersensitivity syndrome (Drug Rash with Eosinophilia and Systemic Symptoms: DRESS) Semin Cutan Med Surg. 1996 12 15 4 250 7 9069593 \n6 Kim DH Koh YI Comparison of diagnostic criteria and determination of prognostic factors for drug reaction with eosinophilia and systemic symptoms syndrome Allergy Asthma Immunol Res. 2014 5 6 3 216 21 Epub 2014 Feb 6 24843796 \n7 Ichiche M Kiesch N De Bels D DRESS syndrome associated with HHV-6 reactivation Eur J Intern Med. 2003 14 8 498 500 14962704 \n8 Kardaun SH Sidoroff A Valeyrie-Allanore L Halevy S Davidovici BB Mockenhaupt M Roujeau JC Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist? Br J Dermatol. 2007 3 156 3 609 11 17300272 \n9 Kardaun SH Sekula P Valeyrie-Allanore L Liss Y Chu CY Creamer D Sidoroff A Naldi L Mockenhaupt M Roujeau JC RegiSCAR study group Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCARstudy Br J Dermatol. 2013 169 5 1071 1080 23855313 \n10 Descamps V Ben Said B Sassolas B Truchetet F Avenel-Audran M Girardin P Guinnepain MT Mathelier-Fusade P Assier H Milpied B Modiano P Lebrun-Vignes B Barbaud A groupe Toxidermies de la Société Française de dermatologie Management of drug reaction with eosinophilia and systemic symptoms (DRESS) Ann Dermatol Venereol. 2010 11 137 11 703 8 Epub 2010 Aug 5 21074653 \n11 Kocaoglu C Cilasun C Solak ES Kurtipek GS Arslan S Successful treatment of antiepileptic drug-induced DRESS syndrome with Pulse Methylprednisolone Case Rep Pediatr. 2013 2013 928910 Epub 2013 Apr 18 23691411 \n12 El omairi N Abourazzak S Chaouki S Atmani S Hida M Drug reaction with Eosinophilia and Systemic Symptom (DRESS) induced by carbamazepine: a case report and literature review Pan Afr Med J. 2014 5 2 18 9 eCollection 2014\n\n",
"fulltext_license": "CC BY",
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"issue": "28()",
"journal": "The Pan African medical journal",
"keywords": "DRESS syndrome; cefotaxime; children; clindamycin",
"medline_ta": "Pan Afr Med J",
"mesh_terms": "D000900:Anti-Bacterial Agents; D002097:C-Reactive Protein; D002439:Cefotaxime; D002648:Child; D002981:Clindamycin; D063926:Drug Hypersensitivity Syndrome; D006801:Humans; D008297:Male; D008775:Methylprednisolone; D010996:Pleural Effusion; D011014:Pneumonia",
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"references": "24843796;25360193;14962704;23165860;23691411;17300272;21074653;21592453;21143513;23855313;9069593;20843501",
"title": "Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome associated with cefotaxime and clindamycin use in a 6 year-old boy: a case report.",
"title_normalized": "drug reaction with eosinophilia and systemic symptoms dress syndrome associated with cefotaxime and clindamycin use in a 6 year old boy a case report"
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"abstract": "Hyperammonaemia is often seen in the context of decompensated liver disease. It may also be triggered by stressful medical conditions in adults with partial enzyme deficiencies of the urea cycle. Occasionally, non-hepatic causes can result in hyperammonaemia severe enough to cause symptoms. The authors report the case of a 52-year-old Turkish woman who presented with acute-on-chronic confusion, drowsiness and lethargy. Laboratory investigations revealed hyperammonaemia which had an unclear cause. Although first thought to be secondary to a concurrent urinary tract infection, the high serum ammonia was eventually attributed to her carbamazepine. The authors recommend that doctors should include urinary tract infection and iatrogenic causes in their differential diagnosis in patients with hyperammonaemia and neurological symptoms, especially when this may be misleading in the diagnostic process.",
"affiliations": "Department of Respiratory Medicine, Homerton University Hospital, London, UK. peterlabib@hotmail.co.uk",
"authors": "Labib|Peter Lawrence Zaki|PL|;Wing|Stevan|S|;Bhowmik|Angshu|A|",
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"mesh_terms": "D003221:Confusion; D003937:Diagnosis, Differential; D005260:Female; D015600:Glasgow Coma Scale; D006801:Humans; D006849:Hydrocephalus; D022124:Hyperammonemia; D008875:Middle Aged; D017287:Ventriculoperitoneal Shunt",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17673917;12383670;8466166;19667003;11677282",
"title": "Transient hyperammonaemia in a patient with confusion: challenges with the differential diagnosis.",
"title_normalized": "transient hyperammonaemia in a patient with confusion challenges with the differential diagnosis"
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{
"companynumb": "GB-AUROBINDO-AUR-APL-2011-05926",
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"abstract": "Thirty-one patients with either advanced AML (18) or blastic CML (13) were treated with an intensive timed sequential combination of VP-16 (100 mg/m2/day i.v., days 1-3 and 8-10), intermediate-dose Ara-C (500 mg/m2 i.v. over 1 h q 12 h, days 1-3 and 8-10) and carboplatin (150 mg/m2/day i.v. continuous infusion, days 1-3 and 8-10). CR rates were 9/18 (50%) for patients with AML and 9/13 (69%) for those with blastic CML, for an overall CR rate of 58%. Among patients with AML, CR rates for specific subgroups were: primary resistant disease 2/6; resistant relapse 1/5; second relapse 6/7. Ten patients were refractory to VAC and three (10%) died of complications during marrow hypoplasia. Median overall survival was 7 months, and median DFS of the 18 responders 4 months. The major toxicity was myelosuppression and infection. The VAC regimen has significant activity and acceptable toxicity in myelogenous leukemias. The very high response rate observed in blastic CML warrants further testing of carboplatin-based regimens in this poor-risk form of leukemia.",
"affiliations": "Hematology, Department of Human Biopathology, University La Sapienza, Rome, Italy.",
"authors": "Amadori|S|S|;Picardi|A|A|;Fazi|P|P|;Testi|A M|AM|;Petti|M C|MC|;Montefusco|E|E|;Mandelli|F|F|",
"chemical_list": "D003561:Cytarabine; D005047:Etoposide; D016190:Carboplatin",
"country": "England",
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"issue": "10(5)",
"journal": "Leukemia",
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"medline_ta": "Leukemia",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001752:Blast Crisis; D016026:Bone Marrow Transplantation; D016190:Carboplatin; D002648:Child; D002675:Child, Preschool; D003561:Cytarabine; D018572:Disease-Free Survival; D005047:Etoposide; D005260:Female; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D007951:Leukemia, Myeloid; D008297:Male; D008875:Middle Aged; D012074:Remission Induction; D016019:Survival Analysis; D016896:Treatment Outcome",
"nlm_unique_id": "8704895",
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"pubdate": "1996-05",
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"title": "A phase II study of VP-16, intermediate-dose Ara-C and carboplatin (VAC) in advanced acute myelogenous leukemia and blastic chronic myelogenous leukemia.",
"title_normalized": "a phase ii study of vp 16 intermediate dose ara c and carboplatin vac in advanced acute myelogenous leukemia and blastic chronic myelogenous leukemia"
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{
"companynumb": "IT-PFIZER INC-2018151002",
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"abstract": "BACKGROUND\nDisseminated fungal infections are a known serious complication in individuals with cystic fibrosis (CF) following orthotopic lung transplantation. Aspergillus fumigatus and Scedosporium species are among the more common causes of invasive fungal infection in this population. However, it is also important for clinicians to be aware of other emerging fungal species which may require markedly different antifungal therapies.\n\n\nMETHODS\nWe describe the first laboratory-documented case of a fatal disseminated fungal infection caused by Rasamsonia aegroticola in a 21-year-old female CF patient status post-bilateral lung transplantation, which was only identified post-mortem. Molecular analysis revealed the presence of the identical Rasamsonia strains in the patient's respiratory cultures preceding transplantation.\n\n\nCONCLUSIONS\nWe propose that the patient's disseminated fungal disease and death occurred as a result of recrudescence of Rasamsonia infection from her native respiratory system in the setting of profound immunosuppression post-operatively. Since Rasamsonia species have been increasingly recovered from the respiratory tract of CF patients, we further review the literature on these fungi and discuss their association with invasive fungal infections in the CF lung transplant host.\n\n\nCONCLUSIONS\nOur report suggests Rasamsonia species may be important fungal pathogens that may have fatal consequences in immunosuppressed CF patients after solid organ transplantation.",
"affiliations": "Division of Pulmonary, Allergy and Critical Care, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.;Department of Pathology, Johns Hopkins University School of Medicine, USA.;Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.;Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.;Division of Infectious Diseases, Johns Hopkins University School of Medicine, USA.;Department of Pathology, Johns Hopkins University School of Medicine, USA.;Microbiology Laboratory, Johns Hopkins Hospital, Baltimore, MD, USA.;Ibis Biosciences, Abbott, Carlsbad, CA, USA.;Ibis Biosciences, Abbott, Carlsbad, CA, USA.;Ibis Biosciences, Abbott, Carlsbad, CA, USA.;Department of Geriatrics, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China.;Fungus Testing Laboratory, 7703 Floyd Curl Drive, MC7750 San Antonio, TX 78229-3900, USA.;Department of Microbiology and Immunology, University of Texas Health Science Center, San Antonio, TX, USA.;Department of Microbiology and Immunology, University of Texas Health Science Center, San Antonio, TX, USA.;Fungus Testing Laboratory, 7703 Floyd Curl Drive, MC7750 San Antonio, TX 78229-3900, USA.;Department of Pathology, Johns Hopkins University School of Medicine, USA; Microbiology Laboratory, Johns Hopkins Hospital, Baltimore, MD, USA. Electronic address: szhang28@jhmi.edu.",
"authors": "Hong|Gina|G|;White|Marissa|M|;Lechtzin|Noah|N|;West|Natalie E|NE|;Avery|Robin|R|;Miller|Heather|H|;Lee|Richard|R|;Lovari|Robert J|RJ|;Massire|Christian|C|;Blyn|Lawrence B|LB|;Liang|Xinglun|X|;Sutton|Deanna A|DA|;Fu|Jianmin|J|;Wickes|Brian L|BL|;Wiederhold|Nathan P|NP|;Zhang|Sean X|SX|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jcf.2017.01.005",
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"issue": "16(2)",
"journal": "Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society",
"keywords": "Cystic fibrosis; Fungal infection; Lung transplantation; Rasamsonia",
"medline_ta": "J Cyst Fibros",
"mesh_terms": "D000328:Adult; D003550:Cystic Fibrosis; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007165:Immunosuppression Therapy; D000072742:Invasive Fungal Infections; D008172:Lung Diseases, Fungal; D016040:Lung Transplantation; D009894:Opportunistic Infections; D011183:Postoperative Complications",
"nlm_unique_id": "101128966",
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"pages": "e3-e7",
"pmc": null,
"pmid": "28185887",
"pubdate": "2017-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fatal disseminated Rasamsonia infection in cystic fibrosis post-lung transplantation.",
"title_normalized": "fatal disseminated rasamsonia infection in cystic fibrosis post lung transplantation"
} | [
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"companynumb": "US-STRIDES ARCOLAB LIMITED-2017SP006244",
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"activesubstance": {
"activesubstancename": "TACROLIMUS"
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{
"abstract": "BACKGROUND\nEfficacy and safety data for combining bevacizumab, gemcitabine, and paclitaxel for locally advanced/metastatic breast cancer are limited.\n\n\nMETHODS\nAVALUZ trial evaluates the combination of bevacizumab 10 mg/kg, gemcitabine 2,000 mg/m(2) plus paclitaxel 150 mg/m(2), on days 1 and 15 of each 28-day course in previously untreated HER-2 negative patients.\n\n\nRESULTS\nMedian progression-free survival (PES): 12.3 months. The overall response and clinical benefit rate (CR + PR + SD) were 72 % (95 % CI 60.9-82.0 %) and 89 % (95 % CI 80.3-95.3 %), respectively. Median overall survival: 27.4 mo. Baseline circulating tumor cell (CTCs) ≥2 versus CTCs <2 was associated with lower PFS, p = 0.046. Overall response was significantly greater in patients with intense angiotensin type 1 receptor (AGTR1) expression (99 vs. 60 % [p = 0.021]). The most frequent grade 3/4 adverse events were: neutropenia (10 %); febrile neutropenia (1 %); sensory neuropathy (13 %); and asthenia (6 %). Grade 3 adverse events of interest with bevacizumab included bleeding (1 %) and hypertension (4 %). One patient developed cardiac ischemia (1 %).\n\n\nCONCLUSIONS\nAdding bevacizumab to chemotherapy appeared feasible and well tolerated, producing toxicity comparable to other effective combined first-line regimens. Baseline circulating endothelial cells and AGTR1 expression are predictive of PFS and response.",
"affiliations": "Department of Oncology, Hospital Universitario de Valme, Carretera de Cadiz, KM 548, 28007, Sevilla, Spain, jsalvad2002@yahoo.es.",
"authors": "Salvador|J|J|;Manso|L|L|;de la Haba|J|J|;Jaen|A|A|;Ciruelos|E|E|;de Villena|M C|MC|;Gil|M|M|;Murias|A|A|;Galan|A|A|;Jara|C|C|;Bayo|J|J|;Baena|J M|JM|;Casal|J|J|;Mel|J R|JR|;Blancas|I|I|;Sanchez Rvira|P|P|",
"chemical_list": "C544065:AGTR1 protein, human; D061067:Antibodies, Monoclonal, Humanized; D044140:Receptor, Angiotensin, Type 1; D003841:Deoxycytidine; D000068258:Bevacizumab; C056507:gemcitabine; D018719:Receptor, ErbB-2; D017239:Paclitaxel",
"country": "Italy",
"delete": false,
"doi": "10.1007/s12094-014-1210-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1699-048X",
"issue": "17(2)",
"journal": "Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico",
"keywords": null,
"medline_ta": "Clin Transl Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D001943:Breast Neoplasms; D003841:Deoxycytidine; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D009360:Neoplastic Cells, Circulating; D017239:Paclitaxel; D011379:Prognosis; D044140:Receptor, Angiotensin, Type 1; D018719:Receptor, ErbB-2; D015996:Survival Rate; D057170:Translational Research, Biomedical",
"nlm_unique_id": "101247119",
"other_id": null,
"pages": "160-6",
"pmc": null,
"pmid": "25119930",
"pubdate": "2015-02",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "20233745;11404498;12637460;19903805;20555067;4332371;21723792;22700443;19487683;16193637;20194852;10655437;18711184;18160686;18281267",
"title": "Final results of a phase II study of paclitaxel, bevacizumab, and gemcitabine as first-line therapy for patients with HER2-negative metastatic breast cancer.",
"title_normalized": "final results of a phase ii study of paclitaxel bevacizumab and gemcitabine as first line therapy for patients with her2 negative metastatic breast cancer"
} | [
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"companynumb": "ES-HQ SPECIALTY-ES-2015INT000670",
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
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{
"abstract": "We describe a patient with an acute middle cerebral artery ischemic stroke developing subtle involuntary movements of the paretic upper limb with cortical origin during rt-PA perfusion. Despite the multiple potential pathophysiological mechanisms for the relationship between thrombolysis and epileptic activity, seizures during this procedure are scarcely reported. Our hypothesis is that subtle and transient clinical seizures, like those described in our patient, may not be detected or are misdiagnosed as nonepileptic involuntary movements. We aimed to draw attention to the recognition challenge of this paroxysmal motor behavior, highlighting this clinical and neurophysiological identification using video recording and back-average analysis of the EEG.",
"affiliations": "Department of Neurology, Hospital de Santa Maria, Avenida Professor Egas Moniz, 1649-028 Lisboa, Portugal ; EEG/Sleep Laboratory, Department of Neurology, Hospital de Santa Maria, Avenida Professor Egas Moniz, 1649-028 Lisboa, Portugal.;Department of Neurology, Hospital de Santa Maria, Avenida Professor Egas Moniz, 1649-028 Lisboa, Portugal ; EEG/Sleep Laboratory, Department of Neurology, Hospital de Santa Maria, Avenida Professor Egas Moniz, 1649-028 Lisboa, Portugal.;Department of Neurology, Hospital de Santa Maria, Avenida Professor Egas Moniz, 1649-028 Lisboa, Portugal.;Department of Neuroradiology, Hospital de Santa Maria, Avenida Professor Egas Moniz, 1649-028 Lisboa, Portugal.;Department of Neurology, Hospital de Santa Maria, Avenida Professor Egas Moniz, 1649-028 Lisboa, Portugal ; Stroke Unit, Department of Neurology, Hospital de Santa Maria, Avenida Professor Egas Moniz, 1649-028 Lisboa, Portugal.;Department of Neurology, Hospital de Santa Maria, Avenida Professor Egas Moniz, 1649-028 Lisboa, Portugal ; Stroke Unit, Department of Neurology, Hospital de Santa Maria, Avenida Professor Egas Moniz, 1649-028 Lisboa, Portugal.",
"authors": "Bentes|Carla|C|;Peralta|Rita|R|;Viana|Pedro|P|;Morgado|Carlos|C|;Melo|Teresa P|TP|;Ferro|José M|JM|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1016/j.ebcr.2014.09.004",
"fulltext": "\n==== Front\nEpilepsy Behav Case RepEpilepsy Behav Case RepEpilepsy & Behavior Case Reports2213-3232Elsevier S2213-3232(14)00046-210.1016/j.ebcr.2014.09.004Case ReportCortical myoclonus during IV thrombolysis for ischemic stroke Bentes Carla ccbentes@gmail.comcarlabentes@fm.ul.ptab⁎Peralta Rita abViana Pedro aMorgado Carlos dMelo Teresa P. acFerro José M. aca Department of Neurology, Hospital de Santa Maria, Avenida Professor Egas Moniz, 1649-028 Lisboa, Portugalb EEG/Sleep Laboratory, Department of Neurology, Hospital de Santa Maria, Avenida Professor Egas Moniz, 1649-028 Lisboa, Portugalc Stroke Unit, Department of Neurology, Hospital de Santa Maria, Avenida Professor Egas Moniz, 1649-028 Lisboa, Portugald Department of Neuroradiology, Hospital de Santa Maria, Avenida Professor Egas Moniz, 1649-028 Lisboa, Portugal⁎ Corresponding author at: Laboratório de EEG/Sono, Serviço de Neurologia, Hospital de Santa Maria — CHLN, Avenida Professor Egas Moniz, 1649-028 Lisboa, Portugal. Tel.: + 351 919310122, + 351 217805472; fax: + 351 217805642. ccbentes@gmail.comcarlabentes@fm.ul.pt16 10 2014 2014 16 10 2014 2 186 188 21 7 2014 3 9 2014 9 9 2014 © 2014 The Authors2014This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).We describe a patient with an acute middle cerebral artery ischemic stroke developing subtle involuntary movements of the paretic upper limb with cortical origin during rt-PA perfusion. Despite the multiple potential pathophysiological mechanisms for the relationship between thrombolysis and epileptic activity, seizures during this procedure are scarcely reported. Our hypothesis is that subtle and transient clinical seizures, like those described in our patient, may not be detected or are misdiagnosed as nonepileptic involuntary movements. We aimed to draw attention to the recognition challenge of this paroxysmal motor behavior, highlighting this clinical and neurophysiological identification using video recording and back-average analysis of the EEG.\n\nKeywords\nSeizuresCerebral infarctRecombinant tissue-type plasminogen activator (rt-PA)EEGBack-average analysis\n==== Body\n1 Introduction\nEarly poststroke seizures (i.e. occurring within one week after stroke) are thought to result from cellular biochemical dysfunction leading to electrically irritable cerebral tissue. Intravenous thrombolysis (IVT) with recombinant tissue-type plasminogen activator (rt-PA) is the gold standard treatment for acute ischemic stroke, and, recently, Alvarez et al., [1] showed that this procedure may be independently associated with early seizures. However, and despite multiple potential pathophysiological mechanisms, seizures coincident with rt-PA administration are seldom reported. Here, we describe a patient with an acute middle cerebral artery (MCA) ischemic stroke who developed subtle involuntary movements of the paretic upper limb, with cortical origin as documented neurophysiologically, during rt-PA perfusion. We aimed to draw attention to the recognition challenge of this paroxysmal motor behavior, highlighting its clinical and neurophysiological identification using video recording and back-average analysis of the EEG.\n\n2 Case report\nA 72-year-old male with a past history of hypertension, dyslipidemia, chronic kidney disease, and an ischemic stroke 15 years ago, with no poststroke seizures and from which he had completely recovered, presented to the emergency department with sudden onset of left central facial palsy, hemiparesis, homonymous hemianopsia, and right gaze deviation (NIHSS score = 10). Electrocardiogram showed atrial fibrillation, and blood analysis revealed acute renal failure (creatinine = 4 mg/dL, blood urea nitrogen = 134 mg/dL). Plain head computed tomography (CT) disclosed old occipital, parietal, and frontal ischemic lesions and a right medial cerebral artery (MCA) hyperdensity. Intravenous recombinant tissue-type plasminogen activator (rt-PA) was started 140 min after symptom onset. Twenty minutes after starting the infusion period, involuntary movements of the upper paretic limb were noticed. The movements involved either the distal or the proximal muscles, independently, and could be jerk-like, irregular, myoclonic-like, or slow and brief (Video). During rt-PA perfusion, a 72-channel EEG (International 10/10 System) with an EMG channel recording the left flexor digitorum superficialis (sample frequency of 1000 Hz) captured brief, repetitive, and almost periodic muscle activations (Fig. 1A). No epileptiform activity was apparent in the raw EEG data. Back-average analysis of the EEG time-locked with the onset of the recorded myoclonus (538 activations) was performed (BESA software, version 6.0), revealing a right frontocentral negative wave. This EEG transient preceded muscle activation by 30 ms (Fig. 1B). No antiepileptic drug was given, and the involuntary movements lasted approximately 40 min, stopping by the end of the rt-PA perfusion. The neurological deficit did not improve after thrombolysis. Transcranial Doppler showed no recanalization. Computed tomography at 24 h disclosed an acute MCA infarct scoring 5 on ASPECTS, with spared cortical areas within the infarct zone (Fig. 2). The patient partially recovered after 7 days (NIHSS score = 6). No further involuntary movements or clinically suspected seizures were observed despite transitory worsening of renal function during hospitalization. One year after stroke, the patient is alive and independent (NIHSS = 1 and mRS = 1), with no report of late poststroke seizures.\n\n3 Discussion\nWe report a patient with an acute MCA ischemic stroke who developed subtle involuntary movements of the paretic upper limb, with cortical origin as documented neurophysiologically, during rt-PA perfusion. Because cortical myoclonus and epileptogenic discharges are generated by neuronal hypersynchronous activities sharing the same physiopathogenic mechanisms, the recorded myoclonus can be considered an acute symptomatic seizure. Because of the subtleness of the movements, the clinical stability of the patient, and the absence of clear epileptiform activity on the immediate raw EEG analysis, no antiepileptic medication was given. Back-average analysis, enlightening the cortical origin of the myoclonus, was only performed after the acute phase.\n\nEven though our patient had multiple risk factors for seizures (acute renal lesion, acute anterior stroke, cortical involvement), the close time relationship of this paroxysmal motor behavior with the therapeutic intervention raises the possibility of an association. It has been documented that seizures during rt-PA perfusion can occur even in the absence of a cerebral lesion, as described in 2 patients submitted to thrombolysis for acute myocardial infarction [2]. In fact, neurotoxic and epileptogenic properties [3] of rt-PA are known. Other postulated mechanisms for seizures during thrombolysis for ischemic stroke include secondary cortical infarct from distal embolization or reperfusion/hyperperfusion syndrome [4].\n\nDespite the multiple potential pathophysiological mechanisms for the relationship between rt-PA and seizures, the frequency of seizures during thrombolysis is not well known. Besides a few reports of overt seizures occurring in close proximity to rt-PA perfusion [4], [2], most larger studies looking at seizure frequency in patients submitted to thrombolysis report a global incidence of seizures within 7 days after stroke and not specifically during the therapeutic procedure. In these studies, patients submitted to thrombolysis have similar frequency of early seizures when compared with patients without thrombolysis. Only one study concluded that thrombolysis is an independent risk factor for early seizures after stroke [1]. These discrepancies may be related to the retrospective collection of the data. Additionally, reporting bias due to increased clinical vigilance in the acute phase of patients undergoing thrombolysis cannot be excluded. Finally, it is also possible that subtle and transient clinical seizures, like those described in our patient, may not be detected or are misdiagnosed as nonepileptic involuntary movements.\n\nThe following is the Supplementary data to this article.Video\nAfter rt-PA bolus, involuntary movements of the upper paretic limb were noticed. The movements involved either the distal or the proximal muscles, independently, and could be jerk-like, irregular, myoclonic-like, or slow and brief.\n\n \n\nStatement and acknowledgment\nThis clinical case is included in the project “EEG in Cerebrovascular Disease” approved by the ethics committee of our hospital. All the persons included in this study gave their informed consent to their inclusion.\n\nThis project was supported by the 2012 Research Grant in Cerebrovascular Diseases of the Sociedade Portuguesa do Acidente Vascular Cerebral (SPAVC) sponsored by Tecnifar. The funding source had no involvement in the study design, collection, analysis, or interpretation of the data.\n\nConflict of interest\nOn behalf of all authors, the corresponding author states that there is no conflict of interest.\n\nFig. 1 A) EMG channel recording the left flexor digitorum superficialis capturing brief, repetitive, and almost periodic muscle activations (arrows). B) EEG back-average analysis disclosing a negative transient (arrows) with a peak (yellow line) of 10 ms before EMG activations (dotted line) at right central electrodes (C4/FC4).\n\nFig. 2 Plain head CT scan 24 h after thrombolysis disclosing an acute right MCA infarct, scoring 5 (I, M1, M2, M5, M6) on ASPECTS score, with spared cortical areas within the infarct zone.\n==== Refs\nReferences\n1 Alvarez V. Rossetti A.O. Papavasileiou V. Michel P. Acute seizures in acute ischemic stroke: does thrombolysis have a role to play? J Neurol 260 1 2013 55 61 22743792 \n2 Hafeez F. Razzaq M.a. Levine R.L. Ramirez M.A.N. Reperfusion seizures: a manifestation of cerebral reperfusion injury after administration of recombinant tissue plasminogen activator for acute ischemic stroke J Stroke Cerebrovasc Dis 16 6 2007 273 277 18035246 \n3 Iyer a.M. Zurolo E. Boer K. Baayen J.C. Giangaspero F. Arcella A. Tissue plasminogen activator and urokinase plasminogen activator in human epileptogenic pathologies Neuroscience 167 3 2010 929 945 20219643 \n4 Rodan L.H. Aviv R.I. Sahlas D.J. Murray B.J. Gladstone J.P. Gladstone D.J. Seizures during stroke thrombolysis heralding dramatic neurologic recovery Neurology 67 11 2006 2048 2049 17159118\n\n",
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"keywords": "Back-average analysis; Cerebral infarct; EEG; Recombinant tissue-type plasminogen activator (rt-PA); Seizures",
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"abstract": "BACKGROUND\nAnti-JC virus antibody status is a risk factor for progressive multifocal leukoencephalopathy after natalizumab treatment in multiple sclerosis. Previous studies have used a cross-sectional approach to conclude that the presence and duration of natalizumab treatment does not influence anti-JCV Ab seropositivity.\n\n\nOBJECTIVE\nUsing a longitudinal approach, we measured change in anti-JCV Ab results after natalizumab treatment.\n\n\nMETHODS\nAnti-JCV Ab results (n = 1154) from the second-generation STRATIFY JCV™ DxSelect™ test were analysed from an observational cohort of MS patients on natalizumab (n = 485; n = 340 with repeat testing; n = 657 repeat tests on natalizumab).\n\n\nRESULTS\nAcross sequential paired tests, seroconversion rate was greater than seroreversion rate (40/364 (11.0%) versus 18/293 (6.1%); p < 0.05). Moreover, anti-JCV Ab index increased across longitudinal paired tests (mA-B 0.102; paired t(656) = 5.0; p < 0.0001). This magnitude of Ab level increase far exceeds that expected due to increasing age alone.\n\n\nCONCLUSIONS\nOur data suggest that natalizumab therapy is associated with a significant and substantial increase in anti-JCV Ab index over time. Further work should focus on the underlying mechanisms of this phenomenon, and the clinical relevance to risk stratification.",
"affiliations": "Department of Medicine, Imperial College London, UK joelraffel@doctors.org.uk.;Department of Medicine, Imperial College London, UK.;Department of Medicine, Imperial College London, UK.;Department of Medicine, Imperial College London, UK.",
"authors": "Raffel|J|J|;Gafson|A R|AR|;Malik|O|O|;Nicholas|R|R|",
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"abstract": "Acute appendicitis in a solid organ transplant recipient is a rare occurrence, and experience remains limited. Appendicitis in uterine transplant recipients has never been reported. Immunocompromised patients with acute abdomen often present late and with attenuated symptoms. The differential diagnosis in a transplanted patient is broad and challenging due to possible existing complications associated with the graft, effects of immunosuppression, and altered anatomical relations.\n\n\n\nA 26-year-old woman suffering from absolute uterine factor infertility received a uterus transplant. In the post-transplant period, she suffered from leukopenia and recurrent acute cellular rejection. Her compliance was suboptimal. She travelled to an exotic destination despite the physician's recommendation not to do so. Following her vacation, she presented with abdominal discomfort, nausea and diarrhoea. There was no sign of acute abdomen; the abdominal ultrasound was negative on day 0. Clostridium difficile colitis was verified and treated with perorally administered vancomycin. On day 4, the discomfort changed to pain; the ultrasound scan revealed a finding suggestive of appendicitis. Surgical exploration revealed perforated appendicitis, and appendectomy was performed. From a surgical point of view, the patient's follow-up was uneventful. The patient underwent a successful embryo transfer 6 months after the appendectomy. The patient gave birth to a healthy boy at the 35th week of gestation.\n\n\n\nA high index of suspicion of an atypical course and symptomatology of acute abdomen should be maintained in immunosuppressed patients.",
"affiliations": "Department of Transplant Surgery, Institute for Clinical and Experimental Medicine, Prague 140 21, Czech Republic;Department of Transplant Surgery, Institute for Clinical and Experimental Medicine, Prague 140 21, Czech Republic;Department of Transplant Surgery, Institute for Clinical and Experimental Medicine, Prague 140 21, Czech Republic;Department of Transplant Surgery, Institute for Clinical and Experimental Medicine, Prague 140 21, Czech Republic;Department of Clinical and Transplant Pathology, Institute for Clinical and Experimental Medicine, Prague 140 21, Czech Republic;Department of Transplant Surgery, Institute for Clinical and Experimental Medicine, Prague 140 21, Czech Republic;Department of Transplant Surgery, Institute for Clinical and Experimental Medicine, Prague 140 21, Czech Republic",
"authors": "Kristek|Jakub|J|;Kudla|Michal|M|;Chlupac|Jaroslav|J|;Novotny|Robert|R|;Mirejovsky|Tomas|T|;Janousek|Libor|L|;Fronek|Jiri|J|",
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"fulltext": "\n==== Front\nWorld J Clin CasesWJCCWorld Journal of Clinical Cases2307-8960Baishideng Publishing Group Inc jWJCC.v7.i24.pg427010.12998/wjcc.v7.i24.4270Case ReportAcute appendicitis in a patient after a uterus transplant: A case report Kristek Jakub Department of Transplant Surgery, Institute for Clinical and Experimental Medicine, Prague 140 21, Czech RepublicDepartment of Anatomy, Second Faculty of Medicine, Charles University, Prague 150 06, Czech Republic. krsj@ikem.czKudla Michal Department of Transplant Surgery, Institute for Clinical and Experimental Medicine, Prague 140 21, Czech RepublicChlupac Jaroslav Department of Transplant Surgery, Institute for Clinical and Experimental Medicine, Prague 140 21, Czech RepublicDepartment of Anatomy, Second Faculty of Medicine, Charles University, Prague 150 06, Czech RepublicNovotny Robert Department of Transplant Surgery, Institute for Clinical and Experimental Medicine, Prague 140 21, Czech RepublicMirejovsky Tomas Department of Clinical and Transplant Pathology, Institute for Clinical and Experimental Medicine, Prague 140 21, Czech RepublicJanousek Libor Department of Transplant Surgery, Institute for Clinical and Experimental Medicine, Prague 140 21, Czech RepublicFirst Faculty of Medicine, Charles University, Prague 121 08, Czech RepublicFronek Jiri Department of Transplant Surgery, Institute for Clinical and Experimental Medicine, Prague 140 21, Czech RepublicDepartment of Anatomy, Second Faculty of Medicine, Charles University, Prague 150 06, Czech RepublicAuthor contributions: Kristek J wrote the manuscript and analyzed the data. Kudla M operated on the patient. Chlupac J and Novotny R co-analyzed the data and provided consultations regarding the risk of thrombosis. Mirejovsky T provided the histological image. Janousek L and Fronek J designed and ran the uterus transplantation trial and provided consultations regarding this case.\n\nCorresponding author: Jakub Kristek, MD, Department of Anatomy, Second Faculty of Medicine, Charles University, V Uvalu 84, Prague 150 06, Czech Republic. krsj@ikem.cz\n\nTelephone: +420-23-6054105 Fax: +420-23-6052822\n\n26 12 2019 26 12 2019 7 24 4270 4276 20 9 2019 7 11 2019 15 11 2019 ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.2019This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is 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.BACKGROUND\nAcute appendicitis in a solid organ transplant recipient is a rare occurrence, and experience remains limited. Appendicitis in uterine transplant recipients has never been reported. Immunocompromised patients with acute abdomen often present late and with attenuated symptoms. The differential diagnosis in a transplanted patient is broad and challenging due to possible existing complications associated with the graft, effects of immunosuppression, and altered anatomical relations.\n\nCASE SUMMARY\nA 26-year-old woman suffering from absolute uterine factor infertility received a uterus transplant. In the post-transplant period, she suffered from leukopenia and recurrent acute cellular rejection. Her compliance was suboptimal. She travelled to an exotic destination despite the physician’s recommendation not to do so. Following her vacation, she presented with abdominal discomfort, nausea and diarrhoea. There was no sign of acute abdomen; the abdominal ultrasound was negative on day 0. Clostridium difficile colitis was verified and treated with perorally administered vancomycin. On day 4, the discomfort changed to pain; the ultrasound scan revealed a finding suggestive of appendicitis. Surgical exploration revealed perforated appendicitis, and appendectomy was performed. From a surgical point of view, the patient’s follow-up was uneventful. The patient underwent a successful embryo transfer 6 months after the appendectomy. The patient gave birth to a healthy boy at the 35th week of gestation.\n\nCONCLUSION\nA high index of suspicion of an atypical course and symptomatology of acute abdomen should be maintained in immunosuppressed patients.\n\nUterusOrgan transplantationNoncomplianceAcute abdomenColitisDifferential diagnosisCase report\n==== Body\nCore tip: Herein, we present a unique report of a woman with a viable transplanted uterus graft who was suffering from concurrent Clostridium difficile colitis and acute appendicitis. The differential diagnosis in an immunosuppressed patient may be complex, and a high index of suspicion of an atypical course of acute abdomen should be maintained in immunosuppressed patients. Sometimes, more than one synchronous pathological condition may be present. This case highlights the ultimate importance of focusing on the achievement of successful embryo transfer in the uterus transplantation recipients as soon as possible since they are vulnerable to a multitude of possible complications.\n\nINTRODUCTION\nUterus transplantation (UTx) is an experimental treatment method for women with uterine factor infertility (UFI). It is a novel, challenging procedure performed in only a few centres around the world; hence, experience with acute abdomen in UTx recipients is rare. The lifetime risk of acute appendicitis (AA) in a normal population has been estimated to be 8.6% and 6.7% for males and females, respectively[1]. AA in solid organ transplant recipients is rare, yet a few small case series have been reported[2,3]. This article presents the first case of a woman with a history of UTx who suffered from AA.\n\nCASE PRESENTATION\nHistory of past illness\nA 26-year-old Caucasian woman suffering from congenital absolute UFI underwent a deceased donor UTx. In the first year of the post-transplant period, 4 episodes of mild acute cellular rejection were diagnosed by cervical biopsy. They were treated with pulses of glucocorticoids and the addition of azathioprine to a maintenance immunosuppressive regimen of tacrolimus. In the further course, the patient developed secondary neutropenia, which was addressed by withdrawal of azathioprine and administration of several pulses of granulocyte colony-stimulating factor.\n\nPersonal and family history\nApart from congenital uterine agenesis which was treated with UTx, the patient was healthy with no history of further operations. Family history was negative for inherent diseases.\n\nHistory of present illness\nFive months after the UTx, the patient’s compliance was suboptimal. She decided to go on vacation to Egypt despite clear physician recommendation not to do so considering the high risk of acquisition of infectious gastroenteritis.\n\nChief complaints\nAfter her return from Egypt, the patient presented with nausea, abdominal discomfort, and diarrhoea. She was hospitalized to receive rehydration therapy and to run necessary tests.\n\nPhysical examination upon admission\nUpon admission, there were no signs of acute abdomen. The abdomen was mildly tender in all quadrants; there were no signs of peritoneal inflammation.\n\nImaging examinations\nUpon admission, her abdominal ultrasound (US) was normal, although the appendix was not differentiated on baseline US. There was no suspicion of acute abdomen, and thrombosis of the uterine graft was excluded using Doppler ultrasound (Figure 1).\n\nFigure 1 Doppler ultrasound scan of the uterine graft showing perfusion present on both sides of the graft. Uterine arteries (white arrows).\n\nLaboratory examinations\nC-reactive protein was 27 mg/L on day 0; the level of leukocytes was within the normal range. However, tests proved to be positive for Clostridium difficile colitis. Due to lack of signs of acute abdomen and verified colitis, we felt it was not necessary to run computed tomography (CT) of the abdomen. A therapy of perorally administered vancomycin 125 mg 4 times a day was started. Viral and parasitic colitis were excluded. Additionally, cytomegalovirus (CMV) polymerase chain reaction was negative. In the course of the next few days, there was a steady progressive elevation of the level of C-reactive protein up to 83 mg/L on day 4. Although the differential blood count showed a normal level of leukocytes, it was considered pathologic because the patient had been leukopenic chronically and there was a new finding of neutrophilia. On day 4, the abdominal discomfort changed to pain and became localized to the right hypogastrium.\n\nFINAL DIAGNOSIS\nA subsequent US scan revealed a nonhomogeneous tubular structure located behind the uterus, i.e., a finding suggestive of AA (Figure 2A and B). The final diagnosis of the presented case is concurrent Clostridium difficile colitis and acute perforated appendicitis.\n\nFigure 2 Ultrasound scan. A: A suspected inflamed appendix next to the uterine graft. Suspected inflamed appendix in a longitudinal view (arrow); the uterine graft (star); B: A suspected inflamed appendix next to the uterine graft. Suspected appendicitis in a transversal view (arrow); the uterine graft (star).\n\nTREATMENT\nThe patient underwent an uncomplicated conversion lap-to-open appendectomy. A gangrenous perforated appendix with localized peritonitis was found dorsal to the uterus (Figures 3 and 4). The patient was treated with metronidazole and amoxicillin with clavulanic acid; the tacrolimus immunosuppressive regimen was not discontinued because she was not septic. Subsequently, the tacrolimus levels increased to toxic levels, probably due to diarrhoea and consequently impaired resorption. The medication was changed, and probiotics were administered.\n\nFigure 3 A photo of the appendix. A perforation of the appendix (black arrow); the base of the caecum (white arrow).\n\nFigure 4 A histological section of the appendix; acute gangrenous appendicitis with perforation of its wall, purulent fibrinous periappendicitis. (Hematoxylin eosin, magnitude 20 ×). A perforation of the appendix (arrow); the lumen of the appendix (star).\n\nOUTCOME AND FOLLOW-UP\nApart from long-lasting diarrhoea and pancytopenia of complex aetiology, the patient’s follow-up was uneventful. The interval between transplant and appendectomy was 502 days. The patient underwent a successful embryo transfer 6 months after the appendectomy. Apart from pregnancy-induced diabetes, the pregnancy was uneventful. The patient gave birth to a healthy boy at week 35 of gestation.\n\nDISCUSSION\nAlthough AA has been rarely observed and described in recipients of solid organ transplants, this is the first reported case of AA in a uterus transplant recipient. According to the official transplant terminology, uterus transplant is not considered a solid organ transplant but a vascularized composite allograft, as are other non-vital transplantable organs, including the face, extremities, abdominal wall, and larynx[4]. The prevalence of AA is reported as 0.35%, 0.49%, and 0.21% in kidney transplant recipients (n = 2880), liver transplant recipients (n = 817), and liver, heart, kidney, pancreas-kidney and heart-kidney transplant recipients (n = 8000), respectively[2,3,5].\n\nGenerally, immunocompromised patients tend to present late and with minimal symptoms; the symptoms of acute abdomen tend to be weakened by the attenuated immune response. Classic signs of peritonitis, e.g., rebound tenderness and fever, may be feeble or even absent in immunocompromised hosts. Furthermore, nonspecific signs such as tachycardia, hypotension, and confusion may present the only warning of existing abdominal catastrophe[6]. Savar et al[2] came to slightly different conclusions, at least with regard to AA. In their cohort of 15 transplant recipients suffering from AA, the physical findings were similar to the findings in the non-transplant population, i.e., abdominal/right hypogastrium pain (present in 94% of cases) and nausea and vomiting (present in 88% of cases)[2]. Generally, after solid organ transplants that are typically placed in the right iliac fossa/retroperitoneum (kidney or pancreas), AA may be misdiagnosed as a graft-related complication, e.g., infection, acute urine outflow obstruction, or acute rejection of the graft. In UTx recipients, thrombosis of the graft remains the most feared complication. Thrombosis of the vascular pedicles of the uterine graft has been repeatedly presented as a cause of loss of the graft in both animal as well as human studies[7,8]. Since diarrhoea may lead to dehydration and the association between dehydration and a higher risk of venous thrombosis is presumed, graft thrombosis was immediately suspected and subsequently excluded using Doppler US in our case[9]. A possible cause of AA after kidney transplantation is CMV infection. Invasive CMV infection must always be excluded by definitive histopathological evaluation. If the test for CMV is positive, effective antiviral treatment must be instituted[10].\n\nThe risk of perforation of an inflamed appendix escalates over time. Perforation is present in approximately 10% of patients by 24 h and in up to 50% of patients by 48 h in the non-transplanted paediatric population[11]. Although the diagnosis of AA is often based on clinical and laboratory findings, the use of either US or CT is recommended if AA is suspected; the sensitivity and specificity of CT are up to 98.5% and up to 98%, respectively[12]. According to a meta-analysis, the rate of a negative appendectomy was 8.7% with the use of preoperative abdominal CT compared to 16.7% based on clinical evaluation alone[13]. However, US may be almost as sensitive as CT in diagnosing AA when performed by well-trained radiologists, with the advantage of no radiation exposure[14].\n\nIn our case, if CT was used upon admission, it may have led to timely diagnosis and appendectomy of inflamed yet non-perforated appendix. However, we have suspicion that Clostridium difficile colitis may have been the very cause of the appendicitis. In other words, it may be a case of Clostridium difficile colitis and subsequent acute appendicitis.\n\nUTx is primarily considered a temporary transplant. It cannot be emphasized enough that UTx recipients should preferentially focus on achieving successful embryo transfer. Since UTx recipients are prone to a variety of complications and the side effects of immunosuppression, it is advisable to obviate any risky activities that might compromise achieving the primary aim.\n\nCONCLUSION\nIn this paper, we present a unique report of a woman with a viable transplanted uterus graft suffering from Clostridium difficile colitis and AA. The differential diagnosis in an immunosuppressed patient may be complex, and a high index of suspicion of atypical course and indefinite symptomatology of acute abdomen should be maintained in immunosuppressed patients. Sometimes, more than one synchronous pathological condition may be present. In transplanted patients, thrombosis of the vascular pedicles must always be excluded if pain or alteration to the graft’s function occurs. UTx recipients should preferentially focus on achieving successful embryo transfer because they are prone to a variety of complications.\n\nACKNOWLEDGEMENTS\nThe author would like to thank Dr. Kornelia Chrapkova, PG Dip, for her invaluable help with review of the literature.\n\nConflict-of-interest statement: The authors declare that they have no conflict of interest.\n\nCARE Checklist (2016) statement: The manuscript was prepared and revised according to the CARE Checklist (2016).\n\nManuscript source: Unsolicited manuscript\n\nPeer-review started: September 20, 2019\n\nFirst decision: October 20, 2019\n\nArticle in press: November 15, 2019\n\nSpecialty type: Medicine, Research and Experimental\n\nCountry of origin: Czech Republic\n\nPeer-review report classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): B\n\nGrade C (Good): 0\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nP-Reviewer: Hefny AF S-Editor: Zhang L L-Editor: A E-Editor: Qi LL\n==== Refs\n1 Addiss DG Shaffer N Fowler BS Tauxe RV The epidemiology of appendicitis and appendectomy in the United States Am J Epidemiol 1990 132 910 925 2239906 \n2 Savar A Hiatt JR Busuttil RW Acute appendicitis after solid organ transplantation Clin Transplant 2006 20 78 80 16556158 \n3 Kwon SH Park SH Lee HY Ko EJ Ban TH Chung BH Yang CW Clinical Characteristics of Acute Appendicitis in Kidney Transplant Recipients Ann Transplant 2019 24 168 173 30910996 \n4 Samuel U Regulatory aspects of VCA in Eurotransplant Transpl Int 2016 29 686 693 26824440 \n5 Wu L Zhang J Guo Z Tai Q He X Ju W Wang D Zhu X Diagnosis and treatment of acute appendicitis after orthotopic liver transplant in adults Exp Clin Transplant 2011 9 113 117 21453228 \n6 Scott-Conner CE Fabrega AJ Gastrointestinal problems in the immunocompromised host. A review for surgeons Surg Endosc 1996 10 959 964 8864085 \n7 Brännström M Wranning CA Altchek A Experimental uterus transplantation Hum Reprod Update 2010 16 329 345 19897849 \n8 Fageeh W Raffa H Jabbad H Marzouki A Transplantation of the human uterus Int J Gynaecol Obstet 2002 76 245 251 11880127 \n9 Verhaeghe R Vermylen J Verstraete M Thrombosis in particular organ veins Herz 1989 14 298 307 2680853 \n10 Posen A Renckens I Sagaert X Kuypers D Subacute cytomegalovirus appendicitis in a renal transplant recipient Transpl Infect Dis 2013 15 96 97 23075276 \n11 Chan MK Wilcox DT Trompeter RS Acute appendicitis in children after renal transplantation Arch Dis Child 1999 81 372 \n12 Pickhardt PJ Lawrence EM Pooler BD Bruce RJ Diagnostic performance of multidetector computed tomography for suspected acute appendicitis Ann Intern Med 2011 154 789 796, W-291 21690593 \n13 Krajewski S Brown J Phang PT Raval M Brown CJ Impact of computed tomography of the abdomen on clinical outcomes in patients with acute right lower quadrant pain: a meta-analysis Can J Surg 2011 54 43 53 21251432 \n14 Doria AS Moineddin R Kellenberger CJ Epelman M Beyene J Schuh S Babyn PS Dick PT US or CT for Diagnosis of Appendicitis in Children and Adults? A Meta-Analysis Radiology 2006 241 83 94 16928974\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2307-8960",
"issue": "7(24)",
"journal": "World journal of clinical cases",
"keywords": "Acute abdomen; Case report; Colitis; Differential diagnosis; Noncompliance; Organ transplantation; Uterus",
"medline_ta": "World J Clin Cases",
"mesh_terms": null,
"nlm_unique_id": "101618806",
"other_id": null,
"pages": "4270-4276",
"pmc": null,
"pmid": "31911907",
"pubdate": "2019-12-26",
"publication_types": "D002363:Case Reports",
"references": "19897849;2680853;8864085;30910996;2239906;16556158;21690593;23075276;26824440;21251432;21453228;11880127;16928974;10577360",
"title": "Acute appendicitis in a patient after a uterus transplant: A case report.",
"title_normalized": "acute appendicitis in a patient after a uterus transplant a case report"
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"companynumb": "CZ-ACCORD-170559",
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"abstract": "BACKGROUND\n/Objectives: Pancreatic adenocarcinoma (PDAC) metastatic to the leptomeninges is a rare and lethal event. Leptomeningeal disease (LMD) research is limited in PDAC, and insights into clinical descriptors, possible disease predictors, and treatment strategies is necessitated.\n\n\nMETHODS\nMemorial Sloan Kettering databases were queried with Institutional Review Board approval to identify patients with LMD and PDAC treated between January 2000 and June 2020. Medical record review was used to abstract clinical, genomic, pathologic, and radiographic data. Overall survival was calculated from date of PDAC diagnosis to date of death. Previously published literature on LMD from PDAC was reviewed.\n\n\nRESULTS\nFour patients with LMD from PDAC were identified, two males and two females. Age at diagnosis ranged from 57 to 68 years. All four patients had predominant lung metastasis and a relatively low burden of intra-abdominal disease. Somatic testing indicated alterations typical of PDAC and no PDAC defining pathogenic germline mutations were identified. An extended clinical course prior to LMD diagnosis was observed in all patients, ranging from 16 to 148 months. Upon diagnosis of LMD, three patients elected for supportive care and one patient received a limited course of craniospinal radiation. The median survival following diagnosis of LMD was 1.6 months (range 0.5-2.8 months).\n\n\nCONCLUSIONS\nLMD from PDAC is a rare occurrence that may be more frequent in patients with lung metastasis and/or a more indolent clinical course. Following diagnosis of LMD, prognosis is poor, and survival is short. New treatment strategies for this manifestation of PDAC are needed.",
"affiliations": "Department of Medicine, Memorial Sloan Kettering Cancer Center, USA.;Department of Medicine, Memorial Sloan Kettering Cancer Center, USA.;Department of Neurology, Memorial Sloan Kettering Cancer Center, USA.;Department of Pathology, Memorial Sloan Kettering Cancer Center, USA.;Department of Pathology, Memorial Sloan Kettering Cancer Center, USA.;Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, USA.;Department of Medicine, Memorial Sloan Kettering Cancer Center, USA; Department of Medicine, Weill Cornell Medical College, USA; David M. Rubenstein Center for Pancreas Cancer Research, USA.;Department of Medicine, Memorial Sloan Kettering Cancer Center, USA; Department of Medicine, Weill Cornell Medical College, USA; David M. Rubenstein Center for Pancreas Cancer Research, USA.;Department of Medicine, Memorial Sloan Kettering Cancer Center, USA; Department of Medicine, Weill Cornell Medical College, USA; David M. Rubenstein Center for Pancreas Cancer Research, USA.;Department of Medicine, Memorial Sloan Kettering Cancer Center, USA; Department of Medicine, Weill Cornell Medical College, USA; David M. Rubenstein Center for Pancreas Cancer Research, USA.;Department of Medicine, Memorial Sloan Kettering Cancer Center, USA; Department of Medicine, Weill Cornell Medical College, USA; David M. Rubenstein Center for Pancreas Cancer Research, USA. Electronic address: oreillye@mskcc.org.",
"authors": "O'Connor|Catherine A|CA|;Park|Jennifer S|JS|;Kaley|Thomas|T|;Kezlarian|Brie|B|;Edelweiss|Marcia|M|;Yang|T Jonathan|TJ|;Park|Wungki|W|;Reidy|Diane|D|;Varghese|Anna M|AM|;Yu|Kenneth H|KH|;O'Reilly|Eileen M|EM|",
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"issue": "21(3)",
"journal": "Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]",
"keywords": "Cerebrospinal fluid; Genomics; Leptomeninges; Pancreatic adenocarcinoma",
"medline_ta": "Pancreatology",
"mesh_terms": "D000368:Aged; D021441:Carcinoma, Pancreatic Ductal; D003131:Combined Modality Therapy; D016208:Databases, Factual; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008577:Meningeal Neoplasms; D008875:Middle Aged; D010190:Pancreatic Neoplasms; D011379:Prognosis; D012189:Retrospective Studies",
"nlm_unique_id": "100966936",
"other_id": null,
"pages": "599-605",
"pmc": null,
"pmid": "33582005",
"pubdate": "2021-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "20069465;26101003;32095126;25038877;20439847;21857581;18541120;30055578;31157963;11843255;15477323;28821205;17608361;2086737;26425578;23936550;32592583;29313949;27539328;28096196;21561347;32257762;32352148;29165794;32487151;29867436;29496399;20598636;30697071;11370554;21381797;25624740;12892239;26827696;22743150;19098414;30654298;18701427;24131140;26184025;15714201",
"title": "Leptomeningeal disease in pancreas ductal adenocarcinoma: A manifestation of longevity.",
"title_normalized": "leptomeningeal disease in pancreas ductal adenocarcinoma a manifestation of longevity"
} | [
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"companynumb": "US-SHILPA MEDICARE LIMITED-SML-US-2021-00765",
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"activesubstancename": "GEMCITABINE"
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"abstract": "Anaplastic ependymomas are rare tumors in adult patients. Maximal safe resection and use of radiation therapy are standard treatment approaches in patients with anaplastic ependymoma. Recurrent anaplastic ependymomas are treated by reoperation when the tumors are surgically accessible, by radiotherapy if not previously administered and by salvage chemotherapy. However, the role of chemotherapy is still unclear. A few retrospective studies showed interesting results with platinum-based regimens, while the administration of temozolomide alone demonstrated conflicting results. We present, for the first time, the case of a patient with anaplastic ependymoma refractory to platinum-based chemotherapy and temozolomide only, but showing a prolonged reduction of the lesion after receiving combination chemotherapy with cisplatin and temozolomide. A brief review of the literature on the treatment of anaplastic ependymoma follows.",
"affiliations": "Medical Oncology 1, Veneto Institute of Oncology - IRCCS, Padua, Italy.",
"authors": "Lombardi|Giuseppe|G|;Pambuku|Ardi|A|;Bellu|Luisa|L|;Della Puppa|Alessandro|A|;Rumanò|Laura|L|;Gardiman|Marina Paola|MP|;Pomerri|Fabio|F|;Zagonel|Vittorina|V|",
"chemical_list": "D000970:Antineoplastic Agents; D003606:Dacarbazine; D002945:Cisplatin; D000077204:Temozolomide",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000355662",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-3157",
"issue": "59(3)",
"journal": "Chemotherapy",
"keywords": null,
"medline_ta": "Chemotherapy",
"mesh_terms": "D000970:Antineoplastic Agents; D001932:Brain Neoplasms; D002945:Cisplatin; D003606:Dacarbazine; D004359:Drug Therapy, Combination; D004806:Ependymoma; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D011859:Radiography; D000077204:Temozolomide; D016896:Treatment Outcome",
"nlm_unique_id": "0144731",
"other_id": null,
"pages": "176-80",
"pmc": null,
"pmid": "24192541",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cisplatin and temozolomide combination in the treatment of supratentorial anaplastic ependymoma.",
"title_normalized": "cisplatin and temozolomide combination in the treatment of supratentorial anaplastic ependymoma"
} | [
{
"companynumb": "IT-MYLANLABS-2015M1044610",
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"activesubstancename": "CISPLATIN"
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{
"abstract": "OBJECTIVE\nCyclosporine (CsA) is currently widely used as a primary immunosuppressive agent in ocular disease, particularly in severe uveitis. Posterior reversible encephalopathy syndrome (PRES) is a significant complication of CsA therapy. However, there are no reports of the occurrence of PRES in response to the treatment of uveitis in the ophthalmological area.\n\n\nMETHODS\nWe report a case with CsA-associated PRES. A 70-year-old woman with sympathetic ophthalmitis was treated with 50 mg/day of CsA for 1 week. However, the trough level in her blood was too low; thus, we increased the dose to 100 mg/day of CsA with prednisolone. She had headaches, hypertension (systolic blood pressure 180-200 mm Hg), loss of consciousness for several hours, and reduced limb movement, and her MRI showed a high signal intensity in both posterior lobes, consistent with PRES. Examination of the cerebrospinal fluid indicated that it was within normal limits. Her CsA trough level in the blood was within normal ranges on the day of the attack. Her symptoms gradually improved over the next several days; however, she presented with cortical blindness, which lasted for several weeks. Finally, she returned to her baseline values from before the attack. Her MRI findings showed that PRES had essentially disappeared.\n\n\nCONCLUSIONS\nPRES is not directly associated with the dosage of CsA administered; however, in general, it is well known that PRES can affect strongly immunosuppressed cases undergoing organ and bone marrow transplantation. Nevertheless, our CsA dose was only 100 mg (1.8 mg/kg). In this study, we report on the occurrence of PRES after the administration of CsA to treat sympathetic ophthalmia. To our knowledge, PRES can also occur after the administration of a small dose of CsA; thus, ophthalmologists using CsA should carefully observe the systemic conditions of CsA-treated patients.",
"affiliations": "Ophthalmology Department, Kobe Kaisei Hospital, Kobe-City, Japan.;Ophthalmology Department, Kobe Kaisei Hospital, Kobe-City, Japan.",
"authors": "Tagami|Mizuki|M|;Azumi|Atsushi|A|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000443826",
"fulltext": "\n==== Front\nCase Rep OphthalmolCase Rep OphthalmolCOPCase Reports in Ophthalmology1663-2699S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000443826cop-0007-0061Published online: January, 2016Cyclosporine-Associated Leukoencephalopathy in a Case of Sympathetic Ophthalmitis Tagami Mizuki *Azumi Atsushi Ophthalmology Department, Kobe Kaisei Hospital, Kobe-City, Japan*Mizuki Tagami, Ophthalmology Department, Kobe Kaisei Hospital, 3-11-15 Shinoharakita-Machi, Nada-Ku, Kobe-City 580072 (Japan) E-Mail m-tagmi@kobe-kaisei.orgJan-Apr 2016 23 1 2016 23 1 2016 7 1 61 66 Copyright © 2016 by S. Karger AG, Basel2016This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Purpose\nCyclosporine (CsA) is currently widely used as a primary immunosuppressive agent in ocular disease, particularly in severe uveitis. Posterior reversible encephalopathy syndrome (PRES) is a significant complication of CsA therapy. However, there are no reports of the occurrence of PRES in response to the treatment of uveitis in the ophthalmological area.\n\nCase Presentation\nWe report a case with CsA-associated PRES. A 70-year-old woman with sympathetic ophthalmitis was treated with 50 mg/day of CsA for 1 week. However, the trough level in her blood was too low; thus, we increased the dose to 100 mg/day of CsA with prednisolone. She had headaches, hypertension (systolic blood pressure 180–200 mm Hg), loss of consciousness for several hours, and reduced limb movement, and her MRI showed a high signal intensity in both posterior lobes, consistent with PRES. Examination of the cerebrospinal fluid indicated that it was within normal limits. Her CsA trough level in the blood was within normal ranges on the day of the attack. Her symptoms gradually improved over the next several days; however, she presented with cortical blindness, which lasted for several weeks. Finally, she returned to her baseline values from before the attack. Her MRI findings showed that PRES had essentially disappeared.\n\nConclusion\nPRES is not directly associated with the dosage of CsA administered; however, in general, it is well known that PRES can affect strongly immunosuppressed cases undergoing organ and bone marrow transplantation. Nevertheless, our CsA dose was only 100 mg (1.8 mg/kg). In this study, we report on the occurrence of PRES after the administration of CsA to treat sympathetic ophthalmia. To our knowledge, PRES can also occur after the administration of a small dose of CsA; thus, ophthalmologists using CsA should carefully observe the systemic conditions of CsA-treated patients.\n\nKey Words\nCyclosporinePosterior reversible encephalopathy syndromeSympathetic ophthalmitis\n==== Body\nIntroduction\nImmunosuppressive treatment-associated leukoencephalopathy is a significant complication of cyclosporine (CsA) therapy [1]. CsA is currently widely used as a primary immunosuppressive agent in ocular disease, particularly in severe uveitis [2].\n\nPosterior reversible encephalopathy syndrome (PRES) is reversible and occurs in the white matter of the occipital lobe and ventricle neighborhood. PRES leads to pathological changes, such as high blood pressure, to immunosuppressive conditions, such as encephalopathy, and is a diffuse collagen disease; CsA administration has been shown to be a cause of PRES.\n\nPRES is not directly associated with the dosage of CsA administered; however, in general, it is well known than PRES can affect strongly immunosuppressed cases undergoing organ and bone marrow transplantation [1]. Nevertheless, our CsA dose was only 100 mg (1.8 mg/kg).\n\nIn this study, we report on the occurrence of PRES after the administration of CsA to treat sympathetic ophthalmia. To our knowledge, this is the first report of the occurrence of CsA-induced PRES in response to treatment for uveitis in the ophthalmological area.\n\nCase Report\nA 70-year-old woman was treated for acute retinal necrosis in both eyes 15 years ago with pars plana vitrectomy and lensectomy without intraocular lens implantation at that time. She was referred by her family doctor for evaluation and treatment of progressive retinal detachment in the right eye. Her past medical history was significant only for hypertension, which was well controlled with oral Ca blockers.\n\nHer best corrected visual acuity (BCVA) was 0.02 OU. She had immediate pars plana vitrectomy with scleral buckling with silicone oil tamponade. However, she went blind in her right eye after 3 months. Two months later, she had blurred vision in her left eye. Her BCVA OS was 0.02, and her intraocular pressure was 12 mm Hg OS. Slit-lamp examination demonstrated cells, fare, and mutton-fat keratic precipitates in the anterior chamber, strong vitreous cavity opacification, and vitreous cells. Fundus examination was difficult because of opacification (fig. 1a). We detected swelling of the choroid, and optical coherence tomography showedserious retinal detachment at the posterior pole. Fluorescein angiography showed leakage corresponding to serious retinal detachment areas (fig. 1b). The results of the laboratory investigations of the serum including angiotensin-converting enzyme, antinuclear antibodies, rheumatoid factor, and antineutrophil cytoplasmic antibodies were unremarkable except for the presence of elevated C-reactive protein. Serological analyses indicated that there was no active infection of syphilis, human T-cell lymphoma virus 1, herpes simplex virus, or varicella zoster virus. We diagnosed sympathetic ophthalmitis.\n\nThe patient then received steroid pulse therapy (1,000 mg/day of methylprednisolone for 3 days/week), followed by 30 mg/day of prednisolone therapy administered orally. However, her intraocular inflammation could not be stabilized, particularly the opacification in the vitreous cavity. Thus, we added 50 mg/day of CsA for 1 week; however, the trough level in her blood was too low, so we increased the dose to 100 mg/day of CsA with 10 mg/day of prednisolone. In addition, her systolic blood pressure was too low (approximately 85–100 mm Hg with no symptoms), so we ceased the administration of Ca blockers for her hypertension (fig. 2).\n\nTwo days later, she displayed a sudden onset of headache and hypertension (systolic blood pressure 180–200 mm Hg), loss of consciousness for several hours, and reduced limb movement. We speculated acute or subacute onset brain infarction; thus, we immediately performed a head MRI. The radiologist first diagnosed acute brain infarction. However, a neurologist in another hospital noted the possibility of PRES. The MRI showed a high signal intensity in both posterior lobes, consistent with PRES (fig. 3a). An electroencephalogram showed diffuse slow and irregular ground activity (data not shown). An examination of the cerebrospinal fluid indicated that it was within normal limits. Her CsA trough level in the blood was 68 ng/ml on the day of the attack.\n\nCsA use was immediately stopped. Her blood pressure was strictly managed in the ICU of the Neurology Department. Her symptoms gradually improved over the next several days; however, she developed cortical blindness, which lasted for several weeks. Finally, she returned to her baseline state before the attack, including her BCVA. The MRI findings with axial views showed that hyperintense spots remained on both posterior lobes 6 months after the day of the attack (fig. 3b). Ocular inflammation could be stabilized by oral prednisolone (fig. 1c, d).\n\nDiscussion\nPosterior encephalopathy and toxemic posterior encephalopathy were first described by Hinchey et al. [1] in 1996.\n\nAlthough PRES patients may have hypertension, this is not always the case [3, 4, 5].\n\nEtiological factors for PRES include hypertension; eclampsia-preeclampsia; immunosuppressant and chemotherapeutic medications such as CsA, tacrolimus, interferon-α, and corticosteroids; renal diseases such as lupus nephritis, acute glomerulonephritis, hemolytic uremic syndrome, and thrombotic thrombocytic purpura; transplantations; infections including influenza A, sepsis, shock, and toxemia; pregnancy; autoimmune diseases, and some vaccinations such as measles. Eclampsia might be a good prognostic factor for PRES [6, 7, 8, 9].\n\nAlthough the detailed mechanisms underlying PRES are not yet clear, some theories have been suggested. Currently, the most widely accepted theory suggests that severe hypertension leads to failed autoregulation, which subsequently causes hyperperfusion with endothelial injury/vasogenic edema [6].\n\nThe use of CsA for the treatment of uveitis was first reported in 1983 [10].\n\nIn many studies, the efficacy of CsA has been confirmed in idiopathic uveitis, Vogt-Koyanagi-Harada disease, birdshot retinochoroidopathy, serpiginous choroiditis, panuveitis, and Behçet's disease [2, 10, 11, 12, 13].\n\nIn Japan, CsA is currently available for endogenous uveitis, particularly for Behçet's disease [14]; however, there are no large statistical reports of severe side effects, such as PRES. Even if PRES has been identified as a side effect, it is rarely experienced by ophthalmologists. In this report, PRES appeared after the administration of a low dosage of CsA (50–100 mg), which is a commonly used dosage, for example, to treat atopic dermatitis [15]. In general, a small amount of CsA is prescribed (50–100 mg/day).\n\nOphthalmologists generally believe that CsA-induced PRES only rarely occurs. However, it has also been reported that PRES is unrelated to the dosage of CsA administered.\n\nOur study demonstrates that PRES occurred after the administration of only a small amount of CsA. This may be because CsA was combined with prednisolone or because blood pressure was poorly controlled at the onset.\n\nIn conclusion, we reported CsA-associated leukoencephalopathy in a case of sympathetic ophthalmitis. Several questions remain, such as the development mechanism and the long-term prognosis. Fortunately, our patient recovered almost completely, despite the fact that PRES can have severe long-term effects. CsA, even a small dose, can induce PRES when it is prescribed for the treatment of uveitis. Therefore, ophthalmologists prescribing CsA should carefully observe the systemic conditions, particularly the blood pressure, of CsA-treated patients.\n\nStatement of Ethics\nWritten informed consent was obtained from the patient.\n\nDisclosure Statement\nNone of the authors has any proprietary or financial interests.\n\nAcknowledgements\nDiagnosis and treatment were supported in part by the Department of Neurology, Shinko Hospital, Kobe, Japan.\n\nFig. 1 a Fundus photography before any treatment. The fundus is nearly invisible because of the opacification of the vitreous cavity. b Optical coherence tomography shows choroidal folds and serious retinal fluid near the posterior pole. c Fundus photography after 6 months of treatment. The fundus is nearly clear. d Optical coherence tomography shows the disappearance of choroidal folds and serious retinal fluid near the posterior pole.\n\nFig. 2 Clinical time course. Administration of Ca blockers was ceased because the patient's systolic blood pressure was much too low; after the attack, it increased significantly and was too high. PSL = Prednisolone.\n\nFig. 3 MRI shows hyperintense imaging on T2. Fluid-attenuated inversion recovery sequences. a Axial views show hyperintensity on both posterior lobes on the day of the attack. b Axial views show that dot hyperintensity spots remain on both posterior lobes 6 months after the day of the attack.\n==== Refs\nReferences\n1 Hinchey J Chaves C Appignani B Breen J Pao L Wang A Pessin MS Lamy C Mas JL Caplan LR A reversible posterior leukoencephalopathy syndrome N Engl J Med 1996 334 494 500 8559202 \n2 Nussenblatt RB Palestine AG Chan CC Cyclosporin A therapy in the treatment of intraocular inflammatory disease resistant to systemic corticosteroids and cytotoxic agents Am J Ophthalmol 1983 96 275 282 6614105 \n3 Doherty H Hameed S Ahmed I Russell IF Post-dural puncture headache and posterior reversible encephalopathy syndrome: a misdiagnosis or co-presentation? Int J Obstet Anesth 2014 23 279 282 24768557 \n4 Brewer J Owens MY Wallace K Posterior reversible encephalopathy syndrome in 46 of 47 patients with eclampsia Am J Obstet Gynecol 2013 208 468.e1 e6 23395926 \n5 Ringelstein EB Knecht S Cerebral small vessel diseases: manifestations in young women Curr Opin Neurol 2006 19 55 62 16415678 \n6 Roy S Gandhi AK Jana M Julka PK Recurrent posterior reversible encephalopathy syndrome after chemotherapy in hematologic malignancy-posterior reversible encephalopathy syndrome can strike twice J Cancer Res Ther 2014 10 393 396 25022403 \n7 Hamano T Takeda T Morita H Muramatsu T Yoneda M Kimura H Kuriyama M Posterior reversible encephalopathy syndrome following measles vaccination J Neurol Sci 2010 298 124 126 20850135 \n8 Yano Y Kario K Fukunaga T Ohshita T Himeji D Yano M Nakagawa S Sakata Y Shimada K A case of reversible posterior leukoencephalopathy syndrome caused by transient hypercoagulable state induced by infection Hypertens Res 2005 28 619 623 16335891 \n9 Pande AR Ando K Ishikura R Nagami Y Takada Y Wada A Watanabe Y Miki Y Uchino A Nakao N Clinicoradiological factors influencing the reversibility of posterior reversible encephalopathy syndrome: a multicenter study Radiat Med 2006 24 659 668 17186320 \n10 Nussenblatt RB Palestine AG Chan CC Cyclosporin A therapy in the treatment of intraocular inflammatory disease resistant to systemic corticosteroids and cytotoxic agents Am J Ophthalmol 1983 96 275 282 6614105 \n11 Masuda K Nakajima A Urayama A Nakae K Kogure M Inaba G Double-masked trial of cyclosporin versus colchicine and long-term open study of cyclosporin in Behçet's disease Lancet 1989 i 1093 1096 2566048 \n12 Michel SS Ekong A Baltatzis S Foster CS Multifocal choroiditis and panuveitis: immunomodulatory therapy Ophthalmology 2002 109 378 383 11825826 \n13 Kacmaz RO Kempen JH Newcomb C Daniel E Gangaputra S Nussenblatt RB Rosenbaum JT Cyclosporine for ocular inflammatory diseases Ophthalmology 2010 117 576 584 20031223 \n14 Yamada Y Sugita S Tanaka H Kamoi K Kawaguchi T Mochizuki M Comparison of infliximab versus ciclosporin during the initial 6-month treatment period in Behçet disease Br J Ophthalmol 2010 94 284 288 19692382 \n15 Ruzicka T Bieber T Schöpf E Rubins A Dobozy A Bos JD Jablonska S Ahmed I Thestrup-Pedersen K Daniel F Finzi A Reitamo S A short-term trial of tacrolimus ointment for atopic dermatitis. European Tacrolimus Multicenter Atopic Dermatitis Study Group N Engl J Med 1997 337 816 821 9295241\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1663-2699",
"issue": "7(1)",
"journal": "Case reports in ophthalmology",
"keywords": "Cyclosporine; Posterior reversible encephalopathy syndrome; Sympathetic ophthalmitis",
"medline_ta": "Case Rep Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "101532006",
"other_id": null,
"pages": "61-6",
"pmc": null,
"pmid": "26933431",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "24768557;19692382;2566048;11825826;20850135;6614105;20031223;8559202;16335891;23395926;17186320;25022403;9295241;16415678",
"title": "Cyclosporine-Associated Leukoencephalopathy in a Case of Sympathetic Ophthalmitis.",
"title_normalized": "cyclosporine associated leukoencephalopathy in a case of sympathetic ophthalmitis"
} | [
{
"companynumb": "JP-MYLANLABS-2016M1045742",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "Perry syndrome (PS) is a rare hereditary neurodegenerative disease characterized by autosomal dominant parkinsonism, psychiatric symptoms, weight loss, central hypoventilation, and distinct TDP-43 pathology. The mutated causative gene for PS is DCTN1, which encodes the dynactin subunit p150Glued. Dynactin is a motor protein involved in axonal transport; the p150Glued subunit has a critical role in the overall function. Since the discovery of DCTN1 in PS, it has been increasingly recognized that DCTN1 mutations can exhibit more diverse phenotypes than previously thought. Progressive supranuclear palsy- and/or frontotemporal dementia-like phenotypes have been associated with the PS phenotypes. In addition, DCTN1 mutations were identified in a family with motor-neuron disease before the discovery in PS. In this review, we analyze the clinical and genetic aspects of DCTN1-related neurodegeneration and discuss its pathogenesis. We also describe three families with PS, Canadian, Polish, and Brazilian. DCTN1 mutation was newly identified in two of them, the Canadian and Polish families. The Canadian family was first described in late 1970's but was never genetically tested. We recently had the opportunity to evaluate this family and to test the gene status of an affected family member. The Polish family is newly identified and is the first PS family in Poland. Although still rare, DCTN1-related neurodegeneration needs to be considered in a differential diagnosis of parkinsonian disorders, frontotemporal dementia, and motor-neuron diseases, especially if there is family history.",
"affiliations": "Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.;Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.;Movement Disorders Unit, Neurology Service, Hospital de Clínicas, Federal University of Paraná, Rua General Carneiro 1103/102, Centro, Curitiba, PR, 80060-150, Brazil.;Department of Neurological-Psychiatric Nursing, Medical University of Gdansk, Poland; Department of Neurology, St. Adalbert Hospital, Copernicus Ltd., Gdansk, Poland.;Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.;Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. Electronic address: Wszolek.Zbigniew@mayo.edu.",
"authors": "Konno|Takuya|T|;Ross|Owen A|OA|;Teive|Hélio A G|HAG|;Sławek|Jarosław|J|;Dickson|Dennis W|DW|;Wszolek|Zbigniew K|ZK|",
"chemical_list": "C000606360:DCTN1 protein, human; D000072159:Dynactin Complex",
"country": "England",
"delete": false,
"doi": "10.1016/j.parkreldis.2017.06.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1353-8020",
"issue": "41()",
"journal": "Parkinsonism & related disorders",
"keywords": "Atypical parkinsonism; DCTN1; Dynactin; FTD; Genetics; PSP; Perry syndrome; Review; TDP-43",
"medline_ta": "Parkinsonism Relat Disord",
"mesh_terms": "D001938:Brazil; D002170:Canada; D003863:Depression; D000072159:Dynactin Complex; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007040:Hypoventilation; D008297:Male; D009154:Mutation; D019636:Neurodegenerative Diseases; D020734:Parkinsonian Disorders; D010641:Phenotype; D011044:Poland",
"nlm_unique_id": "9513583",
"other_id": null,
"pages": "14-24",
"pmc": null,
"pmid": "28625595",
"pubdate": "2017-08",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "22331844;7878030;22542186;27066542;24484619;24881494;18364389;23143281;24500497;1604112;27543298;25109764;12686597;9007109;17576579;18094236;43704;15980862;26702100;24797316;22542187;19505837;19732908;12221106;18305234;18723384;24676999;12627231;18812314;1122173;16505168;3352925;25558820;27132499;15326253;22357714;16149212;16949363;19136952;24132847;20434225;18852346;25374356;20437543;21610160;15473859;17870652;25957632;24343258;27025386;11456310;15852399;23628468;25185702;2247238;22321865;24627108;24604904;8250534;20702129;23361386;25382069;16240349;19506225;26411500;11940687",
"title": "DCTN1-related neurodegeneration: Perry syndrome and beyond.",
"title_normalized": "dctn1 related neurodegeneration perry syndrome and beyond"
} | [
{
"companynumb": "US-ORION CORPORATION ORION PHARMA-ENT 2017-0103",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MIRTAZAPINE"
},
"drugad... |
{
"abstract": "This study aimed to evaluate the safety and reliability of percutaneous computed tomography (CT)-guided lipiodol marking for undetectable pulmonary lesions before video-assisted thoracic surgery (VATS).\n\n\n\nWe retrospectively analysed the cases of CT-guided lipiodol marking followed by VATS in 9 institutes from May 2006 to March 2018. Lipiodol (0.2-0.5 ml) was percutaneously injected closely adjacent to undetectable pulmonary lesions with computed-tomography guidance. Lipiodol spots were identified using C-arm-shaped fluoroscopy during VATS. We grasped the lipiodol spots, including the target lesions, with ring-shaped forceps and resected them.\n\n\n\nOf 1182 lesions, 1181 (99.9%) were successfully marked. In 1 case, the injected lipiodol diffused, and no spot was created. Of the 1181 lesions, 1179 (99.8%) were successfully resected with intraoperative fluoroscopy. Two lipiodol spots were not detected because of the lipiodol distribution during the division of pleural adhesions. The mean lesion size was 9.1 mm (range 1-48 mm). The mean distance from the pleural surface was 10.2 mm (range 0-43 mm). Lipiodol marking-induced pneumothorax occurred in 495 (57.1%) of 867 cases. Of these, chest drainage was required in 59 patients (6.8%). The other complications were 19 (2.2%) cases of bloody sputum, 3 (0.35%) cases of intravascular air, 1 (0.12%) case of pneumonia and 1 (0.12%) case of cerebral infarction. There were no lipiodol marking-induced deaths or sequelae.\n\n\n\nPreoperative CT-guided lipiodol marking followed by VATS resection was shown to be a safe and reliable procedure with a high success rate and acceptably low severe complication rate.",
"affiliations": "Division of Thoracic Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Division of Thoracic Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Division of Thoracic Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Department of Chest Surgery, Nara City Hospital, Nara, Japan.;Department of Thoracic Surgery, Saiseikai Suita Hospital, Suita, Japan.;Department of Thoracic Surgery, Japanese Red Cross Kyoto Daini Hospital, Kyoto, Japan.;Department of Thoracic Surgery, Kyoto Chubu Medical Center, Nantan, Japan.;Department of Thoracic Surgery, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan.;Division of Thoracic Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Department of Thoracic Surgery, Osaka General Hospital of West Japan Railway Company, Osaka, Japan.;Division of Thoracic Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.",
"authors": "Ito|Kazuhiro|K|;Shimada|Junichi|J|;Shimomura|Masanori|M|;Terauchi|Kunihiko|K|;Nishimura|Motohiro|M|;Yanada|Masashi|M|;Iwasaki|Yasushi|Y|;Ueshima|Yasuo|Y|;Kato|Daishiro|D|;Suzuki|Hirofumi|H|;Inoue|Masayoshi|M|",
"chemical_list": "D003287:Contrast Media; D004998:Ethiodized Oil",
"country": "England",
"delete": false,
"doi": "10.1093/icvts/ivz304",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1569-9285",
"issue": "30(4)",
"journal": "Interactive cardiovascular and thoracic surgery",
"keywords": "Preoperative computed tomography-guided lipiodol marking; Small pulmonary nodule; Video-assisted thoracic surgery",
"medline_ta": "Interact Cardiovasc Thorac Surg",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003287:Contrast Media; D004998:Ethiodized Oil; D005260:Female; D005471:Fluoroscopy; D006469:Hemoptysis; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D010994:Pleura; D011030:Pneumothorax; D011183:Postoperative Complications; D015203:Reproducibility of Results; D012189:Retrospective Studies; D020775:Thoracic Surgery, Video-Assisted; D014057:Tomography, X-Ray Computed; D055815:Young Adult",
"nlm_unique_id": "101158399",
"other_id": null,
"pages": "546-551",
"pmc": null,
"pmid": "31899511",
"pubdate": "2020-04-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Safety and reliability of computed tomography-guided lipiodol marking for undetectable pulmonary lesions.",
"title_normalized": "safety and reliability of computed tomography guided lipiodol marking for undetectable pulmonary lesions"
} | [
{
"companynumb": "JP-GUERBET-JP-20200003",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LIDOCAINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nWe conducted a study exploring the clinical safety and efficacy of decitabine in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), combined with a complex karyotype.\n\n\nMETHODS\nFrom April 2009 to September 2013, a total of 35 patients with AML/MDS combined with a complex karyotype diagnosed in the First Affiliated Hospital of Soochow University were included for retrospective analysis. All patients were treated with decitabine alone (20 mg/m2 daily for 5 days) or combination AAG chemotherapy (Acla 20 mg qod*4d, Ara-C 10 mg/m2 q12h*7d, G-CSF 300 μg qd, the dose of G-CSF adjusted to the amount in blood routinely).\n\n\nRESULTS\nIn 35 patients, 15 exhibited a complete response (CR), and 6 a partial response (PR), the overall response rate (CR+PR) being 60% (21 of 35). Median disease-free survival was 18 months and overall survival was 14 months. In the 15 MDS patients with a complex karyotype, the CR rate was 53.3% (8 of 15); in 20 AML patients with complex karyotype, the overall response rate was 65% (13 of 20). The response rate of decitabine alone (22 cases) was 56.5% (13 of 22), while in the combination chemotherapy group (13 cases), the effective rate was 61.5% (8 of 13)(P>0.05). There are 15 patients with chromosome 7 aberration, after treatment with decitabine, 7 CR, 3 PR, overall response rate was 66.7% (10 of 15). Of 18 patients with 3 to 5 kinds of chromosomal abnormalities, 66.7% demonstrated a response; of 17 with more than 5 chromosomal abnormalities, 52.9% had a response. In the total of 35 patients, with one course (23 patients) and ≥two courses (12 patients), the overall response rate was 40.9% and 92.3% (P<0.05). Grade III to IV hematological toxicity was observed in 27 cases (75%). Grade III to IV infections were clinically documented in 7 (20%). Grades I to II non-hematological toxicity were infections (18 patients), haematuria (2 patients), and bleeding (3 patients). With follow-up until September 2013, 7 patients were surviving, 18 had died and 10 were lost to follow-up. In the 6 cases who underwent allogeneic hematopoietic stem cell transplantation (HSCT) all were still relapse-free survivors.\n\n\nCONCLUSIONS\nDecitabine alone or combination with AAG can improve outcome of AML/MDS with a complex karyotype, there being no significant difference decitabine in inducing remission rates in patients with different karyotype. Increasing the number of courses can improve efficiency. This approach with fewer treatment side effects in patients with a better tolerance should be employed in order to create an improved subsequent chance for HSCT.",
"affiliations": "Leukemia Research Division, Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis of the Ministry of Health, First Affiliated Hospital of Soochow University, Suzhou, China E-mail : qiuhuiying@aliyun.com.",
"authors": "Gao|Su|S|;Li|Zheng|Z|;Fu|Jian-Hong|JH|;Hu|Xiao-Hui|XH|;Xu|Yang|Y|;Jin|Zheng-Ming|ZM|;Tang|Xiao-Wen|XW|;Han|Yue|Y|;Chen|Su-Ning|SN|;Sun|Ai-Ning|AN|;Wu|De-Pei|DP|;Qiu|Hui-Ying|HY|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine; D016179:Granulocyte Colony-Stimulating Factor; D015250:Aclarubicin; D000077209:Decitabine; D001374:Azacitidine",
"country": "Thailand",
"delete": false,
"doi": "10.7314/apjcp.2015.16.15.6627",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1513-7368",
"issue": "16(15)",
"journal": "Asian Pacific journal of cancer prevention : APJCP",
"keywords": null,
"medline_ta": "Asian Pac J Cancer Prev",
"mesh_terms": "D059786:Abnormal Karyotype; D015250:Aclarubicin; D000293:Adolescent; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic; D000971:Antineoplastic Combined Chemotherapy Protocols; D001374:Azacitidine; D002648:Child; D002675:Child, Preschool; D003561:Cytarabine; D000077209:Decitabine; D018572:Disease-Free Survival; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D006402:Hematologic Diseases; D006417:Hematuria; D006801:Humans; D060828:Induction Chemotherapy; D007239:Infections; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101130625",
"other_id": null,
"pages": "6627-32",
"pmc": null,
"pmid": "26434886",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Decitabine in the Treatment of Acute Myeloid Leukemia and Myelodysplastic Syndromes, Which Combined with Complex Karyotype Respectively.",
"title_normalized": "decitabine in the treatment of acute myeloid leukemia and myelodysplastic syndromes which combined with complex karyotype respectively"
} | [
{
"companynumb": "CN-OTSUKA-2015_012711",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DECITABINE"
},
"drugadditional": null,
... |
{
"abstract": "Disseminated herpes simplex virus 2 (HSV-2) infection, is a rare but devastating infection in pregnancy women. We present the case of a 30-year-old gravida 3, para 2-0-0-2, at 26 weeks 2 days gestation who presented with eleven days of vague and indolent symptoms before a diagnosis of disseminated HSV-2 infection with associated hepatitis was made. While the patient clinically improved with empiric acyclovir treatment, possibility of significant harm to the fetus remained, and the patient request elective termination. The authors review the epidemiology, diagnosis, treatment, and prognosis of disseminated HSV-2 infection in pregnancy.",
"affiliations": "Larner College of Medicine, University of Vermont, Burlington, VT, United States.;Larner College of Medicine, University of Vermont, Burlington, VT, United States.;Larner College of Medicine, University of Vermont, Burlington, VT, United States.;Larner College of Medicine, University of Vermont, Burlington, VT, United States.;Larner College of Medicine, University of Vermont, Burlington, VT, United States.",
"authors": "Bougioukas|Lauren|L|;Psoinos|Rachel B C|RBC|;Jones|David C|DC|;Morris|Erin A|EA|;Hale|Andrew J|AJ|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.idcr.2021.e01107",
"fulltext": "\n==== Front\nIDCases\nIDCases\nIDCases\n2214-2509\nElsevier\n\nS2214-2509(21)00063-9\n10.1016/j.idcr.2021.e01107\ne01107\nCase Report\nDisseminated herpes simplex virus 2 as a complication of pregnancy\nBougioukas Lauren a\nPsoinos Rachel B.C. ab\nJones David C. abc\nMorris Erin A. ab\nHale Andrew J. Andrew.Hale@UVMhealth.org\nab⁎\na Larner College of Medicine, University of Vermont, Burlington, VT, United States\nb University of Vermont Medical Center, United States\nc Fetal Diagnostic Center, United States\n⁎ Corresponding author at: University of Vermont Medical Center, Infectious Disease Unit, 111 Colchester Avenue, Mailstop 115 SM2, Burlington, VT, 05401, United States. Andrew.Hale@UVMhealth.org\n31 3 2021\n2021\n31 3 2021\n24 e0110711 1 2021\n29 3 2021\n29 3 2021\n© 2021 The Authors\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nDisseminated herpes simplex virus 2 (HSV-2) infection, is a rare but devastating infection in pregnancy women. We present the case of a 30-year-old gravida 3, para 2−0-0−2, at 26 weeks 2 days gestation who presented with eleven days of vague and indolent symptoms before a diagnosis of disseminated HSV-2 infection with associated hepatitis was made. While the patient clinically improved with empiric acyclovir treatment, possibility of significant harm to the fetus remained, and the patient request elective termination. The authors review the epidemiology, diagnosis, treatment, and prognosis of disseminated HSV-2 infection in pregnancy.\n\nKeywords\n\nDisseminated herpes simplex virus 2\nPregnancy\nInfectious complications of pregnancy\n==== Body\nIntroduction\n\nOf the approximately 2–3% of women who acquire primary genital herpes simplex virus 2 (HSV-2) infection during pregnancy, the most dangerous complication is disseminated, systemic infection. With mortality rates up to 50 %, fortunately disseminated HSV-2 remains a rare entity [[1], [2], [3], [4]]. Disseminated HSV-2 demonstrates an affinity for the second half of pregnancy, with 65 % of cases occurring in the third trimester; and an overall 50 % risk of transplacental infection [[5], [6], [7]]. Disseminated HSV-2 hepatitis during pregnancy may progress to fulminant liver failure and is a large contributor to maternal mortality approaching 50 % [8,9]. Acyclovir treatment poses minimal fetal risk and may significantly improve maternal clinical outcomes, although successful maternal therapy may not equate to successful fetal therapy [10,11]. Herein, we report the first elective mid-trimester termination in the setting of maternal disseminated HSV-2 disease with associated hepatitis.\n\nCase\n\nA 30-year-old gravida 3, para 2−0-0−2 presented to our tertiary care center at 26 weeks 2 days gestation with fever, malaise, shortness of breath, abdominal pain, and dysuria for the past eleven days. She denied significant past medical or surgical history, and her only medication was a prenatal vitamin. She had two prior uncomplicated term vaginal deliveries and denied any prior sexually transmitted infections.\n\nShe initially presented to a community emergency department at 245/7 weeks with vaginal bleeding and was discharged following a normal pelvic exam. She next presented to our emergency department at 251/7 weeks with a two-day history of urinary frequency and dysuria. She was afebrile and was discharged with empiric nitrofurantoin. At 253/7 weeks, she presented to a second community emergency department with worsening malaise, abdominal and low back pain, and was discharged following a reassuring exam. She presented to the same emergency department at 255/7 weeks with persistent symptoms. Rapid influenza and respiratory viral panel were negative, and she was discharged with a course of azithromycin for empiric pneumonia treatment.\n\nAt 261/7 weeks gestation, she presented a third time to the community emergency department, now intermittently febrile up to 39.5 °C without localizing symptoms and was admitted for further evaluation. Speculum exam demonstrated clear vaginal fluid, which was nitrazine positive and negative for amniotic ferning. Serum studies were significant for transaminitis, which progressed from twice the upper limit of normal to an ALT of 200 U/L and AST 4of 20 U/L over a two-day admission, with normal total bilirubin. Pertinent negative infectious evaluation included influenza and respiratory syncytial viral (RSV) panels, viral hepatitis panel, urinalysis and culture, and blood cultures. Abdominal magnetic resonance imaging (MRI) and right upper quadrant ultrasound were unrevealing. She received empiric therapy with piperacillin-tazobactam and was discharged within 24 h.\n\nThe following day, the patient presented to our tertiary care facility at 262/7 gestation, complaining of chills, malaise, fever to 39.4 °C, new onset of shortness of breath, dry cough, headache, and copious vaginal discharge over the prior three days. Upon arrival, she was febrile to 39.2 °C, tachycardic to 121 beats per minute, and normotensive with normal oxygen saturation. Physical exam elicited exquisite umbilical, suprapubic, and left flank tenderness. Sterile speculum exam revealed copious thick yellow vaginal fluid and scant pinpoint white cervical lesions, both of which were swabbed for culture and viral polymerase chain reaction (PCR). Vaginal fluid was nitrazine positive; however, microscopy did not reveal amniotic ferns, lowering the suspicion for premature rupture of membranes. The cervix was closed and there was no evidence of active labor. Obstetric ultrasound confirmed a viable fetus with biometry consistent with prior dating. Anatomic survey was normal.\n\nAdmission laboratory studies were remarkable for worsening transaminitis compared to her prior admission, with ALT 265 U/L and AST 602 U/L, with total bilirubin 1.1 mg/dl. Complete blood count showed WBC 5.36 × 103/mm3 with 10.6 % banded neutrophils. Hemoglobin was 10.5 gm/dL, hematocrit was 28.5 %.and creatinine was 0.42 mg/dL. Serum C-reactive protein was elevated at 265.2 mg/L. Urinalysis was significant for moderate ketonuria and leukocyte esterase, many squamous cells and leukocytes, few erythrocytes, and no bacteriuria. Hepatobiliary ultrasound was unremarkable.\n\nThe patient’s exposure history was significant for work in a daycare setting and cat ownership. Additionally, the father of the current pregnancy engaged in recent non-monogamous activity. Due to maternal and neonatal acuity as well as refractory symptoms and clinical status, prompt ultrasound-guided amniocentesis on day of admission evaluated for intraamniotic infection (IAI). Indigo carmine intraamniotic infusion and tampon test were negative, confirming intact amniotic membranes. Rapid testing of amniotic fluid revealed manual leukocyte count of 16 cells/cmm, and fluid glucose of 22 mg/dL, with present neutrophils and absent bacteria, felt to be most consistent with a viral IAI, though bacterial etiology was not dismissed.\n\nDue to the concern for IAI, on hospital day one empiric intravenous ertapenem (1 g daily) and oral azithromycin (500 mg daily) were initiated. Worsening transaminitis through hospital day two (ALT 302 U/L, AST 714 U/L) was initially attributed to sepsis secondary to IAI. The patient’s serum INR and mental status remained normal.\n\nPertinent negative maternal testing included influenza A/B and respiratory syncytial virus nasopharyngeal PCR, serologies for toxoplasma, cytomegalovirus (CMV), and syphilis, Mono-spot, and HIV screening. Urine culture, chlamydia and gonorrhea PCR, and vaginal Group B Streptococcus PCR were negative. Blood and amniotic fluid cultures for aerobic and anaerobic bacteria demonstrated no growth.\n\nLater on hospital day two, HSV-2 PCR of a cervical lesion returned positive and she was started on intravenous acyclovir (10 mg/kg every 8 h). She denied prior oral or genital symptoms or knowledge of HSV-2 infection. As her partner endorsed a history of recent multiple sexual partners, a primary HSV-2 infection was suspected. On hospital day three, HSV-2 PCR of amniotic fluid and serum also returned positive, consistent with disseminated HSV-2 infection with associated hepatitis and suspected congenital infection of the fetus.\n\nErtapenem and azithromycin were discontinued. After 24 h of acyclovir therapy, her fever resolved, and transaminitis began down trending. By hospital day four, transaminitis began to resolve, there was no evidence of hepatic synthetic dysfunction or hepatic failure, and she thereafter remained consistently afebrile.\n\nWhile the patient clinically improved after diagnosis and initiation of targeted therapy, she had ongoing concerns about the fetal and neonatal implications of her diagnosis, and ultimately, she requested pregnancy termination. A multidisciplinary care team, including Maternal Fetal Medicine, Clinical Ethics, and Infectious Disease, was assembled to review the patient’s desire for termination, as well as fetal implications of HSV-2 positive amniotic fluid. The committee determined there was reasonable possibility of significant fetal harm due to maternal primary disseminated HSV-2 infection with evidence of transplacental transmission. The patient ultimately elected to terminate the pregnancy.\n\nFeticide was performed by ultrasound-guided intracardiac injection of potassium chloride on hospital day seven, at 27 weeks 1 day. Upon confirmation of fetal demise, induction of labor was performed by administration of mifepristone, followed by high dose misoprostol, according to Society of Family Planning published practice guidelines [12,13]. During her labor course, she developed pre-eclampsia without severe features. After a three-day induction, the patient delivered a demised male fetus.\n\nPlacental histopathology was significant for high grade fetal vascular malperfusion, acute chorioamnionitis and funisitis, focal chronic chorionic plate vasculitis, and necrotic stromal cells. While there was no evidence of viral cytopathic effect and HSV-2 immunostaining was negative, intradepartmental review determined the findings to be consistent with transplacental HSV-2 infection in the setting of disseminated maternal disease. Fetal autopsy was declined by the patient.\n\nThe patient was discharged on hospital day ten, shortly after delivery. She was transitioned to oral valacyclovir 1 g every 8 h, to complete a 21-day total course. Upon outpatient follow-up she remained afebrile with complete resolution of transaminitis and no evidence of hepatic dysfunction.\n\nDiscussion\n\nAs illustrated here, the diagnosis of disseminated HSV-2 infection during pregnancy can be challenging. Women frequently report no history of HSV-2 infection, and characteristic herpetic lesions may be absent. Providers frequently consider a broad differential, including pre-eclampsia and acute fatty liver. Definitive diagnosis by liver biopsy can be difficult in the pregnancy setting, especially if hepatitis has progressed to a coagulopathic state. Although treatment with acyclovir can result in a successful maternal outcome, disseminated HSV-2 in pregnancy is an overall highly morbid disease for both mother and fetus, and the effect of acyclovir on the fetus remains unclear [10,11,[14], [15], [16]].\n\nThis is borne out in a disseminated HSV-2 case described by Sloan et al. in which second trimester maternal therapy was initially reassuring; however, third trimester fetal ultrasound revealed severe cerebral findings consistent with encephalitis and ultimately neonatal demise [17]. Johansson et al. describe a patient with a self-resolving first trimester flu-like illness, who delivered a preterm neonate severely affected by classic and non-classic constellation of congenital HSV-2 sequelae [18]. This presents in stark contrast to those cases that report successful maternal and neonatal outcomes with acyclovir treatment [14,[19], [20], [21], [22], [23]]. While the advent of PCR testing for HSV-2 in amniotic fluid is a useful tool confirming maternal diagnosis in addition to viral culture, neither has been demonstrated to clearly correlate with reduced neonatal morbidity [20,24].\n\nNeonatal HSV-2 infection affects an estimated 1500 live births annually in the United States with substantial resource utilization [[25], [26], [27]]. Attempts have been made to characterize a classic triad of neonatal presentation including central nervous system, ophthalmologic, and cutaneous involvement, however in cases of intrauterine infection, congenital HSV does not appear to be limited to these manifestations, comprising a spectrum including extremity and bony malformations, altered growth, hydrops, cerebral abnormalities, and fetal demise [[28], [29], [30]]. In a review of 64 cases of intrauterine HSV infection diagnosed prenatally and postnatally, cutaneous lesions were identified in 95 % of cases, while CNS abnormalities were identified in 67 % cases [28]. In 36 cases of congenital HSV infection, 15 were described prenatally, with cerebral anomalies the most commonly reported, and 21 were diagnosed postnatally, most commonly with cutaneous findings that developed in the first weeks of life [29]. Fetal diagnostic imaging including ultrasound and MRI have limited utility in successfully identifying cutaneous manifestations, which can be extensive, as well as determining neurodevelopmental prognosis, as normal anatomic survey does not guarantee a normal neonatal outcome [29,31].\n\nEarly diagnosis of disseminated HSV in pregnancy with acyclovir treatment is often delayed, yet critical in improving maternal outcomes. The literature demonstrates that maternal treatment and reassuring fetal imaging do not guarantee a normal neonatal outcome [17,18]. While intrapartum demise and withholding or withdrawal of supportive care in the immediate postnatal setting have been described in clearly affected neonates [28], this is the first report of an elective mid-trimester induction termination in the setting of maternal disseminated HSV-2 hepatitis.\n\nAuthor contributions\n\nLauren Bougioukas, BA: conceptualization, patient care, writing: original draft; writing: review & editing\n\nRachel B.C. Psoinos, MD, PhD: conceptualization, patient care, writing: original draft; writing: review & editing\n\nDavid C. Jones, MD: conceptualization, patient care, writing: original draft; writing: review & editing\n\nErin A. Morris, MD: conceptualization, patient care, writing: original draft; writing: review & editing\n\nAndrew J. Hale, MD: conceptualization, patient care, writing: original draft; writing: review & editing\n\nFunding\n\nNone.\n\nAuthorship verification\n\nAll co-authors have seen and agree with the contents of the manuscript and have contributed significantly to the work\n\nInformed consent\n\nWritten informed consent was obtained from the patient\n\nDeclaration of Competing Interest\n\nThe authors declare no conflict of interest.\n\nAcknowledgements\n\nInformed consent was obtained from the patient.\n==== Refs\nReferences\n\n1 Brown Z.A. Selke S. Zeh J. Kopelman J. Maslow A. Ashley R.L. The acquisition of herpes simplex virus during pregnancy N Engl J Med 337 8 1997 509 515 9262493\n2 Anzivino E. Fioriti D. Mischitelli M. Bellizzi A. Barucca V. Chiarini F. Herpes simplex virus infection in pregnancy and in neonate: status of art of epidemiology, diagnosis, therapy and prevention Virol J 6 1 2009 40-11\n3 Sauerbrei A. Herpes genitalis: diagnosis, treatment and prevention Geburtshilfe Frauenheilkd 76 12 2016 1310 1317 28017972\n4 Sonpar A. Brown K. Chen J. Megran D. Sabo M. Cervera C. Dual infection in pregnancy: disseminated Mycoplasma hominis and necrotizing herpes simplex 2 hepatitis Int J Infect Dis 71 2018 1 3 29550448\n5 Mudido P. Marshall G.S. Howell R.S. Schmid D.S. Steger S. Adams G. Disseminated herpes simplex virus infection during pregnancy. A case report J Reprod Med 38 12 1993 964 968 8120855\n6 Flewett T.H. Parker R.G. Philip W.M. Acute hepatitis due to Herpes simplex virus in an adult J Clin Pathol 22 1 1969 60 66 4306578\n7 Sauerbrei A. Wutzler P. Herpes simplex and varicella-zoster virus infections during pregnancy: current concepts of prevention, diagnosis and therapy. Part 1: herpes simplex virus infections Med Microbiol Immunol 196 2 2006 89 94 17165093\n8 McCormack A.L. Rabie N. Whittemore B. Murphy T. Sitler C. Magann E. HSV hepatitis in pregnancy: a review of the literature Obstet Gynecol Surv 74 2 2019 93 98 30756123\n9 Young E.J. Chafizadeh E. Oliveira V.L. Genta R.M. Disseminated herpesvirus infection during pregnancy Clin Infect Diseases 22 1 1996 51 58 8824966\n10 Lagrew D.C. Furlow T.G. Hager W.D. Yarrish R.L. Disseminated herpes simplex virus infection in pregnancy. Successful treatment with acyclovir JAMA 252 15 1984 2058 2059 6481915\n11 Berger S.A. Weinberg M. Treves T. Sorkin P. Geller E. Yedwab G. Herpes encephalitis during pregnancy: failure of acyclovir and adenine arabinoside to prevent neonatal herpes Isr J Med Sci 22 1 1986 41 44 3957642\n12 Perritt J.B. Burke A. Edelman A.B. Interruption of nonviable pregnancies of 24-28 weeks’ gestation using medical methods: release date June 2013 SFP guideline #20133 Contraception 88 3 2013 341 349 23756114\n13 Diedrich J. Drey E. Society of Family P Induction of fetal demise before abortion Contraception 81 6 2010 462 473 20472112\n14 Chazotte C. Andersen H.F. Cohen W.R. Disseminated herpes simplex infection in an immunocompromised pregnancy: treatment with intravenous acyclovir Am J Perinatol 4 4 1987 363 364 3651195\n15 Goulding E.A. Barnden K.R. Disseminated herpes simplex virus manifesting as pyrexia and cervicitis and leading to reactive hemophagocytic syndrome in pregnancy Eur J Obstet Gynecol Reprod Biol 180 48 2014 198 199 24890680\n16 Gray M. Rockey D.C. A spotty liver of pregnancy J Invest Med High Impact Case Rep 2 3 2014 2324709614551558\n17 Sloan J.K. Cawyer C.R. Fetal ventriculomegaly and herpes encephalitis following primary maternal herpes simplex infection Taylor Francis 30 4 2017 463 464 2018\n18 Johansson A.-B. Rassart A. Blum D. Van Beers D. Liesnard C. Lower-limb hypoplasia due to intrauterine infection with herpes simplex virus type 2: possible confusion with intrauterine varicella-zoster syndrome Clin Infect Diseases 38 7 2004 e57 62 15034848\n19 Greenspoon J.S. Wilcox J.G. McHutchison L.B. Rosen D.J. Acyclovir for disseminated herpes simplex virus in pregnancy. A case report J Reprod Med 39 4 1994 311 317 8040850\n20 Hillard P. Seeds J. Cefalo R. Disseminated herpes simplex in pregnancy: two cases and a review Obstet Gynecol Surv 37 7 1982 449 453 6752785\n21 Lee R. Nair M. Diagnosis and treatment of herpes simplex 1 virus infection in pregnancy Obstet Med 10 2 2017 58 60 28680463\n22 Linthavong O.R. Franasiak J. Ivester T. Febrile illness in pregnancy: disseminated herpes simplex virus Obstet Gynecol 121 3 2013 675 681 23635632\n23 Young E.J. Killam A.P. Greene J.F. Disseminated herpesvirus infection. Association with primary genital herpes in pregnancy JAMA 235 25 1976 2731 2733 178938\n24 Alanen A. Hukkanen V. Herpes simplex virus DNA in amniotic fluid without neonatal infection Clin Infect Diseases 30 2 2000 363 367 10671342\n25 Ambroggio L. Lorch S.A. Mohamad Z. Mossey J. Shah S.S. Congenital anomalies and resource utilization in neonates infected with herpes simplex virus Sex Transm Dis 36 11 2009 680 685 19617865\n26 Pinninti S.G. Kimberlin D.W. Neonatal herpes simplex virus infections Semin Perinatol 42 3 2018 168 175 29544668\n27 Westhoff G.L. Little S.E. Caughey A.B. Herpes simplex virus and pregnancy: a review of the management of antenatal and peripartum herpes infections Obstet Gynecol Surv 66 10 2011 629 638 22112524\n28 Marquez L. Levy M.L. Munoz F.M. Palazzi D.L. A report of three cases and review of intrauterine herpes simplex virus infection Pediatr Infect Dis J 30 2 2011 153 157 20811312\n29 Fa F. Laup L. Mandelbrot L. Sibiude J. Picone O. Fetal and neonatal abnormalities due to congenital herpes simplex virus infection: a literature review Prenat Diagn 40 4 2020 408 414 31663621\n30 Barefoot K.H. Little G.A. Ornvold K.T. Fetal demise due to herpes simplex virus: an illustrated case report J Perinatol 22 1 2002 86 88 11840250\n31 Duin L.K. Willekes C. Baldewijns M.M.L. Robben S.G.F. Offermans J. Vles J. Major brain lesions by intrauterine herpes simplex virus infection: MRI contribution Prenat Diagn 27 1 2006 81 84\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-2509",
"issue": "24()",
"journal": "IDCases",
"keywords": "Disseminated herpes simplex virus 2; Infectious complications of pregnancy; Pregnancy",
"medline_ta": "IDCases",
"mesh_terms": null,
"nlm_unique_id": "101634540",
"other_id": null,
"pages": "e01107",
"pmc": null,
"pmid": "33889496",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "23756114;17154224;9262493;17165093;10671342;19348670;8824966;29544668;20811312;24890680;26425623;11840250;23635632;28680463;8040850;31663621;6481915;29550448;4306578;22112524;19617865;6752785;3651195;15034848;3957642;8120855;30756123;28017972;20472112;28966468;178938",
"title": "Disseminated herpes simplex virus 2 as a complication of pregnancy.",
"title_normalized": "disseminated herpes simplex virus 2 as a complication of pregnancy"
} | [
{
"companynumb": "US-GLAXOSMITHKLINE-US2021GSK087187",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "POTASSIUM CHLORIDE"
},
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{
"abstract": "Preclinical and clinical studies have demonstrated synergy between bortezomib and pegylated liposomal doxorubicin (PLD) for relapsed/refractory (R/R) multiple myeloma (MM) patients compared to bortezomib as a single agent. This retrospective study evaluated the efficacy and safety of a more frequent low-dose schedule of PLD, bortezomib, and intravenous dexamethasone (DVD) for patients with R/R MM, many of whom were previously treated with bortezomib. Twenty-eight patients with R/R MM were treated, and 23 (83%) had been previously treated with ≥ 1 bortezomib-containing regimen. Treatment consisted of dexamethasone 40 mg intravenously, bortezomib 1.0 mg/m(2), and PLD 5.0 mg/m(2) on days 1, 4, 8, and 11 of a 28-day cycle for a maximum of eight cycles. Patients ranged from 33 to 81 years of age (median, 67) and had received 1-14 prior therapies (median, 5). At baseline, ten, nine, and nine patients were in stages I, II, and III, respectively, as defined by the International Staging System, and eight (29%) patients had elevated serum creatinine levels. The overall response rate was 61%, which included one (4%) complete response, three (11%) very good partial responses, eight (29%) partial responses, and five (18%) minimal responses. Of the 23 patients who had previously received bortezomib, 12 (52%) responded. The regimen was well tolerated with only six patients (21%) who showed worsening of their baseline peripheral neuropathy (PN). One patient discontinued this regimen due to an adverse event (grade II PN). DVD appears to represent a well-tolerated regimen with a high response rate for the treatment of R/R MM patients.",
"affiliations": "James R. Berenson, M.D., Inc, West Hollywood, CA, USA.",
"authors": "Waterman|Gabriel N|GN|;Yellin|Ori|O|;Swift|Regina A|RA|;Mapes|Russell|R|;Eades|Benjamin|B|;Ackerman|Emily|E|;Berenson|James R|JR|",
"chemical_list": "D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D000069286:Bortezomib; D003907:Dexamethasone; D004317:Doxorubicin",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-010-1052-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "90(2)",
"journal": "Annals of hematology",
"keywords": null,
"medline_ta": "Ann Hematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D001897:Boronic Acids; D000069286:Bortezomib; D003907:Dexamethasone; D018572:Disease-Free Survival; D004317:Doxorubicin; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D011092:Polyethylene Glycols; D011719:Pyrazines; D012008:Recurrence; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "193-200",
"pmc": null,
"pmid": "20809423",
"pubdate": "2011-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A modified regimen of pegylated liposomal doxorubicin, bortezomib, and dexamethasone is effective and well tolerated in the treatment of relapsed or refractory multiple myeloma.",
"title_normalized": "a modified regimen of pegylated liposomal doxorubicin bortezomib and dexamethasone is effective and well tolerated in the treatment of relapsed or refractory multiple myeloma"
} | [
{
"companynumb": "US-JNJFOC-20181104124",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BORTEZOMIB"
},
"drugadditional": "1",
"... |
{
"abstract": "BACKGROUND\nIt has been described that treating relapsing-remitting multiple sclerosis (RRMS) patients with alemtuzumab following fingolimod could be less effective due to the different dynamics of lymphocyte repopulation. Effectiveness and safety of alemtuzumab compared to rituximab after fingolimod withdrawal were analyzed.\n\n\nMETHODS\nA follow-up of a cohort of RRMS patients treated with alemtuzumab or rituximab after fingolimod withdrawal was accomplished. Effectiveness, measured by the percentage of patients with no evidence of disease activity (NEDA), and the presence of side effects (SE) were registered.\n\n\nRESULTS\nFifty-five patients, 28 with alemtuzumab and 27 with rituximab, were analyzed. No differences in the washout period or in the baseline lymphocytes counts were observed. After a mean follow-up period of 28.8 months, the annualized relapsing rate was significantly reduced in the alemtuzumab group from 1.29 to 0.004 (p < 0.001) and in the rituximab group from 1.24 to 0.02 (p < 0.001), without differences. A significant reduction of the median EDSS from 2.8 to 2.0 in the alemtuzumab group and from 3.5 to 2.5 (p < 0.01) in the rituximab group was observed, without differences. Eighty-two per cent (n = 28) of patients in alemtuzumab group and 69.2% (n = 26) in rituximab group achieved NEDA criteria, without differences (p = 0.3). Symptoms related to the infusion were the most frequent SE in both groups. No serious SE were registered.\n\n\nCONCLUSIONS\nTreating RRMS patients with alemtuzumab or rituximab after fingolimod withdrawal is effective and safe, without significant differences between both groups in our series.",
"affiliations": "Department of Neurology, La Fe Hospital, 106 Avenue Fernando Abril Martorell, 46026, Valencia, Spain. mc.alcalavicente@gmail.com.;Department of Neurology, Clinic Hospital, Valencia, Spain.;Department of Neurology, La Fe Hospital, 106 Avenue Fernando Abril Martorell, 46026, Valencia, Spain.;Department of Neurology, Clinic Hospital, Valencia, Spain.;Department of Neurology, La Fe Hospital, 106 Avenue Fernando Abril Martorell, 46026, Valencia, Spain.;Department of Neurology, La Fe Hospital, 106 Avenue Fernando Abril Martorell, 46026, Valencia, Spain.",
"authors": "Alcalá|Carmen|C|http://orcid.org/0000-0002-4799-7579;Gascón|F|F|;Pérez-Miralles|Francisco|F|;Domínguez|J A|JA|;Gil-Perotín|S|S|;Casanova|B|B|",
"chemical_list": "D007155:Immunologic Factors; D000074323:Alemtuzumab; D000069283:Rituximab; D000068876:Fingolimod Hydrochloride",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00415-019-09195-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0340-5354",
"issue": "266(3)",
"journal": "Journal of neurology",
"keywords": "Alemtuzumab; Fingolimod withdrawal; Lymphocyte repopulation; Relapsing–remitting multiple sclerosis; Rituximab; Treatment",
"medline_ta": "J Neurol",
"mesh_terms": "D000328:Adult; D000074323:Alemtuzumab; D015331:Cohort Studies; D005260:Female; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007155:Immunologic Factors; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting; D017063:Outcome Assessment, Health Care; D000069283:Rituximab",
"nlm_unique_id": "0423161",
"other_id": null,
"pages": "726-734",
"pmc": null,
"pmid": "30661133",
"pubdate": "2019-03",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "10852536;17101076;18946064;20089954;20937940;21387374;21431380;21571593;23122650;23122652;23494602;23843952;25392320;25402749;26929636;27549763;28101520;28285378;28428119;28607739;28749311;28761351;28835401;28835403;28879412;28966663;29033895;29055450;29528247;29600441;29696498;29774781;29785523;29851435;30050382;30056362;30112230;30178100;30233054",
"title": "Treatment with alemtuzumab or rituximab after fingolimod withdrawal in relapsing-remitting multiple sclerosis is effective and safe.",
"title_normalized": "treatment with alemtuzumab or rituximab after fingolimod withdrawal in relapsing remitting multiple sclerosis is effective and safe"
} | [
{
"companynumb": "ES-CELLTRION INC.-2019ES021694",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nThe oncogenic PI3K/Akt/mTOR pathway is frequently activated in HCC. Data on the mTOR inhibitor, temsirolimus, is limited in HCC patients with concomitant chronic liver disease. The objectives of this study were: (1) In phase I, to determine DLTs and MTD of temsirolimus in HCC patients with chronic liver disease; (2) In phase II, to assess activity of temsirolimus in HCC, and (3) to explore potential biomarkers for response.\n\n\nMETHODS\nMajor eligibility criteria included histologically confirmed advanced HCC and adequate organ function. In Phase I part of the study, temsirolimus was given weekly in 3-weekly cycle; dose levels were 20 mg (level 1), 25 mg (level 2) and 30 mg (level 3). The MTD was used in the subsequent phase II part; the primary endpoint was PFS and secondary endpoints were response and OS. In addition, exploratory analysis was conducted on pre-treatment tumour tissues to determine stathmin, pS6, pMTOR or p-AKT expressions as potential biomarkers for response. Overall survival and PFS were calculated using the Kaplan-Meier method. Reassessment CT scans were done every 6 weeks. All adverse events were reported using CTCAE v3.\n\n\nRESULTS\nThe Phase I part consisted of 19 patients, 2 of 6 patients at level 3 experienced DLT; dose level 2 was determined to be the MTD. The phase II part consisted of 36 patients. Amongst 35 assessable patients, there were 1 PR, 20 SD and 14 PD. Overall, the median PFS was 2.83 months (95% C.I. 1.63-5.24). The median OS was 8.89 months (95% C.I. 5.89-13.30). Grade ≥ 3 that occurred in > 10% of patients included thrombocytopenia (4) and hyponatraemia (4). Exploratory analysis revealed that disease stabilization (defined as CR + PR + SD > 12 weeks) in tumours having high and low pMTOR H-scores to be 70% and 29% respectively (OR 5.667, 95% CI 1.129-28.454, p = 0.035).\n\n\nCONCLUSIONS\nIn HCC patients with chronic liver disease, the MTD of temsirolimus was 25 mg weekly in a 3-week cycle. The targeted PFS endpoint was not reached. However, further studies to identify appropriate patient subgroup are warranted.\n\n\nBACKGROUND\nThis study has been registered in ClinicalTrials.gov (Id: NCT00321594) on 1 December 2010.",
"affiliations": "Comprehensive Cancer Trials Unit, Department of Clinical Oncology, State Key Lab in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong. winnie@clo.cuhk.edu.hk.;Comprehensive Cancer Trials Unit, Department of Clinical Oncology, State Key Lab in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong. l_chan@clo.cuhk.edu.hk.;Comprehensive Cancer Trials Unit, Department of Clinical Oncology, State Key Lab in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong. frankie@clo.cuhk.edu.hk.;Department of Diagnostic and Interventional Radiology, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong. ccm715@ha.org.;Department of Diagnostic and Interventional Radiology, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong. joyce.water@gmail.com.;Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong. jtong@cuhk.edu.hk.;Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong. awh_chan@yahoo.com.hk.;Comprehensive Cancer Trials Unit, Department of Clinical Oncology, State Key Lab in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong. jane@clo.cuhk.edu.hk.;Comprehensive Cancer Trials Unit, Department of Clinical Oncology, State Key Lab in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong. p_hui@clo.cuhk.edu.hk.;Comprehensive Cancer Trials Unit, Department of Clinical Oncology, State Key Lab in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong. h_loong@clo.cuhk.edu.hk.;Comprehensive Cancer Trials Unit, Department of Clinical Oncology, State Key Lab in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong. kirsty.lee@gmail.com.;Comprehensive Cancer Trials Unit, Department of Clinical Oncology, State Key Lab in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong. lileungvil@gmail.com.;Comprehensive Cancer Trials Unit, Department of Clinical Oncology, State Key Lab in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong. brigette@clo.cuhk.edu.hk.;Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong. kfto@cuhk.edu.hk.;Department of Diagnostic and Interventional Radiology, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong. simonyu@cuhk.edu.hk.",
"authors": "Yeo|Winnie|W|;Chan|Stephen L|SL|;Mo|Frankie K F|FK|;Chu|Cheuk M|CM|;Hui|Joyce W Y|JW|;Tong|Joanne H M|JH|;Chan|Anthony W H|AW|;Koh|Jane|J|;Hui|Edwin P|EP|;Loong|Herbert|H|;Lee|Kirsty|K|;Li|Leung|L|;Ma|Brigette|B|;To|Ka F|KF|;Yu|Simon C H|SC|",
"chemical_list": "D000970:Antineoplastic Agents; C401859:temsirolimus; D020123:Sirolimus",
"country": "England",
"delete": false,
"doi": "10.1186/s12885-015-1334-6",
"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 25962426133410.1186/s12885-015-1334-6Research ArticlePhase I/II study of temsirolimus for patients with unresectable Hepatocellular Carcinoma (HCC)- a correlative study to explore potential biomarkers for response Yeo Winnie winnie@clo.cuhk.edu.hk 1Chan Stephen L l_chan@clo.cuhk.edu.hk 1Mo Frankie KF frankie@clo.cuhk.edu.hk 1Chu Cheuk M ccm715@ha.org 2Hui Joyce WY joyce.water@gmail.com 2Tong Joanne HM jtong@cuhk.edu.hk 3Chan Anthony WH awh_chan@yahoo.com.hk 3Koh Jane jane@clo.cuhk.edu.hk 1Hui Edwin P p_hui@clo.cuhk.edu.hk 1Loong Herbert h_loong@clo.cuhk.edu.hk 1Lee Kirsty kirsty.lee@gmail.com 1Li Leung lileungvil@gmail.com 1Ma Brigette brigette@clo.cuhk.edu.hk 1To Ka F kfto@cuhk.edu.hk 3Yu Simon CH simonyu@cuhk.edu.hk 21 Comprehensive Cancer Trials Unit, Department of Clinical Oncology, State Key Lab in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong 2 Department of Diagnostic and Interventional Radiology, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong 3 Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong 12 5 2015 12 5 2015 2015 15 39514 8 2014 22 4 2015 © Yeo et al.; licensee BioMed Central. 2015This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nThe oncogenic PI3K/Akt/mTOR pathway is frequently activated in HCC. Data on the mTOR inhibitor, temsirolimus, is limited in HCC patients with concomitant chronic liver disease. The objectives of this study were: (1) In phase I, to determine DLTs and MTD of temsirolimus in HCC patients with chronic liver disease; (2) In phase II, to assess activity of temsirolimus in HCC, and (3) to explore potential biomarkers for response.\n\nMethods\nMajor eligibility criteria included histologically confirmed advanced HCC and adequate organ function. In Phase I part of the study, temsirolimus was given weekly in 3-weekly cycle; dose levels were 20 mg (level 1), 25 mg (level 2) and 30 mg (level 3). The MTD was used in the subsequent phase II part; the primary endpoint was PFS and secondary endpoints were response and OS. In addition, exploratory analysis was conducted on pre-treatment tumour tissues to determine stathmin, pS6, pMTOR or p-AKT expressions as potential biomarkers for response. Overall survival and PFS were calculated using the Kaplan-Meier method. Reassessment CT scans were done every 6 weeks. All adverse events were reported using CTCAE v3.\n\nResults\nThe Phase I part consisted of 19 patients, 2 of 6 patients at level 3 experienced DLT; dose level 2 was determined to be the MTD. The phase II part consisted of 36 patients. Amongst 35 assessable patients, there were 1 PR, 20 SD and 14 PD. Overall, the median PFS was 2.83 months (95% C.I. 1.63-5.24). The median OS was 8.89 months (95% C.I. 5.89-13.30). Grade ≥ 3 that occurred in > 10% of patients included thrombocytopenia (4) and hyponatraemia (4). Exploratory analysis revealed that disease stabilization (defined as CR + PR + SD > 12 weeks) in tumours having high and low pMTOR H-scores to be 70% and 29% respectively (OR 5.667, 95% CI 1.129-28.454, p = 0.035).\n\nConclusions\nIn HCC patients with chronic liver disease, the MTD of temsirolimus was 25 mg weekly in a 3-week cycle. The targeted PFS endpoint was not reached. However, further studies to identify appropriate patient subgroup are warranted.\n\nTrial registration\nThis study has been registered in ClinicalTrials.gov (Id: NCT00321594) on 1 December 2010.\n\nKeywords\nmTOR inhibitorLiver cancerPalliativeissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nHepatocellular carcinoma (HCC) is the sixth most common cancer globally, and the third leading cause of cancer mortality both in Hong Kong and worldwide [1,2]. The outlook of patients with unresectable HCC is poor. To date, the only systemic agent that has been shown to provide survival benefit is sorafenib [3,4]. In parts of the world including Hong Kong, HCC patients often present with advanced disease stage, but the use of sorafenib has only been approved in recent years as standard therapy.\n\nIt has been well-established that numerous genetic abnormalities are involved in HCC; comprehensive genomic analyses shows that components of the phosphatidylinositol-3 kinase (PI3K)/Akt/mTOR pathway are dysregulated in 40-50% of HCC [5-7]. On the other hand, a meta-analysis of over 450 patients with HCC who received liver transplant demonstrated lower rates of recurrence and mortality for patients who received the mTOR inhibitor (mTORI), sirolimus, for immunosuppression [8]. The expansion of mTORIs as a therapeutic strategy for HCC was also strengthened by their successes in other cancers [9-12]. In various HCC models, mTORIs significantly reduced tumour volume and angiogenesis, delayed tumour growth and increased survival [5,6,13-16].\n\nEverolimus had initially been evaluated in HCC in phase I and II studies. A US study achieved an MTD of 10 mg/day [17]; among the 25 patients enrolled, 10 achieved stable disease, one achieved partial response, and median survival was 8.4 months. In another study, Taiwanese patients tolerated only a daily dose of 7.5 mg, and the median survival was 7.7 months [18]. However, the efficacy of everolimus in HCC has not been confirmed by the recently reported global phase III study (EVOLVE-1, NCT01035229) [19].\n\nTemsirolimus is a prodrug of sirolimus; it is administered intravenously and has a long half-life of 73 hours. To date, there has been limited clinical data on the use of temsirolimus in HCC patients who often suffer from chronic liver disease. We conducted a phase I/II study of temsirolimus (Torisel®) in patients with unresectable HCC, majority of whom had concomitant hepatitis B virus-related chronic liver disease. The objectives in the phase I study were to determine dose limiting toxicity (DLT) and maximum tolerated dose (MTD). Once the MTD was determined, the phase II portion of the study was conducted to determine the activity of temsirolimus.\n\nAlthough promising results have been shown with temsirolimus in a number of malignancies, there has been very limited data on potential biomarkers that could enable appropriate selection of tumours which are likely to undergo a favorable clinical response. Further, the failure to demonstrate efficacy of everolimus in the EVOLVE study has highlighted the potential importance of appropriate patient selection. Thus, in the current study, an exploratory analysis was also conducted to determine if the expression of stathmin, pS6, pMTOR and p-AKT might be predictive for response to temsirolimus in HCC.\n\nMethods\nEligibility criteria included: Histologically/cytologically confirmed unresectable HCC; ECOG ≤2; measurable disease; life expectancy > 12 weeks; absolute neutrophil count ≥ 1.5 × 109/L, platelets ≥ 80 × 109/l, serum creatinine ≤ 150 μmol/L, total bilirubin ≤ 30 umol/l, albumin ≥ 28 g/l, alanine transaminases ≤ 5.0 × UNL (institutional upper normal limit), alkaline phosphatase ≤ 6 × UNL, prothrombin time ≤ 4 sec of ULN, and absence of clinical ascites.\n\nThe main exclusion criteria were Child’s B or C cirrhosis, use of other systemic treatments within 3 weeks prior to study entry; prior use of mTORI; significant cardiovascular disease; severe impairment of lung function; poorly controlled diabetes mellitus; and ≥ grade 2 pre-existing neuropathy.\n\nWritten consent was sought from individual patient to participate in the study and for the exploratory analysis that involved the use of tissue obtained for diagnostic purpose. This study was approved by the Clinical Research Ethics Committee of the Joint NTEC-Review Board of the Chinese University of Hong Kong, and has been registered in ClinicalTrials.gov (Id: NCT00321594).\n\nPretreatment evaluation\nAll patients underwent complete medical history and physical examination, blood profiles including complete blood counts, renal and liver functions, fasting glucose and lipids, clotting profiles, alpha-fetoprotein (AFP), and hepatitis B surface antigen (HBsAg), hepatitis C antibody (anti-HCV), chest x-ray and CT scan of abdomen and/or other disease sites were performed.\n\nTreatment plan\nTemsirolimus was added to 250 mL of 0.9% sodium chloride and administered intravenously over 30 minutes weekly, every 3 weeks. All patients received premedication with diphenhydramine 25 mg or 50 mg IV bolus dose 30 minutes prior to temsirolimus. Standard anti-emetics included at least a 5-HT3 antagonist. Patients who were HBsAg seropositive were also given lamivudine prior to study treatment.\n\nPhase I study\nFor the phase 1 study, there were 5 dose levels of temsirolimus: 10 (level −2), 15 (level −1), 20 (level 1), 25 (level 2) and 30 mg/week (level 3). Level 1 was the starting dose level.\n\nDLT was defined during cycle 1 as: any grade 4 hematological toxicity; grade ≥3 non-hematological toxicity (excluding alopecia); grade 3 nausea, vomiting, or diarrhoea that did not respond to therapy; and treatment delay > 2 weeks.\n\nThe conventional 3 + 3 design was employed. Dose escalation was based on the modified Fibonacci method [20]. The MTD was defined as the dose below which ≥ 2 of 3 or ≥ 2 of 6 patients experiencing DLT. A total of 10 patients were entered into the MTD to further define toxicity.\n\nTreatment delay and modification\nFor each cycle, treatment was delayed if the ANC was <1.5 × 109/L or platelet count was < 75 × 109/ml on the scheduled day of drug administration. Patients who experienced grade 3 non-haematological toxicity, thrombocytopenia or febrile neutropenia, as well as grade 4 neutropenia continued to receive temsirolimus at the next lower dose level upon resolution of all toxicities to grade 1. For an individual, there could be a limit of two dose de-escalations for serious toxicity. The drug was discontinued for toxicities of the following nature: grade 4 non-hematological toxicities, thrombocytopenia/febrile neutropenia/recurrent grade 4 neutropenia despite dose reduction, as well as any haematological or non-haematological toxicity requiring interruption for ≥ 3 weeks.\n\nTreatment was continued provided that toxicities were tolerable or until one of the following criteria applied: disease progression; intercurrent illness that prevented further treatment administration; unacceptable adverse events; patient’s decision; or investigator’s judgment.\n\nPhase II study\nUpon determination of MTD, patients were enrolled into the phase II part of the trial at MTD; the 10 patients at the MTD in phase I were included in the phase II analysis.\n\nDefinitions of response and toxicity\nTumour response assessment with CT every two cycles was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [21]. Toxicity was graded according to Common Toxicity Criteria of the National Cancer Institute (NCI-CTC v3).\n\nMethodology for stathmin, pS6, pMTOR and p-AKT immunohistochemistry\nThirty-four patients had pre-treatment tissues available for this analysis. For immunohistochemistry, 5-μm tissue sections were prepared from each block. Tissue sections were deparaffinized, rehydrated and rinsed in distilled water. Antigen retrieval was done by using pressure cooker with 10 nM citrate buffer (pH 6.0) for 25 minutes. The endogenous peroxidase activity was then blocked by incubating the slides in 3% hydrogen peroxide in methanol for 10 min. The primary antibodies used in this study were STMN1 (1:50), pS6 (Ser235/236, 1:100), pMTOR (Ser2448, 1:50) and p-AKT (Ser473, clone D9E, 1:25) from Cell Signaling Technology (Danvers MA). The primary antibodies were incubated at 4°C overnight and chromogen development was performed using the DAKO EnVision System (Glostrup, Denmark) except for p-AKT, which was detected using the OptiView DAB IHC Detection Kit (Ventana Medical Systems).\n\nAn intensity score of 0 to 3 was assigned for the intensity of tumour cells (0, none; 1, weak; 2, intermediate; 3, strong). A proportional score was given by the estimated proportion of positive tumour cells in percentage. To assess the average degree of staining within a tumour, multiple regions were analyzed, and at least 100 tumour cells were assessed. The cytoplasmic expression was assessed by H-score system [22]. The formula for the H-score is: Histoscore = ∑(I × Pi), where I = intensity of staining and Pi = percentage of stained tumour cells, producing a cytoplasmic score ranging from 0 to 300. The scoring was independently assessed by two assessors (AWHC and JHMT) who were not aware of the clinical outcomes.\n\nStatistical methods\nFor the Phase I portion, the estimated patient number would be 14–19. For the phase II portion, the primary endpoint was progression free survival (PFS). The secondary endpoints were response according to RECIST, overall survival (OS) and toxicity. The PFS was assessed from day 1 of treatment cycle 1 to the date when objective disease progression was observed. OS was calculated from day 1 of treatment cycle 1 to the date of death. Death was regarded as a progression event in those subjects who died before disease progression. Subjects without documented objective progression at the time of the final analysis were censored at the date of their last tumour assessment. Survival curves were constructed using the Kaplan–Meier method.\n\nThe planned accrual for phase II was 30 assessable patients. Patients are considered assessable if they have completed ≥ 1 cycle of treatment or are removed from study due to disease progression. If the PFS at 3 months is ≤ 0.5, the regimen would be considered inactive. If the PFS at 3 months is ≥ 0.66, this regimen would be considered worthy of further investigation. If ≥ 18 of 30 assessable patients are observed to be progression-free by 3 months, the study would have 80% power and 0.18 significance level. An additional 6 patients (i.e. 20%) would be accrued to account for ineligibility, cancellation, major treatment violation, or other reasons. Therefore, the maximum accrual would be 36 patients (including the 10 patients from phase I at MTD). In order to observe enough events for the study, all patients would be followed up for at least 3 months.\n\nExploratory analysis on cytoplasmic expression of the biomarkers was viewed as hypothesis generating. The optimal cutoff for stathmin, pS6, pMTOR and p-AKT was determined by the receiver operating characteristic (ROC) curve distribution analysis [23,24]. Out of a total H-score of 300, the threshold for differentiating between positive and negative immunostaining were set at H-scores of 15, 120, 20 and 5 respectively; tumours were categorized as ‘low H-score’ and ‘high H-score’ depending on whether the individual score were ‘lower than or equal to’ or ‘higher than’ the respective thresholds. Response rates in terms of disease stabilization (defined as complete response [CR] + partial response [PR] + stable disease [SD] ≥ 12 weeks) and AFP drop in association with H-scores of stathmin, pS6, pMTOR and p-AKT cytoplasmic were compared using Fisher’s exact and proportional hazard model where applicable. Response assessment based on AFP was conducted for patients whose baseline AFP > 20 ng/ml and who had 2 cycles of study treatment. The drop in AFP based on baseline AFP was compared with the lowest level of AFP detected after 2 cycles of study treatment, and AFP response was defined as a > 20% decrease in AFP value [25].\n\nResults\nFrom November 2009 to December 2011, a total of 45 patients were consented and entered.\n\nPhase I study\nPatient characteristics and study drug dosing\nNineteen patients were entered, 3 in level 1, 10 in level 2 and 6 in level 3 (Table 1). The median age was 56.0 years (range 36–77). Fifteen (79%) were male, 14 (78%) had ECOG 0. Fifteen (79%) had chronic HBV and 1 was hepatitis C seropositive.Table 1 \nSummary of dose level and dose-limiting toxicities in phase 1\n\n\nPatient no.\tDose level\tDose-limiting toxicities\t\n001\t1\tnil\t\n002\t1\tnil\t\n003\t1\tnil\t\n004\t2\tnil\t\n005\t2\tnil\t\n006\t2\tnil\t\n007\t3\tnil\t\n008\t3\tGrade 3 syncope\t\n009\t3\tnil\t\n010\t3\tnil\t\n011\t3\tnil\t\n012\t3\tTreatment delay for > 2 weeks due to prolonged neutropenia\t\n013\t2\tnil\t\n014\t2\tnil\t\n015\t2\tnil\t\n016\t2\tnil\t\n017\t2\tnil\t\n018\t2\tnil\t\n019\t2\tnil\t\n\n\nTwo out of 6 patients developed DLTs at level 3 (dose being 30 mg/week), including 1 who developed grade 3 syncope and 1 who had treatment delay for > 2 weeks due to prolonged neutropenia. Temsirolimus dose of 25 mg/week was declared as the MTD and the recommended phase II dose; at the MTD, temsirolimus was well tolerated with no DLTs. The 10 patients enrolled into the phase I study at MTD were included in the phase II analysis.\n\nPhase II study\nPatient characteristics\nThe following analyses pertain to the 36 patients who were being enrolled into the phase II study.\n\nPatient characteristics are shown in Table 2. Of note, 27 patients had BCLC stage C [26], 9 had BCLC stage B (including 8 who failed multiple lines of loco-regional therapies and 1 who had extensive intrahepatic disease); 24 (66.7%) had vascular involvement and 21 (58.3%) had extrahepatic metastases. Twenty-nine patients (80.5%) had received prior treatment for HCC; 13 (36.1%) had received ≥1 line of prior systemic therapies; 10 of the latter had received anti-vascular endothelial growth factor tyrosine kinase inhibitors (anti-VEGF TKIs). The median number of cycles was 3.5 (range: 1–16). Twelve (34%) patients underwent at least 6 cycles of temsirolimus. The follow-up data was frozen on 31 December 2013. The median follow-up was 8.89 months (95% C.I. 5.89-13.30). At the time of data cutoff, all patients had died; 34 (94.4%) were due to progressive disease, 1 due to liver failure and another due to pneumonia.Table 2 \nBaseline patient characteristics in phase II study\n\n\nCharacteristic\tNo. of patients\t%\t\nNo. of patients\t36\t100\t\nGender\t\t\t\nMale\t31\t86.1\t\nFemale\t5\t13.9\t\nAge, years\t\t\t\nMedian\t56\t\t\nRange\t26-77\t\t\nECOG performance status\t\t\t\n0\t24\t66.7\t\n1\t12\t33.3\t\nHepatitis status\t\t\t\nHepatitis B\t29\t80.5\t\nHepatitis C\t1\t2.8\t\nNon-B non-C\t6\t16.7\t\nBaseline AFP > 10 μg/l\t\t\t\nYes\t25\t69.4\t\nNo\t11\t30.6\t\nTumour Burden\t\t\t\nBCLC Stage B\t28\t\t\n BCLC stage C\t8\t\t\n Macroscopic vascular invasion\t24\t66.7\t\nExtrahepatic disease\t21\t58.3\t\nPrior therapy for HCC of any forms\t29\t80.6\t\nBlood parameters (median, range):\t\t\t\nTotal bilirubin\t16 (5–34) umol/l\t\t\nAlbumin\t39. (32–48) g/l\t\t\nAlanine transaminase\t40 (18–140) iu/l\t\t\nAlkaline phosphatase\t108 (52–434) iu/l\t\t\nAFP\t82 (1–118712) ug/l\t\t\nINR\t1.06 (0.89-1.26)\t\t\nCreatinine\t82 (44–136) umol/l\t\t\nGlucose\t5.4 (4.0-8.5) mmol/l\t\t\nTriglyceride\t0.9 (0.5-2.0) mmol/l\t\t\nLDL cholesterol\t2.65 (1.6-7.3) mmol/l\t\t\nHDL cholesterol\t1.15 (0.7-2.5) mmol/l\t\t\nTotal cholesterol\t4.45 (3.0-8.9) mmol/l\t\t\nPrior systemic therapy\t\t\t\n1 line\t11\t30.5\t\n2 lines\t1\t2.8\t\n3 lines\t1\t2.8\t\nPrior local +/− regional therapy\t\t\t\nSurgery\t23\t63.9\t\n*Local ablation\t4\t11.0\t\nTransarterial therapy\t20\t55.5\t\n*2 had radiofrequency ablation and 2 had percutaneous ethanol injection.\n\n\n\nResponse and survival\nOne patient was not assessable for response as he went abroad after receiving cycle 1 week 1 of temsirolimus. Amongst the 35 assessable patients, the best responses were: 1 PR (3%), 20 SD (57%) and 14 progressive disease [PD] (40.0%); 40% had disease stabilization.\n\nOverall, the median PFS was 2.83 months (95% C.I. 1.63-5.24); the 3-month PFS was 0.47 (95% C.I. 0.31-0.64) (Figure 1a). The median OS was 8.89 months (95% C.I. 5.89-13.30) (Figure 1b).Figure 1 (a) Progression-free survival; (b) Overall survival of patients in the phase II study.\n\n\n\nUnplanned exploratory analyses revealed that patients who received prior anti-VEGF TKIs had similar PFS and OS compared with those who did not. In addition, treatment outcome was not associated with viral etiologies (data not shown).\n\nToxicity\nIn the phase II portion study, toxicity was assessable in the 35 patients (Table 3). The most common adverse events that occurred in > 30% of patients included oral mucositis, rash, fatigue, cough, non-neutropenic fever, anorexia, insomnia, diarrhea, thrombocytopenia, and pain in abdomen and head. Grade ≥ 3 events that occurred in > 10% included hyponatraemia and thrombocytopenia.Table 3 \nHaematological and non-haematological toxicities according to the NCI CTC (version 3.0) (n = 35)\n\n\n\tWorst grade (number of patients)\t\nToxicities\t1-2\t3\t4\t\nMucositis- oral\t26\t1\t0\t\nRash\t20\t0\t0\t\nFatigue\t17\t1\t0\t\nCough\t15\t1\t0\t\nFever\t14\t0\t0\t\nAnorexia\t13\t0\t0\t\nPulmonary-Other\t13\t0\t0\t\nInsomnia\t12\t0\t0\t\nPain- head\t12\t0\t0\t\nPain- abdomen\t10\t1\t0\t\nHaemorrhage, nose\t10\t0\t0\t\nOedema- limb\t10\t0\t0\t\nPruritus\t10\t0\t0\t\nGastrointestinal-Other\t9\t0\t0\t\nDiarrhoea\t8\t3\t0\t\nDysphagia\t8\t1\t0\t\nNausea\t8\t0\t0\t\nPain- others\t8\t0\t0\t\nPlatelets\t7\t4\t0\t\nDyspnoea\t7\t1\t0\t\nConstipation\t7\t0\t0\t\nDistension\t7\t0\t0\t\nDry mouth\t7\t0\t0\t\nHaemorrhage, other\t6\t0\t0\t\nRigors/chills\t6\t0\t0\t\nVomiting\t6\t0\t0\t\nHyperglycaemia\t5\t1\t0\t\nDizziness\t5\t0\t0\t\nDry skin\t5\t0\t0\t\nMusculoskeletal-Other\t5\t0\t0\t\nPain- muscle\t5\t0\t0\t\nTaste alteration\t5\t0\t0\t\nHypokalaemia\t4\t1\t1\t\nHemorrhoids\t4\t1\t0\t\nHyponatraemia\t0\t4\t0\t\nAscites\t4\t0\t0\t\nInfection- others with normal neutrophil counts\t4\t0\t0\t\nAlanine transaminase\t3\t2\t0\t\nHyperbilirubinaemia\t1\t2\t1\t\nInfection- upper airway with normal neutrophil counts\t1\t3\t0\t\n\n\nOf note, hyperglycaemia occurred in 6 patients (17%; 4 grade 1–2 and 1 grade 3), while 1 patient developed grade 2 hypercholesterolaemia; all could be managed with standard medical therapies. Two patients developed interstitial pneumonitis, which resolved with corticosteroid and discontinuation of temsirolimus.\n\nExploratory analysis\nOf the 35 assessable patients, 34 had pre-treatment tumour tissues available for this analysis, there were 14 patients who achieved disease stabilization.\n\nThe H-scores for stathmin, pS6, pMTOR and pAKT of individual patient’s tumour are listed in Table 4. The immunohistochemical findings with respect to H-scores for stathmin, pS6, pMTOR and pAKT are illustrated in Figure 2. Analysis of the H-scores in association with disease stabilization and AFP drop are detailed in Table 5. Only pMTOR was found to be associated with disease stabilization, 7 of the 10 patients (70%) who had high H-scores (> 20/300) achieved disease stabilization, in contrast to 7 out of 24 (29%) who had low H-scores (p = 0.028). The odds ratio (OR) for disease stabilization for high vs. low pMTOR H-scores is 5.667 (95% C.I. 1.129-28.454, p = 0.035).Table 4 \nVirological status, H-scores for stathmin, pS6, pMTOR and pAKT and clinical outcome in terms of having achieved disease stabilization of individual patient’s tumour\n\n\nPatient no.\tHBV/HCV/ Non-B non-C\tStathmin\tpS6\tpMTOR\tpAkt\tDisease stabilization\t\nPW004\tHBV\tHigh\tLow\tLow\tHigh\tNo\t\nPW005\tHBV\tHigh\tHigh\tLow\tHigh\tNo\t\nPW014\tHBV\tLow\tHigh\tLow\tLow\tNo\t\nPW018\tHBV\tHigh\tLow\tLow\tLow\tNo\t\nPW019\tHBV\tLow\tHigh\tLow\tLow\tNo\t\nPW020\tNon-B, Non C\tLow\tHigh\tLow\tHigh\tNo\t\nPW023\tHCV\tHigh\tLow\tHigh\tLow\tNo\t\nPW024\tHBV\tHigh\tHigh\tLow\tHigh\tNo\t\nPW025\tHBV\tHigh\tLow\tLow\tHigh\tNo\t\nPW028\tHBV\tHigh\tLow\tLow\tHigh\tNo\t\nPW029\tNon-B, Non C\tLow\tLow\tLow\tLow\tNo\t\nPW030\tHBV\tHigh\tLow\tLow\tLow\tNo\t\nPW031\tHBV\tHigh\tLow\tLow\tLow\tNo\t\nPW032\tHBV\tHigh\tHigh\tLow\tLow\tNo\t\nPW034\tHBV\tHigh\tHigh\tLow\tHigh\tNo\t\nPW035\tNon-B, Non C\tLow\tLow\tHigh\tLow\tNo\t\nPW036\tHBV\tLow\tHigh\tHigh\tLow\tNo\t\nPW039\tHBV\tHigh\tLow\tLow\tLow\tNo\t\nPW040\tNon-B, Non C\tHigh\tHigh\tLow\tLow\tNo\t\nPW042\tHBV\tHigh\tLow\tLow\tLow\tNo\t\nPW015\tHBV\tHigh\tHigh\tHigh\tLow\tYes\t\nPW016\tHBV\tHigh\tHigh\tLow\tLow\tYes\t\nPW017\tNon-B, Non C\tLow\tLow\tLow\tLow\tYes\t\nPW021\tHBV\tLow\tLow\tHigh\tLow\tYes\t\nPW022\tNon-B, Non C\tLow\tLow\tHigh\tLow\tYes\t\nPW026\tHBV\tLow\tLow\tLow\tLow\tYes\t\nPW027\tHBV\tHigh\tHigh\tLow\tHigh\tYes\t\nPW033\tHBV\tHigh\tLow\tHigh\tHigh\tYes\t\nPW037\tHBV\tLow\tHigh\tHigh\tLow\tYes\t\nPW038\tHBV\tHigh\tHigh\tLow\tLow\tYes\t\nPW043\tHBV\tHigh\tHigh\tHigh\tHigh\tYes\t\nPW044\tHBV\tLow\tLow\tLow\tLow\tYes\t\nPW045\tHBV\tLow\tHigh\tHigh\tHigh\tYes\t\nPW046\tHBV\tHigh\tHigh\tLow\tLow\tYes\t\nHBV- hepatitis B virus, HCV- hepatitis C virus, Non-B non-C- negative for hepatitis B or C.\n\nDisease stabilization rate = (CR + PR + SD) >12 weeks.\n\nFigure 2 Immunohistochemical staining of pretreatment tumour tissues. A. high stathmin H-score (2/300). B. low stathmin H-score (210/300). C. high pS6 H-score (0/300). D. low pS6 H-score (270/300). E. high pMTOR H-score (3/300). F. low pMTOR H-score (105/300). G. high p-AKT H-score (5/300). H. low p-AKT H-score (240/300).\n\nTable 5 \nExploratory analysis on H-scores for stathmin, pS6, pMTOR and pAKT\n\n\n\nStathmin\n\t\nH-scores Range: 0-300/300; Optimal Cut-off*: 15/300\t\nH-scores: High vs. Low\tHigh H-scores (>15/300)\tLow H-scores (≤15/300)\t\t\nDisease stabilization rate**\t7/21 (33%)\t7/13 (46%)\tp = 0.238\t\nOR for disease stabilization**\t0.429 (95% CI 0.104-1.770)\tp = 0.242\t\nAFP response***\t2/6 (33%)\t6/16 (38%)\tp = 0.376\t\n\npS6\n\t\nH-scores Range: 0-300/300; Optimal Cut-off*:120/300\t\nH-scores: High vs. Low\tHigh H-scores (>120/300)\tLow H-scores (≤120/300)\t\t\nDisease stabilization rate**\t8/17 (47%)\t6/17 (35%)\tp = 0.489\t\nOR for disease stabilization**\t1.630 (95% CI 0.411-6.459)\tp = 0.487\t\nAFP response***\t4/11 (36%)\t4/11 (36%)\tp = 0.341\t\n\npMTOR\n\t\nH-scores Range: 0-180/300; Optimal Cut-off*: 20/300\t\nH-scores: High vs. Low\tHigh H-scores (>20/300)\tLow H-scores (≤20/300)\t\t\nDisease stabilization rate**\t7/10 (70%)\t7/24 (29%)\tp = 0.028\t\nOR for disease stabilization**\t5.667 (95% CI 1.129-28.454)\tp = 0.035\t\nAFP response\t4/16 (25%)\t4/6 (67%)\tp = 0.085\t\n\npAKT\n\t\nH-scores Range: 0-240/300; Optimal Cut-off*: 5/300\t\nH-scores: High vs. Low\tHigh H-scores (>5/300)\tLow H-scores (≤5/300)\t\t\nDisease stabilization rate**\t4/11 (36%)\t10/23 (43%)\tp = 0.693\t\nOR for disease stabilization**\t0.743 (95% CI 0.169-3.262)\tp = 0.694\t\nAFP response***\t7/16 (44%)\t1/6 (17%)\tp = 0.215\t\n*H-scores Optimal Cut-off based on ROC.\n\n**Disease stabilization rate (CR + PR + SD) ≥12 weeks, number of patients available for analysis = 34; disease stabilization in association with H-scores were compared using Fisher’s exact and proportional hazard model.\n\n***AFP response, number of patients available for analysis = 22; AFP drop in association with H-scores were compared using Fisher’s exact.\n\n\n\nOf the 36 patients, 22 were eligible for AFP response; there were 8 AFP responders and 14 non-responders. Correlation study of AFP response with H-scores for stathmin, pS6, pMTOR and pAKT showed no association. Of interest, AFP response for high vs. low pMTOR scores occurred in 67% and 20% respectively (p = 0.085).\n\nDiscussion\nThe present study confirmed the MTD for temsirolimus in patients with chronic liver disease and advanced HCC to be 25 mg weekly, which is the approved dose for metastatic renal cell carcinoma [9,10]. Common adverse reactions of temsirolimus noted in this study were consistent with the reported toxicity profile of this agent, which included skin and mucosal toxicities, constitutional symptoms (fatigue, anorexia, insomnia), myelosuppression, metabolic disturbances (disturbances in glucose and lipids controls) and the uncommon but well-known occurrence of interstitial pneumonitis.\n\nIn an unselected population of advanced HCC patients, the current study reveals that the use of temsirolimus yielded a 3-month PFS of 0.47, which is lower than the pre-specified limit considered to be efficacious. The present finding is in line with that of the EVOLVE study, in which everolimus has failed to achieve the primary endpoint in improving OS in an unselected HCC patient population who had progressed on sorafenib [19]. The discouraging result sheds light to the potential importance of suitable patient selection.\n\nThere has been limited ability to identify biomarkers for appropriate utilization of mTORIs. In the phase I study of everolimus, 11 HCC patients had pre-treatment tumour tissues available for assessment, one patient achieved PR and the tumour showed moderate to high levels of p-AKT, p-MTOR and pS6 [17]. The key effector in the PI3K/Akt/mTOR pathway is mTOR, which has a critical role in regulating cell proliferation, survival and angiogenesis [27,28]. PIK3CA has also been suggested as a predictive marker for effective mTOR inhibition in breast cancer [29,30], unfortunately, a recent report on endometrial cancer did not support this [31]. Further, the reported rate of mutations in the PIK3CA gene has been inconsistent in HCC varying from 0-35% [32,33]. Activated PI3K propels two downstream effectors: mTOR complex 2 (mTORC2) and Akt. Akt activates mTORC1 which in turn activates downstream effector, the serine/threonine kinase, S6K1. S6K1 participates in numerous cellular processes central to promoting cell proliferation, cell growth and cell cycle progression [34,35]. Phosphorylated mTOR and p-S6K is elevated in approximately 40% of HCC [6,27,36]. It has been observed that loss of PTEN, the negative regulator of PI3K, results in robust activation of this pathway [37,38], and stathmin, encoded by the signature gene STMN1, has been suggested to be a more accurate immunohistochemical marker of the PTEN signature [39]. These data have prompted us to explore the possibility of stathmin, pAKT, pMTOR and pS6 as potential biomarkers for response.\n\nThe present exploratory analyses show pMTOR to be the only marker associated with disease stabilization effect of temsirolimus. Although some studies suggested that pMTOR overexpression may have prognostic impact independent of temsirolimus, studies in different tumour types have reported conflicting results [40-42]. Specifically, a study in HCC patients undergoing orthotopic liver transplantation reported mTOR pathway to be active in 40% of the patients, but none of the biomarkers [PTEN, p-AKT, p-mTOR, p-p70S6K and p-4EBP-1] were associated with survival [43]. In this current study, assessment of pMTOR in relation to presence of vascular invasion and tumour grading was attempted; unfortunately, 22 of the 34 tumour analyzed were biopsy samples which limits detail pathological assessment.\n\nOn the other hand, the effect of rapalogs on Akt may vary with drug dose, with lower doses increasing Akt activation while higher doses diminishing Akt activity [44,45]. In addition, the effect on Akt also varies with cell type [46]. Thus, determining the clinical effects of different dosages of mTORIs could be an important tactic to overcoming such limitation.\n\nFurther, combining mTORIs with other systemic agents could improve clinical efficacy. The combination of everolimus and sorafenib has been reported to synergistically inhibit proliferation and tumor growth in HCC cell lines and xenografts [14]. A phase I study of this combination in advanced HCC patients yielded an encouraging 8% PR and 60% SD [47]. In addition, studies have shown that the activation of Akt markedly increases the resistance against microtubule-directed cytotoxic agents while mTORIs could inhibit this resistance [48,49].\n\nConclusions\nIn summary, this study demonstrates that temsirolimus enables disease stabilization with tolerable toxicity profile among HCC patients. Although the efficacy data has not reached the pre-specified PFS endpoint, patients with tumours having a high pMTOR score were more likely to achieve disease stabilization. In this respect, a recent study among bladder cancer patients have reported that everolimus was more effective in patients with a somatic mutation in the TSC1 complex [50]. Therefore, the role pMTOR and TSC1 mutation as potential biomarkers for efficacy of mTOR inhibition should further be explored to enable better selection of appropriate patient population. However, further improvement in clinical efficacy for HCC will likely require combining mTORIs with other novel compounds.\n\nAbbreviations\nHCCHepatocellular carcinoma\n\nDLTsDose limiting toxicities\n\nMTDMaximum tolerated dose\n\nCRComplete response\n\nPRPartial response\n\nSDStatic disease\n\nPFSProgression free survival\n\nOSOverall survival\n\nmTORImTOR inhibitor\n\npMTORPhosphorylated mTOR\n\npS6KPhosphorylated serine/threonine kinase\n\nROCReceiver operating characteristic\n\nAFPAlfa-fetoprotein\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nWY, FKFM, KFT and SCHY designed research directions and protocols. WY, SLC, EPH, JK, LL, CMC, JWYH, BM and SCHY acquired clinical data. JHMT, AWHC and KF. To conducted biomarker correlative analyses. WY, FKFM, HL and KL analyzed and interpreted data. WY, JWYH, JHMT, EPH and KL wrote the manuscript. All authors read and approved the final manuscript.\n\nAcknowledgements\nThe study was sponsored by Pfizer Corporation Inc. (drug support, funding of imaging required in the study, and funding for personnel for data entry and data analysis), and the Chinese University of Hong Kong Direct Grant for Research (Grant Ref No. 2012.1.011). The investigators were responsible for data collection, data analysis, data interpretation, and writing of the report.\n==== Refs\nReferences\n1. Parkin DM Bray F Ferlay J Pisani P Global cancer statistics 2002 CA Cancer J Clin 2005 55 74 108 10.3322/canjclin.55.2.74 15761078 \n2. Leading cancer sites in Hong Kong in 2012. Hong Kong Cancer Registry. Hospital Authority 2014; 1: 1.\n3. Llovet JM Ricci S Mazzaferro V Hilgard P Gane E Blanc JF Sorafenib in advanced hepatocellular carcinoma N Engl J Med 2008 359 4 378 90 10.1056/NEJMoa0708857 18650514 \n4. 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Saala LH Johanssonc P Holmb K Gruvberger-Saal SK She QB Maurer M Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity Proc Natl Acad Sci U S A 2007 104 18 7564 9 10.1073/pnas.0702507104 17452630 \n40. Zhou L Huang Y Li J Wang Z The mTOR pathway is associated with the poor prognosis of human hepatocellular carcinoma Med Oncol 2010 27 2 255 61 10.1007/s12032-009-9201-4 19301157 \n41. Yu G Wang J Chen Y Wang X Pan J Li G Overexpression of phosphorylated mammalian target of rapamycin predicts lymph node metastasis and prognosis of Chinese patients with gastric cancer Clin Cancer Res 2009 15 5 1821 9 10.1158/1078-0432.CCR-08-2138 19223493 \n42. Lee D Do IG Choi K Jang KT Choi D Heo JS The expression of phospho-AKT1 and phospho-MTOR is associated with a favorable prognosis independent of PTEN expression in intrahepatic cholangiocarcinomas Mod Pathol 2012 25 1 131 9 10.1038/modpathol.2011.133 21874010 \n43. Sieghart W Fuereder T Schmid K Cejka D Werzowa J Wrba F Mammalian target of rapamycin pathway activity in hepatocellular carcinomas of patients undergoing liver transplantation Transplantation 2007 83 4 425 32 10.1097/01.tp.0000252780.42104.95 17318075 \n44. Phung TL Ziv K Dabydeen D Eyiah-Mensah G Riveros M Perruzzi C Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin Cancer Cell 2006 10 159 70 10.1016/j.ccr.2006.07.003 16904613 \n45. Stoeltzing O Meric-Bernstam F Ellis L Intracellular signaling in tumor and endothelial cells: The expected, and yet again, the unexpected Cancer Cell 2006 10 89 91 10.1016/j.ccr.2006.07.013 16904605 \n46. Sarbassov DD Ali SM Sengupta S Sheen JH Hsu PP Bagley AF Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB Mol Cell 2006 22 159 68 10.1016/j.molcel.2006.03.029 16603397 \n47. Kelley RK Nimeiri HS Munster PN Vergo MT Huang Y Li CM Temsirolimus combined with sorafenib in hepatocellular carcinoma: a phase I dose-finding trial with pharmacokinetic and biomarker correlates Ann Oncol 2013 24 1900 7 10.1093/annonc/mdt109 23519998 \n48. Zhou Q, Wong CH, Lau CP, Hui CW, Lui VW, Chan SL, et al. Enhanced antitumor activity with combining effect of mTOR inhibition and microtubule stabilization in hepatocellular carcinoma. Int J Hepatol. 2013;103830.\n49. Zhou Q Lui VW Lau CP Cheng SH Ng MH Cai Y Sustained antitumor activity by co-targeting mTOR and the microtubule with temsirolimus/vinblastine combination in hepatocellular carcinoma Biochem Pharmacol 2012 83 1146 58 10.1016/j.bcp.2012.01.013 22285225 \n50. Iyer G Hanrahan AJ Milowsky MI Al-Ahmadie H Scott SN Janakiraman M Genome sequencing identifies a basis for everolimus sensitivity Science 2012 338 221 10.1126/science.1226344 22923433\n\n",
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"title": "Phase I/II study of temsirolimus for patients with unresectable Hepatocellular Carcinoma (HCC)- a correlative study to explore potential biomarkers for response.",
"title_normalized": "phase i ii study of temsirolimus for patients with unresectable hepatocellular carcinoma hcc a correlative study to explore potential biomarkers for response"
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"abstract": "We retrospectively evaluated the efficacy of pomalidomide/cyclophosphamide/dexamethasone (PCd) treatment in seven patients with extramedullary disease (EMD). Three of the seven patients achieved VGPR (very good partial response) with PCd therapy. We handled a patient complicated with secondary plasma cell leukemia, which was completely cured with PCd regimen and succeeded to autologous stem cell transplantation. In addition, there were no severe infections during the treatment period. This is the first report demonstrating the efficiency and tolerability of PCd treatment for EMD.",
"affiliations": "Department of Hematology, Eiju General Hospital.;Department of Hematology, Eiju General Hospital.;Department of Hematology, Eiju General Hospital.;Department of Hematology, Eiju General Hospital.;Department of Hematology, Eiju General Hospital.;Department of Hematology, Eiju General Hospital.",
"authors": "Hagihara|Masao|M|;Ide|Shiro|S|;Ohara|Shin|S|;Uchida|Tomoyuki|T|;Inoue|Morihiro|M|;Hua|Jian|J|",
"chemical_list": "D013792:Thalidomide; D003907:Dexamethasone; D003520:Cyclophosphamide; C467566:pomalidomide",
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"keywords": "Cyclophosphamide; Extramedullary myeloma; Pomalidomide",
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"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D003907:Dexamethasone; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D009101:Multiple Myeloma; D012008:Recurrence; D012189:Retrospective Studies; D013792:Thalidomide; D014182:Transplantation, Autologous",
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"title": "Pomalidomide/cyclophosphamide/dexamethasone combination therapy for relapsed/refractory multiple myeloma accompanied by extramedullary lesions.",
"title_normalized": "pomalidomide cyclophosphamide dexamethasone combination therapy for relapsed refractory multiple myeloma accompanied by extramedullary lesions"
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"abstract": "Cor pulmonale is a rare complication of pulmonary aspergillosis (CPA). A 45-year-old Ugandan male with a history of recurrent community-acquired pneumonias was admitted with symptoms of progressive difficulty in breathing, chronic productive cough, non-exertional left sided chest pain and progressive weight loss occurring over a 12-month period. Chest CT scan and echocardiography confirmed the diagnosis of CPA with an aspergilloma complicating bronchiectasis, complicated with cor pulmonale. However, this was previously clinically misdiagnosed as PTB.",
"affiliations": "Department of Internal Medicine, College of Health Sciences, Makerere University, Kampala, Uganda.;Infectious Diseases Institute, College of Health Sciences, Makerere University, Kampala, Uganda.;Department of Internal Medicine, College of Health Sciences, Makerere University, Kampala, Uganda.;Department of Internal Medicine, College of Health Sciences, Makerere University, Kampala, Uganda.",
"authors": "Bongomin|Felix|F|;Kwizera|Richard|R|;Atukunda|Angella|A|;Kirenga|Bruce J|BJ|",
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"doi": "10.1016/j.mmcr.2019.07.001",
"fulltext": "\n==== Front\nMed Mycol Case RepMed Mycol Case RepMedical Mycology Case Reports2211-7539Elsevier S2211-7539(19)30047-810.1016/j.mmcr.2019.07.001Case ReportCor pulmonale complicating chronic pulmonary aspergillosis with fatal consequences: Experience from Uganda Bongomin Felix drbongomin@gmail.comab*Kwizera Richard cdAtukunda Angella aKirenga Bruce J. ada Department of Internal Medicine, College of Health Sciences, Makerere University, Kampala, Ugandab Department of Medical Microbiology & Immunology, Faculty of Medicine, Gulu University, Gulu, Ugandac Infectious Diseases Institute, College of Health Sciences, Makerere University, Kampala, Ugandad Makerere University Lung Institute, College of Health Sciences, Makerere University, Kampala, Uganda* Corresponding author. Department of Internal Medicine, College of Health Sciences, Makerere University, Kampala, Uganda. drbongomin@gmail.com05 7 2019 9 2019 05 7 2019 25 22 24 15 5 2019 11 6 2019 4 7 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Cor pulmonale is a rare complication of pulmonary aspergillosis (CPA). A 45-year-old Ugandan male with a history of recurrent community-acquired pneumonias was admitted with symptoms of progressive difficulty in breathing, chronic productive cough, non-exertional left sided chest pain and progressive weight loss occurring over a 12-month period. Chest CT scan and echocardiography confirmed the diagnosis of CPA with an aspergilloma complicating bronchiectasis, complicated with cor pulmonale. However, this was previously clinically misdiagnosed as PTB.\n\nKeywords\nChronic pulmonary aspergillosisCor pulmonaleRecurrent community acquired pneumoniaItraconazoleUganda\n==== Body\n1 Introduction\nChronic pulmonary aspergillosis (CPA) is a slowly progressive and destructive parenchymal lung disease caused by Aspergillus species, typically Aspergillus fumigatus [1]. It occurs in ostensibly immunocompetent or subtly immunocompromised patients with current or prior lung diseases [2]. CPA is estimated to affect approximately three million people worldwide [3]. Patients with CPA can be classified into; chronic fibrosing pulmonary aspergillosis (CFPA), chronic necrotizing pulmonary aspergillosis (CNPA) and chronic cavitary pulmonary aspergillosis (CCPA) based on histopathology, clinical findings and radiology findings [1]. Patients with CPA commonly present with pulmonary symptoms such as a persistent and/or productive cough, breathlessness, chest discomfort and haemoptysis, and constitutional symptoms; usually lasting up to 24 weeks or more. This makes it clinically indistinguishable and more often misdiagnosed as pulmonary tuberculosis (PTB) [4]. CPA can mimic smear-negative PTB. Herein, we present a case of a human immunodeficiency virus (HIV) sero-negative Ugandan male with a past medical history of recurrent community acquired pneumonias that progressed into bronchiectasis leading to CPA with an aspergilloma, but was clinically misdiagnosed as PTB with several complications.\n\n2 Case\nIn December 2018 (day 0), we received a 45-year-old Ugandan male who was referred to Mulago National Referral Hospital with symptoms of progressive difficulty in breathing, chronic productive cough, non-exertional left sided chest pain and progressive weight loss occurring over a 12-month period. His cough was productive of mucopurulent sputum without associated haemoptysis. Eight months prior to this admission, he also noted lower limb swelling that was painless but associated with abdominal swelling, easy fatigability, orthopnoea and paroxysmal nocturnal dyspnoea. He was commenced on anti-tuberculous therapy on clinical basis/suspicion despite negative sputum microbiology for PTB and was on third month of continuation phase at the time of admission. He had never smoked, and his routine testing for HIV was negative. He was a non-alcoholic and employed as a pastor/preacher. He had a significant past medical history of previous hospitalisations for recurrent community acquired pneumonia. He had right inguinal herniorrhaphy eight months before this admission.\n\nPhysical examination (day 0) revealed that the patient was a middle-aged man, moderately wasted, with bilateral pitting non-tender pedal oedema, and moderate-pallor without any palpable peripheral lymphadenopathy. He had no digital clubbing neither did he have peripheral or central cyanosis. He had no obvious anatomical chest abnormality, but was in obvious respiratory distress and he had a tachypnoea of 28 breaths per minute. Bronchial breath sounds were auscultated in the left supramammary region with bilateral diffuse coarse crepitations. He had a tachycardia of 110bpm, however, radial pulses were of normal volume and synchronous. There was a loud P2 without a split, raised jugular venous pressure and the point of maximum impulse was at the 5th intercostal space left mid-clavicular line with an apical heave. His abdomen was mildly distended, with a positive shifting dullness and tender hepatomegaly of about 4 cm below the coastal margin. The rest of the examination was essentially normal.\n\nChest computed tomographic (CT) scan (day +1) showed bilateral bronchiectasis, right lower lobe bullae, left upper lobe cavity with a mass and pericavitary fibrosis (Fig. 1). A complete blood count (day +1) done was essentially normal, except for normocytic normochromic anaemia of 10.1g/dl. Urea and creatinine (day +1) were 15.9mg/dl and 1.6mg/dl respectively. He had a serum aspartate transferase and alanine transferase levels of 41.9 IU/L and 19.2 IU/L respectively with a hypoalbulinaemia of 28.6mg/dl. Repeat HIV serology and sputum Gene Xpert MTB/RIF (day +3) were negative. Abdominal ultrasound (day+3) showed moderate ascites, hepatosplenomegaly and normal kidneys. Cardiac echocardiography (day+3) showed moderate pulmonary hypertension and dilated right cardiac chambers. Electrocardiography (day+3) demonstrated sinus tachycardia and features of right atrial enlargement. Chest x-ray was not done since a CT scan was available. With these investigations, based on radiology, we made a diagnosis of CPA with an aspergilloma complicating bronchiectasis post-recurrent community acquired pneumonia, complicated with cor pulmonale (day+3).Fig. 1 Chest CT scan: The scan shows left apical cavitation with visible fungal balls and pericavitary fibrosis.\n\nFig. 1\n\nThe patient was first (day 0) initiated on ceftriaxone 2g once daily in combination with azithromycin 500mg once daily for a presumptive diagnosis of pneumonia as PTB was being ruled out and prior to the confirmation of the diagnosis of CPA. The patient meanwhile continued his anti-TB medication that he came with. After the CPA diagnosis (day+3), he was initiated on oral itraconazole 200mg twice daily for the treatment of CPA, heart failure regime (intravenous frusemide at a dose of 40mg twice daily and oral bisoprolol at a dose of 5mg once daily) and sildenafil 100mg once daily for pulmonary hypertension. Supplemental oxygen therapy was given via nasal prongs to address his hypoxaemia (day +3 to day+14). He also received 2 doses (day +4 and day+5) of intravenous albumin to correct his hypoalbuminaemia. However, he progressively deteriorated and passed on 2 weeks (day +14) after admission possibly due to cardiorespiratory failure. Autopsy was not performed.\n\n3 Discussion\nAccording to a recent publication that aimed to make a unified case definition of CPA in resource-constrained settings [5], CPA is defined by “illness of ≥3 months and all of: 1) weight loss; persistent cough and/or haemoptysis; 2) chest images showing progressive cavitary infiltrates and/or a fungal ball and/or pericavitary fibrosis or infiltrates or pleural thickening; and 3) a positive Aspergillus IgG assay or other evidence of Aspergillus infection”. However, for this case we did not use the third criterion (i.e. a positive Aspergillus IgG assay). Serological diagnosis of CPA is unavailable in our hospital. However, the CT scan was typical for CPA. This report therefore illustrates a classic case of radiologically diagnosed CPA previously misdiagnosed as PTB resulting into complications and eventually death. Detection of Aspergillus antibodies is still an important tool in the diagnosis and management of the patients with pulmonary aspergillosis. However, the detection of Aspergillus-specific antibodies does not imply that the patient has an active fungal disease. A previous study done in Uganda showed that “Aspergillus-specific IgG antibodies were elevated in 4% of HIV-infected Ugandan adults at the start of TB treatment and in 9% at the end of TB treatment” [6].\n\nThe burden of CPA in Africa is not well described. Recent evidence shows that CPA can account for progressive destruction of the lungs and the persistence of pulmonary symptoms after successful completion of TB treatment [4,[6], [7], [8]] and can also mimic smear-negative PTB, as it was the case in this patient. In patients with CPA, creation of new cavities or expansion of existing ones is typical, manifesting with prominent respiratory and/or systemic symptoms. A review done in Uganda showed that “CPA was estimated to affect up to 22% of TB patients with cavities and 4% in those without cavities in Uganda” [9]. Similarly, a recent prospective study done in Uganda showed that 5% of the participants had pulmonary cavities at the end of TB treatment [6]. These cavities can get colonized with fungi to form a fungal ball, which essentially is a biofilm.\n\nThis patient had recurrent community acquired pneumonias that could have predisposed him to bronchiectasis. The recurrent pneumonias together with bronchiectasis could have caused the cavities leading to non-invasive forms of Aspergillus lung disease. The patient developed cor pulmonale as one of the complications. However, there are case reports that have described cor pulmonale before in pulmonary aspergillosis among immunocompetent Africans [10].\n\nConflict of interest\nThere are none.\n\nAcknowledgements\nThis case was presented as a poster at the 1st international lung science symposium and Makerere University Lung Institute inauguration in April 2019. RK is currently supported through the DELTAS Africa Initiative grant # DEL-15-011 to THRiVE-2, from Wellcome Trust grant # 107742/Z/15/Z and the UK Government.\n==== Refs\nReferences\n1 Denning D.W. Riniotis K. Dobrashian R. Sambatakou H. Chronic cavitary and Fibrosing pulmonary and pleural aspergillosis: case series, proposed nomenclature change, and review Clin. Infect. Dis. 37 2003 S265 S280 12975754 \n2 Hayes G.E. Denning D.W. Frequency, diagnosis and management of fungal respiratory infections Curr. Opin. Pulm. Med. 19 3 2013 259 265 23411576 \n3 Bongomin F. Gago S. Oladele R.O. Denning D.W. Global and multi-national prevalence of fungal diseases—estimate precision J. Fungi 3 4 2017 57 \n4 Denning D.W. Pleuvry A. Cole D.C. Global burden of chronic pulmonary aspergillosis as a sequel to pulmonary tuberculosis Bull. World Health Organ. 89 12 2011 864 872 22271943 \n5 Denning D.W. Page I.D. Chakaya J. Jabeen K. Jude C.M. Cornet M. Case definition of chronic pulmonary aspergillosis in resource-constrained settings Emerg. Infect. Dis. 24 8 2018 \n6 Kwizera R. Parkes-Ratanshi R. Page I.D. Sekaggya-Wiltshire C. Musaazi J. Fehr J. Elevated Aspergillus-specific antibody levels among HIV infected Ugandans with pulmonary tuberculosis BMC Pulm. Med. 17 1 2017 149 29162063 \n7 Page I. Worodria W. Andama A. Ayakaka I. Kwizera R. Davis L. Onset of chronic pulmonary aspergillosis (CPA) may occur during active pulmonary tuberculosis 7th Advances against Aspergillosis Conference; 3-5 March 2016; Manchester UK 2016 p. abstract No: 100 \n8 Page I.D. Byanyima R. Hosmane S. Onyachi N. Opira C. Richardson M. Chronic pulmonary aspergillosis commonly complicates treated pulmonary tuberculosis with residual cavitation Eur. Respir. J. 53 3 2019 1801184 30705126 \n9 Parkes‐Ratanshi R. Achan B. Kwizera R. Kambugu A. Meya D. Denning D. Cryptococcal disease and the burden of other fungal diseases in Uganda; where are the knowledge gaps and how can we fill them? Mycoses 58 S5 2015 85 93 26449512 \n10 Garko S. Ekweani C. Okpe I. Pulmonary Aspergillosis Presenting as Cor-Pulmonale in an Immunocompetent Nigerian Man: a Case Report 2002\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2211-7539",
"issue": "25()",
"journal": "Medical mycology case reports",
"keywords": "Chronic pulmonary aspergillosis; Cor pulmonale; Itraconazole; Recurrent community acquired pneumonia; Uganda",
"medline_ta": "Med Mycol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101598259",
"other_id": null,
"pages": "22-24",
"pmc": null,
"pmid": "31333999",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports",
"references": "12975754;22271943;23411576;26449512;29162063;29371573;30016256;30705126",
"title": "Cor pulmonale complicating chronic pulmonary aspergillosis with fatal consequences: Experience from Uganda.",
"title_normalized": "cor pulmonale complicating chronic pulmonary aspergillosis with fatal consequences experience from uganda"
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{
"companynumb": "UG-ALKEM LABORATORIES LIMITED-UG-ALKEM-2019-07951",
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"activesubstancename": "AZITHROMYCIN ANHYDROUS"
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"abstract": "We report a case of coronary artery spasm documented with angiography in a patient with severe chest pain, electrocardiographic ST-segment elevations and highly elevated troponin I. Symptom onset was 15 min after the patient's first-ever intake of losartan. Although parts of the clinical presentation suggested allergy or anaphylaxis, laboratory testing did not support this.",
"affiliations": "Department of Cardiology, University Hospital of Örebro, Örebro, Sweden. johan.josefsson@orebroll.se",
"authors": "Josefsson|Johan|J|;Fröbert|Ole|O|",
"chemical_list": "D000959:Antihypertensive Agents; D019808:Losartan",
"country": "England",
"delete": false,
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"mesh_terms": "D000959:Antihypertensive Agents; D003329:Coronary Vasospasm; D003331:Coronary Vessels; D005260:Female; D006801:Humans; D019808:Losartan; D008875:Middle Aged",
"nlm_unique_id": "101526291",
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"pmid": "23093500",
"pubdate": "2012-10-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "1793697;20159412;20726206;9609137",
"title": "Losartan-induced coronary artery spasm.",
"title_normalized": "losartan induced coronary artery spasm"
} | [
{
"companynumb": "SE-IPCA LABORATORIES LIMITED-IPC201303-000093",
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"abstract": "Second-generation antipsychotics are utilized extensively in the treatment of psychotic disorders and other psychiatric conditions, but the effects of these medications on human brain white matter are not well understood. We thus investigated the effects of second-generation antipsychotics on white matter integrity using tract-based spatial statistics in patients experiencing a first episode of psychosis with little or no prior antipsychotic exposure, and how potential changes were associated with metabolic side effects. Thirty-five (26 men/9 women) patients experiencing a first episode of psychosis received diffusion tensor imaging (DTI) exams, clinical assessments, and provided fasting blood samples at the onset of antipsychotic treatment, and then again after 12 weeks of treatment with either risperidone or aripiprazole in a double-blind randomized clinical trial. In addition, 35 (26 men/9 women) healthy volunteers received DTI exams at a baseline time point and then after 12 weeks. Patients demonstrated significant (p<0.05; family-wise error corrected) fractional anisotropy reductions within the parietal and occipital white matter following antipsychotic treatment. Greater overall fractional anisotropy reduction was significantly correlated with greater increases in low-density lipoprotein. There were no significant fractional anisotropy increases among patients following treatment. Moreover, healthy volunteers did not demonstrate either significant increases or decreases in fractional anisotropy across a comparable 12-week interval. The use of antipsychotics may be associated with a subtle loss of white matter integrity that is related to greater side effects, thus raising potentially important considerations regarding risk/benefit in their usage. Limitations of the current study, however, include a prior history of substance use among patients and our inability to exclude the possibility of disease progression.",
"affiliations": "1] Center for Psychiatric Neuroscience, The Feinstein Institute for Medical Research, Manhasset, NY, USA [2] Division of Psychiatry Research, Zucker Hillside Hospital, North Shore-LIJ Health System, Glen Oaks, NY, USA [3] Department of Communication Sciences and Disorders, School of Applied Sciences, University of Mississippi, University, MS, USA.;1] Center for Psychiatric Neuroscience, The Feinstein Institute for Medical Research, Manhasset, NY, USA [2] Division of Psychiatry Research, Zucker Hillside Hospital, North Shore-LIJ Health System, Glen Oaks, NY, USA [3] Department of Communication Sciences and Disorders, School of Applied Sciences, University of Mississippi, University, MS, USA.;Departments of Psychiatry and Molecular Medicine, Hofstra North Shore-LIJ School of Medicine, Hempstead, NY, USA.;1] Center for Psychiatric Neuroscience, The Feinstein Institute for Medical Research, Manhasset, NY, USA [2] Division of Psychiatry Research, Zucker Hillside Hospital, North Shore-LIJ Health System, Glen Oaks, NY, USA.;1] Center for Psychiatric Neuroscience, The Feinstein Institute for Medical Research, Manhasset, NY, USA [2] Division of Psychiatry Research, Zucker Hillside Hospital, North Shore-LIJ Health System, Glen Oaks, NY, USA [3] Department of Communication Sciences and Disorders, School of Applied Sciences, University of Mississippi, University, MS, USA.;1] Center for Psychiatric Neuroscience, The Feinstein Institute for Medical Research, Manhasset, NY, USA [2] Division of Psychiatry Research, Zucker Hillside Hospital, North Shore-LIJ Health System, Glen Oaks, NY, USA [3] Department of Communication Sciences and Disorders, School of Applied Sciences, University of Mississippi, University, MS, USA.;1] Center for Psychiatric Neuroscience, The Feinstein Institute for Medical Research, Manhasset, NY, USA [2] Division of Psychiatry Research, Zucker Hillside Hospital, North Shore-LIJ Health System, Glen Oaks, NY, USA [3] Department of Communication Sciences and Disorders, School of Applied Sciences, University of Mississippi, University, MS, USA.",
"authors": "Szeszko|Philip R|PR|;Robinson|Delbert G|DG|;Ikuta|Toshikazu|T|;Peters|Bart D|BD|;Gallego|Juan A|JA|;Kane|John|J|;Malhotra|Anil K|AK|",
"chemical_list": "D014150:Antipsychotic Agents; D008077:Lipoproteins, LDL; D010879:Piperazines; D015363:Quinolones; D000068180:Aripiprazole; D018967:Risperidone",
"country": "England",
"delete": false,
"doi": "10.1038/npp.2013.288",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0893-133X",
"issue": "39(6)",
"journal": "Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology",
"keywords": null,
"medline_ta": "Neuropsychopharmacology",
"mesh_terms": "D016880:Anisotropy; D014150:Antipsychotic Agents; D000068180:Aripiprazole; D001921:Brain; D056324:Diffusion Tensor Imaging; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008077:Lipoproteins, LDL; D008137:Longitudinal Studies; D008297:Male; D009413:Nerve Fibers, Myelinated; D009778:Occipital Lobe; D010296:Parietal Lobe; D010879:Piperazines; D011618:Psychotic Disorders; D015363:Quinolones; D018967:Risperidone; D055815:Young Adult",
"nlm_unique_id": "8904907",
"other_id": null,
"pages": "1324-31",
"pmc": null,
"pmid": "24549105",
"pubdate": "2014-05",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "16413757;22119061;10197834;16027736;21084552;22555017;17151160;21300943;23558741;17407804;20455859;17581532;16319302;22009159;18501637;23442742;21705426;19715613;18694971;14642481;18558643;15964176;17684494;19616412;16150576;21839137;15862213;22139809;16624579;21979382;23172976;21183934;18188754;15741480;17070705;14764421;15756305;23512884;15793579;22740320;17945195;15254070;11264981;15809403;21105275;21721915;22438182;21767934;20237131;12414282;16280340",
"title": "White matter changes associated with antipsychotic treatment in first-episode psychosis.",
"title_normalized": "white matter changes associated with antipsychotic treatment in first episode psychosis"
} | [
{
"companynumb": "US-JNJFOC-20140417030",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
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... |
{
"abstract": "Background Antipsychotic polypharmacy (\"polypharmacy\") is the concurrent prescribing of more than one antipsychotic. It is widely practised, as reported in the literature, and is known to increase the risk of adverse outcomes for patients. Objective To quantify the prevalence and magnitude of polypharmacy in patients with schizophrenia or schizoaffective disorder and identify potential factors contributing to this practice. Setting Armadale Mental Health Service (a public inpatient and outpatient psychiatric facility in Perth, Western Australia). Method A retrospective, cross-sectional study was conducted, evaluating the medical records of adult (18-64 years old) patients fulfilling the established inclusion criteria in the period between August and December 2016. Data collected included the number and doses of antipsychotic(s) prescribed and documented rationale for polypharmacy. Defined daily doses and proportions of maximum licensed daily doses were calculated for all regularly prescribed antipsychotics and were evaluated as measures of antipsychotic load. Main Outcome Measure The percentage prevalence of antipsychotic polypharmacy; defined daily antipsychotic doses and proportions of maximum licensed daily doses. Results Seventy-seven patients were assessed, with a polypharmacy prevalence of 39.0%. Total defined daily doses ranged from 0.9 to 5.9 and maximum licensed daily doses from 0.4 to 2.3. Documented rationales for polypharmacy included poor symptom control, patient's preference, hesitancy to amend other prescribers' management plans, off-label antipsychotic indications and medication cross-titration. Conclusion Antipsychotic polypharmacy occurred in more than one-third of patients. Individual antipsychotics were typically prescribed at doses within the licensed range, however, the total proportion of combined maximum licensed doses and combined daily defined doses often exceeded 100%. Due to suboptimal documentation, prescribing rationale was unclear in the majority of cases. The magnitude of polypharmacy aims to foster a greater appreciation of the prescribed antipsychotic load, increasing clinician self-awareness of prescribing practices and facilitating future opportunities to optimise prescribing.",
"affiliations": "School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, GPO Box U1987, Perth, WA, 6845, Australia. mylinh.nguyen@postgrad.curtin.edu.au.;School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, GPO Box U1987, Perth, WA, 6845, Australia.;School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, GPO Box U1987, Perth, WA, 6845, Australia.;School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, GPO Box U1987, Perth, WA, 6845, Australia.;School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, GPO Box U1987, Perth, WA, 6845, Australia.",
"authors": "Nguyen|My Linh|ML|http://orcid.org/0000-0001-9175-7049;Sunderland|Bruce|B|;Lim|Stephen|S|;Hattingh|Laetitia|L|;Chalmers|Leanne|L|",
"chemical_list": "D014150:Antipsychotic Agents",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s11096-019-00930-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "41(6)",
"journal": "International journal of clinical pharmacy",
"keywords": "Antipsychotic load; Australia; Defined daily doses; Polypharmacy; Schizoaffective disorder; Schizophrenia",
"medline_ta": "Int J Clin Pharm",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D003430:Cross-Sectional Studies; D004282:Documentation; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019338:Polypharmacy; D010818:Practice Patterns, Physicians'; D015995:Prevalence; D011618:Psychotic Disorders; D012189:Retrospective Studies; D012559:Schizophrenia; D055815:Young Adult",
"nlm_unique_id": "101554912",
"other_id": null,
"pages": "1642-1651",
"pmc": null,
"pmid": "31677120",
"pubdate": "2019-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The hidden magnitude of polypharmacy: using defined daily doses and maximum licensed daily doses to measure antipsychotic load.",
"title_normalized": "the hidden magnitude of polypharmacy using defined daily doses and maximum licensed daily doses to measure antipsychotic load"
} | [
{
"companynumb": "US-OTSUKA-2019_041884",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "Soft tissue sarcoma is a rare neoplasm of mesenchymal origin, accounting for only ~1% of all adult cancers and consisting of 75 histological subtypes. In the present report, the unique case of a 14 year-old female with metastatic malignant peripheral nerve sheath tumor (formerly, malignant melanotic schwannoma) of the parotid gland, who experienced a durable response and sustained tumor control with Rexin-G®, a tumor-targeted retroviral expression vector encoding an anti-cyclin G1 construct, is described. Post-parotidectomy, and prior to the administration of Rexin-G®, the patient received various chemotherapy regimens, including doxorubicin, ifosfamide, temozolomide, sorafenib, and an immunological therapy with interleukin-2, which only resulted in the further progression of lung metastases. The patient subsequently participated in a Phase 1/2 gene therapy study, during which she received intravenous Rexin-G® as monotherapy for two years with minimal drug-associated adverse events. Currently, the patient has no evidence of active disease 9 years after commencing the Rexin-G® treatment, and with no additional anti-cancer therapy. In conclusion, Rexin-G® may be a viable therapeutic option for malignant peripheral nerve sheath tumors, and should be further investigated in prospective histology-specific clinical trials for this type, and possibly other types, of chemotherapy-resistant sarcoma.",
"affiliations": "Sarcoma Oncology Center/Cancer Center of Southern California, Santa Monica, CA 90403, USA.;Department of Pediatrics, Division of Pediatric Hematology/Oncology, Mattel Children's Hospital at UCLA, Los Angeles, CA 90095, USA.;Sarcoma Oncology Center/Cancer Center of Southern California, Santa Monica, CA 90403, USA.;Counterpoint Biomedica LLC, Santa Monica, CA 90403, USA.;Sarcoma Oncology Center/Cancer Center of Southern California, Santa Monica, CA 90403, USA.",
"authors": "Kim|Seth|S|;Federman|Noah|N|;Gordon|Erlinda M|EM|;Hall|Frederick L|FL|;Chawla|Sant P|SP|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3892/mco.2017.1231",
"fulltext": "\n==== Front\nMol Clin OncolMol Clin OncolMCOMolecular and Clinical Oncology2049-94502049-9469D.A. Spandidos 10.3892/mco.2017.1231MCO-0-0-1231ArticlesRexin-G®, a tumor-targeted retrovector for malignant peripheral nerve sheath tumor: A case report Kim Seth 1Federman Noah 2Gordon Erlinda M. 13Hall Frederick L. 3Chawla Sant P. 11 Sarcoma Oncology Center/Cancer Center of Southern California, Santa Monica, CA 90403, USA2 Department of Pediatrics, Division of Pediatric Hematology/Oncology, Mattel Children's Hospital at UCLA, Los Angeles, CA 90095, USA3 Counterpoint Biomedica LLC, Santa Monica, CA 90403, USACorrespondence to: Dr Erlinda M. Gordon, Sarcoma Oncology Center/Cancer Center of Southern California, 2811 Wilshire Boulevard, Suite 414, Santa Monica, CA 90403, USA, E-mail: erlinda.gordon@gmail.com6 2017 28 4 2017 28 4 2017 6 6 861 865 08 12 2016 29 3 2017 Copyright: © Kim et al.2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.Soft tissue sarcoma is a rare neoplasm of mesenchymal origin, accounting for only ~1% of all adult cancers and consisting of 75 histological subtypes. In the present report, the unique case of a 14 year-old female with metastatic malignant peripheral nerve sheath tumor (formerly, malignant melanotic schwannoma) of the parotid gland, who experienced a durable response and sustained tumor control with Rexin-G®, a tumor-targeted retroviral expression vector encoding an anti-cyclin G1 construct, is described. Post-parotidectomy, and prior to the administration of Rexin-G®, the patient received various chemotherapy regimens, including doxorubicin, ifosfamide, temozolomide, sorafenib, and an immunological therapy with interleukin-2, which only resulted in the further progression of lung metastases. The patient subsequently participated in a Phase 1/2 gene therapy study, during which she received intravenous Rexin-G® as monotherapy for two years with minimal drug-associated adverse events. Currently, the patient has no evidence of active disease 9 years after commencing the Rexin-G® treatment, and with no additional anti-cancer therapy. In conclusion, Rexin-G® may be a viable therapeutic option for malignant peripheral nerve sheath tumors, and should be further investigated in prospective histology-specific clinical trials for this type, and possibly other types, of chemotherapy-resistant sarcoma.\n\ntargeted gene therapy vectorcell cycle controlmetastatic sarcoma\n==== Body\nIntroduction\nMalignant peripheral nerve sheath tumor (MPNST; formerly, melanotic schwannoma) is a rare neoplasm of Schwann cell origin capable of melanogenesis (1,2). Clinicopathologically, it is considered a distinct entity from conventional schwannoma due to genetic and clinical differences (3). Immunophenotypic indicators for schwannomas with melanotic differentiation include the presence of epitheloid cells with variably sized nuclei, and a marked accumulation of melanin (2), but differential diagnosis typically requires further analysis through ultrastructural and immunohistochemical testing. In terms of clinical management, it is of paramount importance to distinguish primary melanin-containing lesions from malignant melanoma in order to plan an appropriate therapeutic approach.\n\nCase report\nA 14 year-old female initially presented with a non-painful swelling of the right posterior mandible with right facial weakness. A magnetic resonance imaging (MRI) scan of the face and neck revealed a 5.3 cm mass of the right parotid gland, and a chest computed tomography (CT) scan revealed several small, non-specific opacities in the upper right lobe. A histopathological examination performed by core needle biopsy revealed a malignant melanotic spindle cell neoplasm, with atypical spindle cell proliferation arranged in a fascicular pattern. The tumor was histologically and immunophenotypically consistent with MPNST. The patient underwent a right radical parotidectomy and a right modified radical neck dissection with reconstructive surgery. Note was made of the extension of the neoplasm into the soft tissues around the parotid gland with perineural invasion. Immunohistochemical analysis confirmed the diagnosis, with the involvement of three out of eight tumorous lymph nodes staining positive for laminin, homatropine methylbromide 45 (HMB-45), and tyrosinase, and negative for melanoma-associated antigen recognized by T cells (MART-1) and S-100 protein. In March 2007, the patient started chemotherapy with temozolomide (75 mg/m2 given orally, daily for 45 days), and in April 2007, sorafenib (40 mg by mouth, twice daily), due to the increased sizes of nine lung lesions. In spite of these treatments, however, a repeat positron emission tomography (PET)/CT scan in June 2007 revealed diffuse progression in the lungs, thighs, and left flank. The patient was admitted for treatment with high-dose interleukin-2, but only received 7 of 14 doses due to unacceptable toxicity and disease progression. After three cycles of ifosfamide (1,800 mg/m2/day for 5 days) as continuous infusion with mesna, and doxorubicin (37.5 mg/m2/day intravenously for 2 days), a repeat PET/CT scan revealed further tumor progression; therefore, the chemotherapy was discontinued.\n\nIn March 2008, the patient participated in a Phase 1/2 clinical trial using intravenous Rexin-G® (developed at the USC Keck School of Medicine, Los Angeles, CA, USA) for advanced chemoresistant sarcoma (clinical trial protocol no. NCT00505713; see Table I). The patient received dose level 3 of Rexin-G® [3×10e11 colony-forming units (cfu)] three times a week as an outpatient. Objective tumor responses were evaluated by a number of parameters, including Response Evaluation Criteria In Solid Tumors (RECIST) v1 (4), tumor volume, mm3 (length × width2 × 0.52), tumor density in Hounsfeld units (HU) and the maximum standardized uptake value (SUVmax) by fluorodeoxyglucose (18-FDG) PET-CT (4,5). Based on the RECIST v1 and other radiological parameters, the patient experienced sustained disease control (Fig. 1). The patient's clinical course was complicated by an episode of nephrotic syndrome, which was attributed to the bi-weekly subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF) injections, and therefore these were discontinued. The patient received a total of 205 Rexin-G® vector infusions over a 2-year period with minimal toxicity and no serious adverse events. Following the last infusion in June 2010, the patient underwent a PET/CT scan, comparing the results with those images taken prior to treatment. The radiology report stated that there was a marked overall improvement in the patient's pulmonary metastases, with all but one nodule being either markedly improved in size, or resolved. It was also noted that the right pleural effusion and previous significant ascites had been resolved. Currently, nine years after commencing the Rexin-G® treatment, the patient is alive and well, with no evidence of active neoplastic disease.\n\nDiscussion\nPeripheral nerve sheath tumor (PNST) is a rare subset of soft tissue sarcomas displaying an immunophenotype consistent with that of conventional schwannomas, along with cytoplasmic melanin deposition characteristic of melanomas (3,6,7). These tumors occur most frequently at nerve roots, although other locations along the peripheral nervous system have been described (8). Tumors originating from the bone, soft tissues, heart, mouth, esophagus, bronchus, retroperitoneum, uterine cervix, orbit, parotid gland, as well as the spinal cord, acoustic nerve, cerebellum, and sympathetic chain, have been reported (1,9). Statistics have revealed a 1.1:1 male: female ratio (9). The ages of those afflicted vary between 10 and 84 years (7,9), although the peak incidence occurs with patients in their fourth decade (7). There have been fewer than 200 cases of PNST reported since it was first described in 1932 (10,11), with approximately 40 reported malignancies as of 2014 (12). To date, there have been no published cases of MPNST originating from the parotid gland. Therefore, this case is unique and worthy of report, particularly with respect to the patient's impressive response to an innovative tumor-targeted gene therapy vector, designated Rexin-G®.\n\nTo make a differential diagnosis between MPNST and spindle cell melanoma is very difficult, particularly in small biopsy specimens, due to the diverse range of tumor derivations from a Schwann cell lineage (13) and similar histological features, including cell pleomorphisms with prominent nucleoli (1). In the present case study, immunohistochemical staining and ultrastructural examinations proved to be useful in guiding the diagnostic process. All reported cases of MPNST, including the present patient's case, have revealed positive gene expression of HMB-45 and tyrosinase, indicative of melanocytic differentiation, but negative expression of MART-1 and S-100 protein, thereby eliminating a diagnosis of melanoma (14). Further studies for the expression of laminin, which was displayed intensely in two-thirds of the reported cases (15), concluded that the tumor represented a Schwannian differentiation, based on the biphasic pattern (i.e. individual cell and nested) in the external lamina.\n\nThe prognosis for PNST is unpredictable at best, with 10% of all cases developing metastasis (8,10,14). Although generally considered benign, the tumor is prone to malignancy and recurrence, occurring in ~20% of patients (1,8,16). Surgery has been the primary treatment option (9), followed by radiation therapy or adjuvant chemotherapy. For the patient described in the present case report, a right parotidectomy was performed, and systemic chemotherapy was administered post-surgery to treat the metastatic lung lesions, albeit without success.\n\nRexin-G® is the first tumor-targeted gene therapy vector that has been tested in the clinic (4). Injected intravenously, the targeted retroviral particles operate within the vascular system via a high-affinity collagen-binding motif derived from von Willebrand coagulation factor (17). Atypical amounts of exposed collagenous (XC) proteins are located in areas of tumor invasion, neoangiogenesis and stroma formation, possibly resulting from exposure to protease activity within the tumor microenvironment (TME; Fig. 2). Rexin-G® accumulates in these metastatic deposits by seeking out the abnormal XC proteins, thereby increasing effective vector concentration in the TME in close association with the cancer cells. The function of the genetic payload (a dominant negative cyclin G1 construct is encoded in Rexin-G®) is to halt the G1 phase of the cell cycle, thus inducing cell death via apoptosis-mediated pathways (Fig. 3) (17–20).\n\nBased on a critical evaluation of its safety and potential efficacy, as well as the unmet medical need, Rexin-G® was granted Orphan Drug status for soft tissue sarcoma and osteosarcoma by the US Food and Drug Administration (FDA) in 2008 (21); and in 2010, Phase 1 and Phase 2 clinical trials using Rexin-G® for chemotherapy-resistant soft tissue sarcoma and osteosarcoma, respectively, were successfully completed (5,21). The results of these studies demonstrated the overall safety and, in clinical trials for sarcoma and pancreatic cancer, the dose-dependent efficacy in controlling tumor growth and improving survival rates with the use of Rexin-G®, particularly at the higher dose levels (Table I). Accordingly, long-term survival follow-up (up to 15 years post-treatment) is required by the US FDA for investigational gene therapy products; to date, there have been no reports of delayed or late adverse events associated with Rexin-G® treatment.\n\nIn summary, in the present report, the unique case of a 14 year-old patient with widely metastatic MPNST of the parotid gland, who experienced a durable response and sustained tumor control (and minimal toxicity) with an innovative therapy treatment of Rexin-G®, an XC-/tumor-targeted retrovector bearing a cytocidal gene construct, is described. On the basis of these results, the continued development of Rexin-G® for this rare type of mesenchymal cancer, and potentially other chemoresistant sarcomas, is highly recommended.\n\nAcknowledgements\nThe authors are grateful to Heather C. Gordon (Art Consultant, Sarcoma Oncology Center, Santa Monica, CA, USA) for graphic illustrations and editorial assistance in the writing of this manuscript (see www.heathergordondrawings.com).\n\nAbbreviations\nCTcomputed tomography\n\nMRImagnetic resolution imaging\n\nMPNSTmalignant peripheral nerve sheath tumor\n\nPNSTperipheral nerve sheath tumor\n\nPETpositron emission tomography\n\nGM-CSFgranulocyte-macrophage colony-stimulating factor\n\nXCexposed collagenous\n\nTMEtumor microenvironment\n\nFigure 1. Various tumor parameters of the patient monitored over time. (A) Individual tumor volume measurements over time. Tumor volumes of individual target lesions (measured by CT imaging), in mm3, were calculated using O'Reilly's formula (length × width2 × 0.52). (B) Individual tumor density measurements over time. Tumor densities of individual target lesions, in HU, were calculated by radiographic image analysis. (C) Individual FDG avidity measurements over time. Avidities of individual target lesions for 18-FDG (SUVmax) were measured in individual target lesions using a PET/CT scan. CT, computed tomography; PET, positron emission tomography; HU, Hounsfeld units; FDG, fluorodeoxyglucose; SUVmax, maximum standardized uptake value.\n\nFigure 2. Illustration of the tumor microenvironment compared with normal tissues. (A) Normal tissue. (B) The XC-targeting motif enables the vector to seek out and accumulate in the tumor microenvironment by binding to abnormally exposed proteins found abundantly in tumors, e.g., as a result of tumor invasion, ECM remodeling and neoangiogenesis, but not in normal tissues. Xc, exposed collagenous; ECM, extracellular matrix.\n\nFigure 3. An illustration of the mechanism of action of Rexin-G®. The Rexin-G® nanoparticle displays an XC-targeting motif, derived from the coagulation factor, vWF, on its surface amphotropic gp70 envelope protein. When injected intravenously, Rexin-G® seeks out and accumulates in cancerous lesions by binding to exposed collagenous (XC) proteins. This chimeric retrovector has the innate property of binding to a tumor's natural viral/cell receptor, fusing, entering, uncoating, and integrating randomly into the chromosomes of only actively dividing cells (i.e., cancer cells). This selective property spares all terminally differentiated and/or non-replicative cells of normal organs, including hepatocytes, neuronal cells and myocardial cells. Rexin-G® carries a cytocidal dominant negative cyclin G1 construct, which causes cell death via apoptosis. vWF, von Willebrand factor; XC, exposed collagenous.\n\nTable I. USA-based clinical trials using tumor-targeted Rexin-G® for chemotherapy-resistant solid malignancies.\n\nClinical trial protocol number/dose levela\tClinical site(s)/Phase\tClinical indication\tNo. of patients\tOutcome\t\nNCT00121745; dose level, minus 3-minus 1\tRochester, MN, USA: Phase 1\tPancreas CA\t12\t0% 1-year OS\t\nNCT00504998b; dose level, 1–3\tSanta Monica, CA, USA/Manhattan, NY, USA/(Duke) Durham, NC, USA: Phase 1/2\tPancreas CA\t20\t26.7% 1-year OS 13.3% 2-year OS 1 alive in sustained remission, 9-year OS\t\nNCT00505713b; dose level, 1–4\tSanta Monica, CA, USA: Phase 1/2\tBone and soft tissue sarcoma\t36\t38.5% 1-year OS; 31% 2-year OS 1 alive with no active disease, 9-year OS\t\nNCT00505271; dose level, 1–4\tSanta Monica, CA, USA/Manhattan, NY, USA: Phase 1/2\tBreast CA\t20\t60% 1-year OS\t\nNCT00572130; dose level, 1–2\tSanta Monica, CA, USA: Phase 2\tOsteosarcoma\t22\t27.3% 1-year OS 22.7% 2-year OS 1 alive in sustained remission, 8 years\t\na Dose levels were calculated as follows: Dose level 1=1×10e11 cfu; dose level 2=2×10e11 cfu; dose level 3=3×10e11 cfu; and dose level 4=4×10e11 cfu.\n\nb A randomization test on the log-rank statistic using 20,000 random samples revealed a dose-response association between overall survival and the Rexin-G dosage (P=0.002 for sarcoma and 0.04 for pancreas cancer). Analysis was done using NCSS software (Number Cruncher Statistical Systems, Kaysville, UT, USA). Statistical analysis was performed by a biostatistician who was not otherwise involved in the study. CA, carcinoma; cfu colony forming units; OS, overall survival.\n==== Refs\nReferences\n1 Vallat-Decouvelaere AV Wassef M Lot G Catala M Moussalam M Caruel N Mikol J Spinal melanotic schwannoma: A tumour with poor prognosis Histopathology 35 558 566 1999 10.1046/j.1365-2559.1999.00786.x 10583580 \n2 Rodriguez FJ Folpe AL Giannini C Perry A Pathology of peripheral nerve sheath tumors: Diagnostic overview and update on selected diagnostic problems Acta Neuropathol 123 295 319 2012 10.1007/s00401-012-0954-z 22327363 \n3 Louis DN Perry A Reifenberger G von Deimling A Figarella-Branger D Cavenee WK Ohgaki H Wiestler OD Kleihues P Ellison DW The 2016 world health organization classification of tumors of the central nervous system: A summary Acta Neuropathol 131 803 820 2016 10.1007/s00401-016-1545-1 27157931 \n4 Chawla SP Chawla NS Quon D Chua-Alcala V Blackwelder WC Hall FL Gordon EM An advanced phase 1/2 study using an XC-targeted gene therapy vector for chemotherapy resistant sarcoma Sarcoma Res Int 3 1024 2016 \n5 Gordon EM Cornelio GH Lorenzo CC III Levy JP Reed RA Liu L Hall FL First clinical experience using a ‘pathotropic’ injectable retroviral vector (Rexin-G) as intervention for stage IV pancreatic cancer Int J Oncol 24 177 185 2004 14654955 \n6 Er U Kazanci A Eyriparmak T Yigitkanli K Senveli E Melanotic schwannoma J Clin Neurosci 14 676 678 2007 10.1016/j.jocn.2006.03.010 17532504 \n7 Kurtkaya-Yapicier O Scheithauer B Woodruff JM The pathobiologic spectrum of Schwannomas Histol Histopathol 18 925 934 2003 12792904 \n8 Welling LC Guirado VM Tessari M Felix AR Zanellato C Figueiredo EG Taricco MA Teixeira MJ Spinal melanotic schwannomas Arq Neuropsiquiatr 70 156 157 2012 10.1590/S0004-282X2012000200018 22311225 \n9 Faria MH Dória-Netto RH Osugue GJ Lde S Queiroz Chaddad-Neto FE Melanotic schwannoma of the cervical spine progressing with pulmonary metastasis: Case report Neurol Med Chir (Tokyo) 53 712 716 2013 10.2176/nmc.cr2012-0203 24077273 \n10 Pan SY Cheng YC Kao TH Intramedullary melanotic schwannoma: Case report and review of the literature Surg Neurol Int 5 Suppl 4 S181 S184 2014 10.4103/2152-7806.136742 \n11 Khoo M Pressney I Hargunani R Tirabosco R Melanotic schwannoma: An 11-year case series Skeletal Radiol 45 29 34 2016 10.1007/s00256-015-2256-8 26386847 \n12 Torres-Mora J Dry S Li X Binder S Amin M Folpe AL Malignant melanotic schwannian tumor: A clinicopathologic, immunohistochemical, and gene expression profiling study of 40 cases, with a proposal for the reclassification of ‘melanotic schwannoma’ Am J Surg Pathol 38 94 105 2014 10.1097/PAS.0b013e3182a0a150 24145644 \n13 Röhrich M Koelsche C Schrimpf D Capper D Sahm F Kratz A Reuss J Hovestadt V Jones DT Bewerunge-Hudler M Methylation-based classification of benign and malignant peripheral nerve sheath tumors Acta Neuropathol 131 877 887 2016 10.1007/s00401-016-1540-6 26857854 \n14 Küsters-Vandevelde HV van Engen-van Grunsven IA Küsters B van Dijk MR Groenen PJ Wesseling P Blokx WA Improved discrimination of melanotic schwannoma from melanocytic lesions by combined morphological and GNAQ mutational analysis Acta Neuropathol 120 755 764 2010 10.1007/s00401-010-0749-z 20865267 \n15 Huang HY Park N Erlandson RA Antonescu CR Immunohistochemical and ultrastructural comparative study of external lamina structure in 31 cases of cellular, classical, and melanotic schwannomas Appl Immunohistochem Mol Morphol 12 50 58 2004 10.1097/00129039-200403000-00010 15163020 \n16 Killeen RM Davy CL Bauserman SC Melanocytic schwannoma Cancer 62 174 183 1988 10.1002/1097-0142(19880701)62:1<174::AID-CNCR2820620127>3.0.CO;2-G 3289725 \n17 Hall FL Liu L Zhu NL Stapfer M Anderson WF Beart RW Gordon EM Molecular engineering of matrix-targeted retroviral vectors incorporating a surveillance function inherent in von Willebrand factor Hum Gene Ther 11 983 993 2000 10.1089/10430340050015293 10811227 \n18 Chawla SP Chua VS Fernandez L Quon D Blackwelder WC Gordon EM Hall FL Advanced phase I/II studies of targeted gene delivery in vivo: Intravenous Rexin-G for gemcitabine-resistant metastatic pancreatic cancer Mol Ther 18 435 441 2010 10.1038/mt.2009.228 19826403 \n19 Gordon EM Levy JP Reed RA Petchpud WN Liu L Wendler CB Hall FL Targeting metastatic cancer from the inside: A new generation of targeted gene delivery vectors enables personalized cancer vaccination in situ Int J Oncol 33 665 675 2008 18813779 \n20 Gordon EM Lopez FF Cornelio GH Lorenzo CC III Levy JP Reed RA Liu L Bruckner HW Hall FL Pathotropic nanoparticles for cancer gene therapy Rexin-G IV: Three-year clinical experience Int J Oncol 29 1053 1064 2006 17016635 \n21 Gordon EM Hall FL Rexin-G, a targeted genetic medicine for cancer Expert Opin Biol Ther 10 819 832 2010 10.1517/14712598.2010.481666 20384524\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2049-9450",
"issue": "6(6)",
"journal": "Molecular and clinical oncology",
"keywords": "cell cycle control; metastatic sarcoma; targeted gene therapy vector",
"medline_ta": "Mol Clin Oncol",
"mesh_terms": null,
"nlm_unique_id": "101613422",
"other_id": null,
"pages": "861-865",
"pmc": null,
"pmid": "28588778",
"pubdate": "2017-06",
"publication_types": "D016428:Journal Article",
"references": "27157931;26857854;19826403;18813779;20865267;10583580;10811227;3289725;22327363;15163020;17532504;26386847;20384524;22311225;14654955;24145644;17016635;12792904;24077273",
"title": "Rexin-G®, a tumor-targeted retrovector for malignant peripheral nerve sheath tumor: A case report.",
"title_normalized": "rexin g a tumor targeted retrovector for malignant peripheral nerve sheath tumor a case report"
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"abstract": "To report preliminary outcomes of a case series of in-office intralesional steroid injections for treatment of laryngeal sarcoidosis.\nAfter diagnosis of laryngeal sarcoidosis, 3 patients were offered in-office steroid injections for primary or adjunctive treatment. Triamcinolone 40 was injected into supraglottic sarcoidosis lesions in the office using a channel laryngoscope. Response to treatment and need for further injections was determined based on patient symptoms and repeat flexible laryngoscopy.\nIn-office intralesional steroid injections provided rapid symptom relief within days that lasted for months, thus decreasing the frequency of operative interventions. For one of the patients in this series, these injections even eliminated the need for tracheostomy. No complications were observed.\nIn-office intralesional steroid injection is an emerging adjunctive treatment for laryngeal sarcoidosis. Prospective studies are required to determine efficacy and long-term risk profiles in relation to the current standard of operative management and systemic treatments.",
"affiliations": "Department of Otolaryngology-Head and Neck Surgery, Michigan Medicine, Ann Arbor, Michigan, USA.;University of Michigan Medical School, Ann Arbor, Michigan, USA.;Department of Otolaryngology-Head and Neck Surgery, Michigan Medicine, Ann Arbor, Michigan, USA.;Department of Otolaryngology-Head and Neck Surgery, Michigan Medicine, Ann Arbor, Michigan, USA.",
"authors": "Farlow|Janice L|JL|https://orcid.org/0000-0003-1214-4960;Park|Jiwon V|JV|;Morrison|Robert J|RJ|https://orcid.org/0000-0002-2313-8542;Kupfer|Robbi A|RA|",
"chemical_list": "D005938:Glucocorticoids; D014221:Triamcinolone",
"country": "United States",
"delete": false,
"doi": "10.1177/0003489421995287",
"fulltext": null,
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"issn_linking": "0003-4894",
"issue": "130(8)",
"journal": "The Annals of otology, rhinology, and laryngology",
"keywords": "ambulatory surgical procedures; laryngoscopy; laryngostenosis; larynx; sarcoidosis; steroids",
"medline_ta": "Ann Otol Rhinol Laryngol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000553:Ambulatory Care; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D015552:Injections, Intralesional; D007818:Laryngeal Diseases; D008875:Middle Aged; D012507:Sarcoidosis; D014221:Triamcinolone",
"nlm_unique_id": "0407300",
"other_id": null,
"pages": "976-979",
"pmc": null,
"pmid": "33583192",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Office-Based Intralesional Steroid Injection for Treatment of Laryngeal Sarcoidosis.",
"title_normalized": "office based intralesional steroid injection for treatment of laryngeal sarcoidosis"
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"companynumb": "US-MYLANLABS-2021M1069622",
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"abstract": "Radiation-induced brain edema (RIBE) is a serious complication of radiation therapy. It may result in dramatic clinico-radiological deterioration. At present, there are no definite guidelines for management of the complication. Corticosteroids are the usual first line of treatment, which frequently fails to provide long-term efficacy in view of its adverse complication profile. Bevacizumab has been reported to show improvement in cases of steroid-resistant radiation injury. The objective of this study is to evaluate the role of Bevacizumab in post-radiosurgery RIBE.\nSince 2012, 189 out of 1241 patients who underwent radiosurgery at our institution developed post-radiosurgery RIBE, 17 of which did not respond to high-dose corticosteroids. We systematically reviewed these 17 patients of various intracranial pathologies with clinic-radiological evidence of RIBE following gamma knife radiosurgery (GKRS). All patients received protocol-based Bevacizumab therapy. The peer-reviewed literature was evaluated.\n82 percent of the patients showed improvement after starting Bevacizumab. The majority began to improve after the third cycle started improvement after the third cycle of Bevacizumab. Clinical improvement preceded radiological improvement by an average of eight weeks. The first dose was 5 mg/kg followed by 7.5-10 mg/kg at with two-week intervals. Bevacizumab needs to be administered for an average of seven cycles (range 5-27, median 7) for best response. Steroid therapy could be tapered in most patients by the first follow-up. One patient did not respond to Bevacizumab and needed surgical decompression for palliative care. One noncompliant patient died due to radiation injury.\nBevacizumab is a effective and safe for treatment of RIBE after GKRS. A protocol-based dose schedule in addition to frequent clinical and radiological evaluations are required. Bevacizumab should be considered as an early treatment option for RIBE.",
"affiliations": "Department of Neurosurgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Department of Radiodiagnosis, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Department of Neurosurgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Department of Radiotherapy, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Department of Neurosurgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Department of Endocrinology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Department of Neurosurgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Department of Neurosurgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Department of Neurosurgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Department of Neurosurgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Department of Neurosurgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Department of Neurosurgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Department of Anaesthesia, Postgraduate Institute of Medical Education and Research, Chandigarh, India.",
"authors": "Tripathi|Manjul|M|;Ahuja|Chirag K|CK|;Mukherjee|Kanchan K|KK|;Kumar|Narendra|N|;Dhandapani|Sivashanmugam|S|;Dutta|Pinaki|P|;Kaur|Rupinder|R|;Rekhapalli|Rajashekhar|R|;Batish|Aman|A|;Gurnani|Jenil|J|;Kamboj|Parwinder|P|;Agrahari|Abhinav|A|;Kataria|Ketan|K|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab",
"country": "India",
"delete": false,
"doi": "10.4103/0028-3886.271242",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3886",
"issue": "67(5)",
"journal": "Neurology India",
"keywords": "Arteriovenous malformation; Bevacizumab; edema; gamma knife; meningioma; psychosurgery; radiation; radiosurgery; tumor; vestibular schwannoma",
"medline_ta": "Neurol India",
"mesh_terms": "D000328:Adult; D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab; D001929:Brain Edema; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011832:Radiation Injuries; D016634:Radiosurgery; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "0042005",
"other_id": null,
"pages": "1292-1302",
"pmc": null,
"pmid": "31744962",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The Safety and Efficacy of Bevacizumab for Radiosurgery - Induced Steroid - Resistant Brain Edema; Not the Last Part in the Ship of Theseus.",
"title_normalized": "the safety and efficacy of bevacizumab for radiosurgery induced steroid resistant brain edema not the last part in the ship of theseus"
} | [
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"companynumb": "IN-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-328717",
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"actiondrug": "5",
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"activesubstancename": "DEXAMETHASONE"
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"abstract": "Women with recurrent ovarian cancer have a poor prognosis and short survival. However, some women are long-term survivors and it is unclear whether they share specific common characteristics.\n\n\n\nWe present the case of a 63-year-old woman with histologically-proven recurrent ovarian cancer and a survival time of 16 years after the diagnosis of recurrence. She underwent initial debulking surgery in 1994, followed by 6 cycles of adjuvant chemotherapy with cisplatin and paclitaxel. After recurrent disease was diagnosed by re-laparotomy in 2000, she underwent four lines of systemic chemotherapy from 2000 to 2009 (carboplatin/paclitaxel, topotecan, etoposide/treosulfan and liposomal doxorubicin) and four lines of endocrine therapy between 2002 and 2014 (tamoxifen, goserelin, tamoxifen and exemestane). In 2014, she underwent secondary debulking surgery and was tumor-free until 2015. Upon progression, she was then started on the fifth-line of endocrine therapy, fulvestrant, which was changed to the mTOR inhibitor everolimus in June 2016. In a PUBMED literature search, 360 cases of long-term survivors of recurrent ovarian cancer (LTSROC), defined as women with survival >5 years after the diagnosis of recurrence, were identified with a mean post-recurrence survival time of 7.5 years. Comparing the patient and therapy details of these women, we identified common characteristics of LTSROC, i.e. young age and optimal debulking at initial surgery, a long time span between first-line therapy and first recurrence and the combined use of optimal cytoreductive surgery and systemic chemotherapy.\n\n\n\nLTSROC are rare, with 360 cases described in the literature. LTSROC are characterized by young age, low tumor stage, long recurrence-free interval and combined modality treatment with optimal cytoreductive surgery and systemic chemotherapy.",
"affiliations": "Department of Obstetrics and Gynecology, Ruhr University Bochum, Bochum, Germany.;Department of Hematology/Oncology, Ruhr University Bochum, Bochum, Germany.;Department of Pathology, Ruhr University Bochum, Bochum, Germany.;Department of Obstetrics and Gynecology, Ruhr University Bochum, Bochum, Germany.;Department of Obstetrics and Gynecology, Ruhr University Bochum, Bochum, Germany.;Department of Obstetrics and Gynecology, St. Anna Hospital, Herne, Germany.;Department of Obstetrics and Gynecology, University of Witten/Herdecke, Witten, Germany.;Department of Obstetrics and Gynecology, Ruhr University Bochum, Bochum, Germany clemens.tempfer@rub.de.",
"authors": "Hilal|Ziad|Z|;Schultheis|Beate|B|;Hartmann|Franziska|F|;Dogan|Askin|A|;Cetin|Cem|C|;Krentel|Harald|H|;Schiermeier|Sven|S|;Tempfer|Clemens B|CB|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.21873/anticanres.11110",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "36(10)",
"journal": "Anticancer research",
"keywords": "Ovarian cancer; chemotherapy; long-term survivor; recurrence; therapy response",
"medline_ta": "Anticancer Res",
"mesh_terms": "D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010051:Ovarian Neoplasms; D017741:Survivors",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "5365-5371",
"pmc": null,
"pmid": "27798900",
"pubdate": "2016-10",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "What Characterizes Long-term Survivors of Recurrent Ovarian Cancer? Case Report and Review of the Literature.",
"title_normalized": "what characterizes long term survivors of recurrent ovarian cancer case report and review of the literature"
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"companynumb": "DE-MYLANLABS-2019M1077484",
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"activesubstancename": "GOSERELIN ACETATE"
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{
"abstract": "Anti-TNFα drugs have strongly changed the way in which we deal with moderate and severe psoriasis. However, it is debatable whether biological drugs could increase the risk of developing cancer. The correlation between anti-TNFα drugs and lymphomas is well-known and is reported in all the technical details of biologic drugs. However, the association between anti-TNFα agents and solid tumors is still controversial. The authors report a case of bilateral salivary gland tumor in a psoriatic patient treated with several immunosuppressive therapies including anti-TNFα inhibitors.",
"affiliations": "IRCCS A.O.U. San Martino-IST, Di.S.Sal, Section of Dermatology, University of Genoa, Italy.;IRCCS A.O.U. San Martino-IST, Di.S.Sal, Section of Dermatology, University of Genoa, Italy emanuele.cozzani@unige.it.;IRCCS A.O.U. San Martino-IST, Di.S.Sal, Section of Dermatology, University of Genoa, Italy.;IRCCS A.O.U. San Martino-IST, Di.S.Sal, Section of Dermatology, University of Genoa, Italy.;Department of Anatomic Pathology, IRCCS A.O.U. San Martino-IST, Genoa, Italy.;IRCCS A.O.U. San Martino-IST, Di.S.Sal, Section of Dermatology, University of Genoa, Italy.",
"authors": "Burlando|M|M|;Cozzani|E|E|;Chinazzo|C|C|;Larosa|M|M|;Boggio|M|M|;Parodi|A|A|",
"chemical_list": "D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha",
"country": "England",
"delete": false,
"doi": "10.1177/0394632015572742",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0394-6320",
"issue": "28(1)",
"journal": "International journal of immunopathology and pharmacology",
"keywords": "TNFα therapy; Warthin tumor; psoriasis",
"medline_ta": "Int J Immunopathol Pharmacol",
"mesh_terms": "D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D011565:Psoriasis; D014409:Tumor Necrosis Factor-alpha; D009396:Wilms Tumor",
"nlm_unique_id": "8911335",
"other_id": null,
"pages": "138-41",
"pmc": null,
"pmid": "25816418",
"pubdate": "2015-03",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Bilateral Warthin tumor in psoriatic patients in therapy with multiple immunosuppressive therapy.",
"title_normalized": "bilateral warthin tumor in psoriatic patients in therapy with multiple immunosuppressive therapy"
} | [
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"companynumb": "IT-AMGEN-ITASP2016046268",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "EFALIZUMAB"
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"abstract": "BACKGROUND\nNaloxone is an opioid antagonist that can reverse an opioid overdose. Increased opioid-related mortality rates led to greater distribution of naloxone without a prescription and administration of naloxone by laypersons. This study fills a gap in knowledge of naloxone experiences among active users of opioids living in suburban communities.\n\n\nOBJECTIVE\nThe purpose of this article is to provide nurse practitioners with an in-depth understanding of current naloxone use practices among people who experience overdose events. The specific aims are to compare access to naloxone in diverse suburban towns, to examine administration differences across settings, and to understand perspectives on naloxone experiences from people who are actively using opioids.\nThe data for this analysis were drawn from an ethnographic study in the suburban towns around Atlanta, Georgia; Boston, Massachusetts; and New Haven, Connecticut. Short surveys and in-depth interviews were collected. Inductive methods were used to compare data across settings.\n\n\nMETHODS\nThe sample of 106 included 48% female, 62% White, 24% African American/Black, 13% more than one race, and 21% Hispanic/Latinx. The mean age was 41.35 years.\n\n\nCONCLUSIONS\nDifferences between study settings in access to naloxone, administration frequency, and delivery systems were found. Findings suggest more education and training is needed in overdose prevention and harm reduction intervention. Studies on delivery systems need to address the increase in fentanyl-related overdoses.\n\n\nCONCLUSIONS\nNurse practitioners can help to target distribution of naloxone in local communities, facilitate collaboration with harm reduction services, and provide evidence-based education and training to laypersons.",
"affiliations": "Sociology Department, Bentley University, Waltham, Massachusetts.;Department of Public Health, Southern Connecticut State University, New Haven, Connecticut.",
"authors": "Boeri|Miriam|M|;Lamonica|Aukje K|AK|",
"chemical_list": "D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D009270:Naloxone",
"country": "United States",
"delete": false,
"doi": "10.1097/JXX.0000000000000371",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2327-6886",
"issue": "33(4)",
"journal": "Journal of the American Association of Nurse Practitioners",
"keywords": null,
"medline_ta": "J Am Assoc Nurse Pract",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D062787:Drug Overdose; D005260:Female; D040261:Harm Reduction; D006801:Humans; D008297:Male; D009270:Naloxone; D009292:Narcotic Antagonists",
"nlm_unique_id": "101600770",
"other_id": null,
"pages": "294-303",
"pmc": null,
"pmid": "32251033",
"pubdate": "2020-04-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Naloxone perspectives from people who use opioids: Findings from an ethnographic study in three states.",
"title_normalized": "naloxone perspectives from people who use opioids findings from an ethnographic study in three states"
} | [
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"companynumb": "US-MYLANLABS-2022M1026643",
"fulfillexpeditecriteria": "1",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FENTANYL"
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"drugadditional": "3",
... |
{
"abstract": "Oral mucositis (OM) is one of the most uncomfortable adverse events experienced by cancer patients undergoing chemotherapy. Previous reports have revealed that the oral administration of an elemental diet (ED) may prevent OM. However, the incidence of OM has not been accurately determined by specialized diagnostic methods and the effects of an ED on OM remain unclear. We investigated the dose that could feasibly be administered and its effects with regard to the suppression of OM in esophageal cancer patients undergoing chemotherapy.\n\n\n\nWe performed a prospective multi-center feasibility study of the administration of an ED (160 g/day) with 2 cycles of docetaxel/cisplatin/5-FU (DCF) chemotherapy. We assessed compliance to the ED for 49 days and the incidence of OM according to the amount of the ED that was orally administered. The incidence of OM was graded by a dental specialist who was experienced in dental oncology using a central OM review system.\n\n\n\nFourteen of 20 patients (70%) were able to complete the orally administered ED (160 g/day) during the course of chemotherapy. Three patients (15%) could not take the ED orally for 9, 14, and 21 days, respectively, while 1 patient (5%) took the ED orally at an average dose of 80 g/day for 35 days. The remaining 2 patients (10%) could not take the 80 g/day dose for 11 and 12 days, respectively. The incidence of grade ≥ 2 OM in the ED completion group (15.4%, 2 of 13 patients) was significantly lower than that in the non-completion group (66.7%, 4 of 6 patients) (p = 0.046).\n\n\n\nAn ED might be a one of the test treatment to reduce the incidence of OM in esophageal cancer patients treated with DCF and should be evaluated in further randomized study.\n\n\n\nThe date of submission: Dec 08th, 2017.",
"affiliations": "Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, Gifu, 501-1194, Japan. yoshihirotana11@hotmail.com.;Dental Division of National Cancer Center, Tokyo, Japan.;Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.;Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.;Department of Surgery, Graduate School of Medicine, Keio University, Tokyo, Japan.;Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.;Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.;Department of Surgery, Graduate School of Medicine, Keio University, Tokyo, Japan.;Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, Gifu, 501-1194, Japan.",
"authors": "Tanaka|Yoshihiro|Y|0000-0002-0300-7924;Ueno|Takao|T|;Yoshida|Naoya|N|;Akutsu|Yasunori|Y|;Takeuchi|Hiroya|H|;Baba|Hideo|H|;Matsubara|Hisahiro|H|;Kitagawa|Yuko|Y|;Yoshida|Kazuhiro|K|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s10388-018-0620-1",
"fulltext": "\n==== Front\nEsophagusEsophagusEsophagus1612-90591612-9067Springer Japan Tokyo 3022574562010.1007/s10388-018-0620-1Original ArticleThe effect of an elemental diet on oral mucositis of esophageal cancer patients treated with DCF chemotherapy: a multi-center prospective feasibility study (EPOC study) http://orcid.org/0000-0002-0300-7924Tanaka Yoshihiro +810582306000yoshihirotana11@hotmail.com 1Ueno Takao 2Yoshida Naoya 3Akutsu Yasunori 4Takeuchi Hiroya 5Baba Hideo 3Matsubara Hisahiro 4Kitagawa Yuko 5Yoshida Kazuhiro 11 0000 0004 0370 4927grid.256342.4Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, Gifu 501-1194 Japan 2 0000 0001 2168 5385grid.272242.3Dental Division of National Cancer Center, Tokyo, Japan 3 0000 0001 0660 6749grid.274841.cDepartment of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan 4 0000 0004 0370 1101grid.136304.3Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan 5 0000 0004 1936 9959grid.26091.3cDepartment of Surgery, Graduate School of Medicine, Keio University, Tokyo, Japan 31 5 2018 31 5 2018 2018 15 4 239 248 12 12 2017 15 5 2018 © The Author(s) 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Purpose\nOral mucositis (OM) is one of the most uncomfortable adverse events experienced by cancer patients undergoing chemotherapy. Previous reports have revealed that the oral administration of an elemental diet (ED) may prevent OM. However, the incidence of OM has not been accurately determined by specialized diagnostic methods and the effects of an ED on OM remain unclear. We investigated the dose that could feasibly be administered and its effects with regard to the suppression of OM in esophageal cancer patients undergoing chemotherapy.\n\nMethods\nWe performed a prospective multi-center feasibility study of the administration of an ED (160 g/day) with 2 cycles of docetaxel/cisplatin/5-FU (DCF) chemotherapy. We assessed compliance to the ED for 49 days and the incidence of OM according to the amount of the ED that was orally administered. The incidence of OM was graded by a dental specialist who was experienced in dental oncology using a central OM review system.\n\nResults\nFourteen of 20 patients (70%) were able to complete the orally administered ED (160 g/day) during the course of chemotherapy. Three patients (15%) could not take the ED orally for 9, 14, and 21 days, respectively, while 1 patient (5%) took the ED orally at an average dose of 80 g/day for 35 days. The remaining 2 patients (10%) could not take the 80 g/day dose for 11 and 12 days, respectively. The incidence of grade ≥ 2 OM in the ED completion group (15.4%, 2 of 13 patients) was significantly lower than that in the non-completion group (66.7%, 4 of 6 patients) (p = 0.046).\n\nConclusions\nAn ED might be a one of the test treatment to reduce the incidence of OM in esophageal cancer patients treated with DCF and should be evaluated in further randomized study.\n\nClinical trial\nThe date of submission: Dec 08th, 2017.\n\nElectronic supplementary material\nThe online version of this article (10.1007/s10388-018-0620-1) contains supplementary material, which is available to authorized users.\n\nKeywords\nChemotherapyOral mucositisEsophageal carcinomaDCFCentral review systemissue-copyright-statement© The Japan Esophageal Society and Springer Japan KK, part of Springer Nature 2018\n==== Body\nIntroduction\nAdvances in medical device development have reduced the incidence of complications after surgery for esophageal cancer; however, even in patients in whom curative resection is achieved, the 5-year survival rate is only 20–36% [1]. In patients with operable esophageal cancer, there is evidence to support the use of preoperative chemotherapy or chemoradiation [2, 3]. Meanwhile, unresectable or metastatic esophageal cancer has also been treated with chemotherapy [4]. Chemotherapy can significantly improve the clinical outcomes of cancer patients, but it can also result in serious adverse effects [5, 6].\n\nThe current standard neoadjuvant chemotherapy for esophageal cancer is 5-fluorouracil (5-FU)/cisplatin (FP) [7]. Moreover, more effective chemotherapy regimens using docetaxel/cisplatin/5-FU (DCF) have been reported [8]. However, this regimen is associated with an increased incidence of severe adverse effects, including hematological and gastrointestinal (GI) toxicities. To overcome such adverse events, we recently showed that a modified DCF regimen can reduce the hematological toxicity of the regimen [9, 10]; however, oral mucositis (OM) was often observed. GI toxicities caused by chemotherapy can negatively affect a patient’s nutritional status and result in the discontinuation of chemotherapy. OM—one of the most common GI toxicities—results in increased pain, difficulty in swallowing, nutritional compromise, and an increased risk of infection.\n\nTaxanes, platinum-containing drugs, and FUs are all reported to cause mucosal damage, with an incidence of up to 70% [11, 12]. However, several countermeasures to prevent OM with chemo(radio)therapy have been reported [13–15], those effects might not be sufficient for multidrug anticancer agents. A report indicated that the oral glutamine (Gln) administration reduced the duration and severity of OM after cytotoxic cancer chemotherapy. [16]. Thus, we previously conducted a randomized phase II trial to study the effects of Gln plus one pack (80 g) of elemental diet {ED [(Elental®; EA Pharma Co., Ltd.)]}/day: total Gln 8862 mg/day or Gln alone: 8910 mg/day compared to no prevention of OM in patients with esophageal cancer undergoing chemotherapy including FP and triplet regimen [17]. Only the Gln plus an ED group showed a significant preventive effect on the development and severity of OM. We concluded that the oral administration of Gln plus an ED [one pack (80 g)] may prevent OM. Even though the total amount of Gln administered to the two treatment groups: Gln plus an ED group and Gln group was nearly equal, only the addition of the ED group had a significant preventive effect against OM. Thus, the ED was thought to have an inhibitory effect against OM due to other amino acids such as histidine which has also anti-inflammatory effect [18] like Gln contained in the ED. In addition, the mechanism of the effects of the ED might involve the maintenance of the mucosal integrity, which is indicated by significant higher levels of plasma diamine oxidase (DAO) activity [17]. In the present study, we evaluated the preventive effect of ED alone against OM in patients undergoing DCF chemotherapy. Considering that Gln formulation was not added in the combination of 1 pack of an ED (80 g) this time and that OM was likely to occur with the DCF regimen, we thought that ED would require at least more than 2 packs (160 g). On that occasion, in consideration of the situation that it was not easy to drink 1 pack (80 g)/day of an ED during chemotherapy in Ogata et al.’s report, we thought that 2 packs (160 g) were appropriate this time. So, we set the dosage of the ED to 2 packs (160 g)/day, which was twice the dosage of our previous report. We assessed compliance to the ED and the incidence of OM according to the amount of the ED that was orally administered.\n\nMethods\nStudy design\nEndpoints and methods\nThe primary endpoint of this study was the completion rate of an orally administered ED 2 packs (160 g/day) during 2 cycles of DCF chemotherapy. The secondary endpoints were the incidence of OM (CTCAE ver. 3.0) in patients who completed taking the orally administered ED (160 g/day; completion group) and in those who could not complete it (non-completion group); the rate of weight fluctuation; DAO activity, which is a reliable indicator of intestinal mucosal integrity; the turnover rate of plasma proteins (prealbumin, lymphocyte count), which was used as an indicator of the nutritional status per compliance with the orally administered ED; adverse events other than OM (CTCAE ver. 3.0); and the objective response rate to chemotherapy.\n\nIn the present study, the patients were scheduled to receive an ED at a dose of 2 packs (160 g/day). The ED was administered orally 1 week before chemotherapy and was continued during chemotherapy for a total of 49 days. The rate of weight fluctuation, DAO activity, prealbumin level, and lymphocyte count were measured on days 1, 8, and 15 in each of the 2 chemotherapy cycles. All patients received preventative oral care before chemotherapy.\n\nWe constructed a central review system (CRS) to judge the oral environment. The CRS judge assessed the oral mucosa of each patient before chemotherapy and on day 1, 8, and 15 of each of the 2 cycles of DCF using the CRS. Oral and maxillofacial surgeons at each institution used instruments to examine the oral cavity. Six photographs (that included the posterior surface of the upper and lower lips, right and left buccal mucosa, and right and left lingual surfaces) were taken using a specialized intraoral imaging camera (Online Resource 1) and transmitted as a 4 MB electronic file to the data server prior to the diagnosis of OM. In each case, OM was graded by a CRS judge (a dental specialist who was experienced in dental oncology) who did not belong to the institutions with registered patients, and who was unaware of the patients’ background information.\n\nOM was graded according to CTCAE ver 3.0 [19], based on the results of a clinical examination, as follows: Grade 1, erythema of the mucosa; Grade 2, patchy ulcerations or pseudomembranes; Grade 3, confluent ulcerations or pseudomembranes, bleeding with minor trauma; Grade 4, tissue necrosis, significant spontaneous bleeding, life-threatening consequences; and Grade 5, death.\n\nPatients were enrolled from four institutions: Gifu University Hospital, Keio University Hospital, Kumamoto University Hospital, and Chiba University Hospital.\n\nEligibility criteria\nPatients who were > 18 years of age at the time of registration, and who had histologically or cytologically confirmed Stage II/III esophageal squamous cell carcinoma or adenocarcinoma were included in the present study. The staging of all patients was defined by the guidelines of the Japanese Society for Esophageal Disease (10th edition). The other inclusion criteria were as follows: an Eastern Cooperative Oncology Group performance status of 0–1; a life expectancy of > 12 weeks; and adequate liver, bone marrow, renal, and cardiovascular functions [serum bilirubin ≤ 1.5 mg/dl; neutrophil count ≥ 1500/mm3; serum aspartate aminotransferase and alanine aminotransferase levels ≤ twice the upper limit of normal range; platelet count ≥ 10 × 104/mm3; hemoglobin ≥ 8.0 g/dl; and creatinine ≤ 1.2 mg/dl (or creatinine clearance > 60 ml/min)].\n\nPatients who had previously received chemotherapy for malignant disease were excluded from the study. The other major exclusion criteria were as follows: serious concomitant illness, symptomatic infectious disease, severe allergy, peripheral neuropathy, or uncontrolled diabetes mellitus.\n\nThe treatment regimen and operation, and the assessment of the tumor response and adverse events\nDCF chemotherapy consisted of a 1-h intravenous (i.v.) infusion of docetaxel (70 mg⁄m2), a 2-h infusion of cisplatin (70 mg⁄m2) on Day 1, and a continuous i.v. infusion of 5-FU (750 mg⁄m2⁄day) on days 1–5. This regimen was repeated every 3 weeks. This regimen was administered as preoperative chemotherapy to all patients. Two cycles of this regimen were administered within 2 weeks after registration in this study. Prophylactic antibiotics were routinely used for 10 days from Day 6 of each cycle. Prophylactic administration of granulocyte-colony stimulating factor (G-CSF) on the chemotherapy day was not allowed, and G-CSF was permitted to administer when neutropenia or fever occurred. After an interval of 4–6 weeks from the completion of chemotherapy, radical esophageal resection and lymphadenectomy were scheduled by open thoracotomy or video-assisted surgery.\n\nThe tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors guidelines [20] after the second cycle of chemotherapy and 4 weeks later. A barium meal study, endoscopy, ultrasonography, and computed tomography were used to evaluate the response of measurable lesions. A complete response (CR) was defined as the complete disappearance of all clinically detectable malignant disease; a partial response (PR) was defined as a > 30% decrease in the sum of the perpendicular diameters of all measurable lesions that was present for at least 4 weeks. Progressive disease (PD) was defined as either a > 20% increase in the sum of the products of measurable lesions over the smallest sum observed or the appearance of new lesions. Stable disease (SD) did not qualify as a CR, PR, or PD. Safety and adverse events were assessed according to the National Cancer Institute CTCAE (ver. 3.0).\n\nStatistical analysis\nAccording to the Ogata et al.’s report [21], the setting dose of an ED during chemotherapy for colon cancer was 1 pack (80 g)/day, but the average amount of the ED that was able to be taken was 51.7%. This study is a triplet regimen for esophageal cancer, so the setting dose of an ED is 2 packs (160 g)/day. The sample size was calculated at 75% expected completion rate, 45% threshold completion rate with 80% detection power. The number of cases required was 20. We calculated the percentage of ED compliance for all registered patients. The differences between the 2 groups in ED compliance were analyzed using the Wilcoxon rank sum test {median [25th percentile (Q1), 75th percentile (Q3)]}. The factors affecting expression of OM ≥ Grade 2 were analyzed using logistic regression analysis. The digestive system adverse events were compared to those in the historical data of other report using Fisher’s exact test. p values of < 0.05 were considered to indicate statistical significance. All of the statistical analyses were performed using the SAS software program (ver. 9.4; SAS Institute Inc., Cary, NC, USA).\n\nEthical considerations\nThis trial was conducted in accordance with the World Medical Association Declaration of Helsinki and was registered with the University Hospital Medical Information Network Clinical Trials Registry (Registration number: UMIN000010860). The study protocol was approved by the independent ethics committees of each of the four participating institutions, and written informed consent was obtained from all of the patients.\n\nResults\nPatients\nTwenty patients were enrolled, 19 patients (one case was missing photographic data) were targeted as subjects for the analysis of the secondary endpoints (Table 1). The median age was 68 years (range 37–75 years). The performance status was 0 in 8 patients and 1 in 11 patients. The tissue types included squamous cell carcinoma (n = 18) and adenocarcinoma (n = 2).Table 1 Patient characteristics in the feasibility study (n = 20)\n\n\tNo. of patients\t(%)\t\nAge (years)\t\n Median (range)\t68 (37-75)\t\t\nSex\t\n Males/females\t20/0\t100/0\t\nECOG performance status\t\n 0/1/missing data\t8/11/1\t40/55/5\t\nHistological type\t\n Squamous cell carcinoma/adenocarcinoma\t18/2\t90/10\t\nSite of primary tumor\t\n Ce/Ut/Mt/Lt/Ae\t2/1/10/5/2\t10/5/50/25/10\t\nDifferentiation\t\n Well/moderate/poor/unknown\t6/10/2/4\t30/50/10/20\t\nClinical T stage\t\n cT1b/T2/T3\t2/4/14\t10/20/70\t\nClinical N stage\t\n cN0/N1/N2/N3\t1/8/8/3\t5/40/40/15\t\nClinical stage\t\n II/III\t4/16\t20/80\t\nECOG Eastern Cooperative Oncology Group, Ut upper thoracic esophagus, Mt middle thoracic esophagus, Lt lower thoracic esophagus, Ae abdominal esophagus\n\n\n\n\nCompliance with the orally administered ED\nFourteen of the 20 patients [70%: 95% confidence interval (CI) 48.1–85.5%]= completed the orally administered ED (160 g/day; the completion group); 6 patients could not (non-completion group). Of these 6 patients, 3 (15%) could not take the ED orally for 9, 14, and 21 days, respectively, while 1 patient (5%) took the ED orally at an average dose of 80 g/day for 35 days. The remaining 2 patients (10%) could not take the 80 g/day dose for 11 and 12 days, respectively.\n\nThe incidence of OM\nBased on the results of the CRS, OM was observed in all 19 patients (100%), and grade ≥ 2 OM was found in 6 of the 19 patients (31.6%: 95% CI 12.6–56.6%). The grades of OM in the 19 patients were as follows: grade 1 (n = 13; 68.4%); grade 2 (n = 5; 26.3%), and grade 3 (n = 1; 5.3%).\n\nThe incidence of OM was as follows: grade 0 (n = 0; 0%), grade 1 (n = 11; 84.6%), grade 2 (n = 2; 15.4%), and grade 3 (n = 0; 0%) in the completion group (n = 13); and grade 0 (n = 0; 0%), grade 1 (n = 2; 33.3%), grade 2 (n = 3; 50%), and grade 3 (n = 1; 16.7%) in the non-completion group (n = 6).\n\nThe incidence of grade ≥ 2 OM in the ED completion group (15.4%; 2 of 13 patients) was significantly lower than that in the non-completion group (66.7%; 4 of 6 patients) (p = 0.046).\n\nThe relationship between compliance with the ED and other parameters\nNo significant difference was observed between the two groups in the rate of body weight change during chemotherapy. Although the change in DAO activity during chemotherapy did not differ between the groups to a statistically significant extent, the change in DAO activity tended to be greater in the completion group [17.45 (− 1.55, 60.95)] than that in the non-completion group [− 23.00 (− 64.80, 15.60)], especially on Day 15 in cycle 1 (p = 0.1939) (Table 2). During the second cycle of chemotherapy, the prealbumin level in the completion group was significantly higher than that in the non-completion group (Day 1, p = 0.0037; Day 8, p = 0.0451). There was no significant difference between the groups with regard to the change in the lymphocyte count during chemotherapy (Table 2).Table 2 Compliance with oral administration of ED and rates of change of each parameter Wilcoxon rank-sum test\n\n\tCycle 1, Day 1\tCycle 1, Day 8\tCycle 1, Day 15\tCycle 2, Day 1\tCycle 2, Day 8\tCycle 2, Day 15\t\nBody weight ΔMedian (Q1, Q3) (%)\t\n Completion group (n = 14)\t\t− 0.05 (− 1.40, 0.90)\t− 1.00 (− 1.90, 1.10)\t0.70 (− 0.30, 2.15)\t1.40 (− 0.45, 2.25)\t0.75 (0.00, 2.70)\t\n Non-completion group (n = 6)\t\t− 1.45 (− 2.30, 0.00)\t0.70 (− 3.40, 1.80)\t0.85 (− 2.45, 3.05)\t0.30 (0.00, 0.70)\t− 1.45 (− 4.35, 0.50)\t\n\tp = 0.3219\tp = 0.6294\tp = 1.0000\tp = 0.7517\tp = 0.1290\t\nDAO ΔMedian (Q1, Q3) (%)\t\n Completion group (n = 14)\t\t− 10.30 (− 40.30, 16.90)\t17.45 (− 1.55, 60.95)\t27.60 (− 13.45, 50.35)\t− 14.85 (− 25.25, 19.90)\t9.35 (− 10.05, 38.50)\t\n Non-completion group (n = 6)\t\t− 17.10 (− 44.10, 32.60)\t− 23.00 (− 64.80, 15.60)\t9.40 (− 63.50, 17.50)\t− 2.50 (− 98.40, 43.50)\t20.20 (7.50, 32.90)\t\n\tp = 1.0000\tp = 0.1939\tp = 0.1939\tp = 0.8852\tp = 1.0000\t\nPrealbumin ΔMedian (Q1, Q3) (%)\t\n Completion group (n = 14)\t\t30.55 (5.90, 50.00)\t0.00 (− 17.10, 13.00)\t9.15 (− 4.55, 24.50)\t55.50 (20.80, 68.40)\t15.60 (5.80, 46.55)\t\n Non-completion group (n = 6)\t\t15.35 (− 31.30, 36.80)\t− 19.40 (− 37.50, − 16.70)\t− 24.10 (− 33.30, − 9.70)\t− 3.30 (− 5.30, 6.50)\t1.15 (− 32.85, 47.25)\t\n\tp = 0.2831\tp = 0.0745\tp = 0.0037※\tp = 0.0451※\tp = 0.6276\t\nLymphocytes ΔMedian (Q1, Q3) (%)\t\n Completion group (n = 14)\t\t− 2.25 (− 11.60, 0.40)\t− 8.70 (− 255.70, − 3.20)\t− 8.55 (− 12.60, 1.20)\t− 5.85 (− 20.10, 8.45)\t− 8.25 (− 15.70, 14.30)\t\n Non-completion group (n = 6)\t\t− 6.60 (− 22.30, 0.60)\t− 17.80 (− 24.30, − 8.80)\t− 9.25 (− 30.40, 6.20)\t− 7.00 (− 20.80, 1.00).\t− 11.65 (− 29.90, 0.95)\t\n\tp = 0.6207\tp = 0.4829\tp = 0.7079\tp = 0.7518\tp = 0.4669\t\n※p < 0.05\n\n\n\n\nAdverse events other than OM\nThe grade 3 adverse events were as follows: fatigue (n = 3; 15%), fever (n = 3; 15%), anorexia (n = 3, 15%); diarrhea (n = 2; 10%), and nausea (n = 1; 5%) (Table 3). One patient in the non-completion group died due to sudden cardiac arrest after 2 cycles of chemotherapy; the patient’s death was probably related to DCF toxicity. The incidence of grades 1–3 anorexia was as follows: grade 0 (n = 4; 28.6%), grade 1 (n = 5; 35.7%), grade 2 (n = 5; 35.7%), and grade 3 (n = 0; 0%) in the completion group (n = 14); and grade 0 (n = 0; 0%), grade 1 (n = 2; 33.3%), grade 2 (n = 1; 16.7%); and grade 3 (n = 3; 50%) in the non-completion group (n = 6). grade ≥ 2 anorexia occurred in 5 of the 14 patients (35.7%) in the completion group and in 4 of the 6 patients (66.7%) in the non-completion group (p = 0.3359).Table 3 All adverse events excluding the oral mucositis (n = 20)\n\n\tGrade\tAll grades n (%)\t≥ Grade 2 n (%)\t≥ Grade 3 n (%)\t\n1\t2\t3\t4\t\nHearing disturbance\t0\t0\t0\t0\t0 (0)\t0 (0)\t0 (0)\t\nFatigue\t4\t3\t3\t0\t10 (50)\t6 (30)\t3 (15)\t\nFever\t2\t1\t3\t0\t6 (30)\t4 (20)\t3 (15)\t\nAlopecia\t13\t3\t–\t–\t16 (80)\t3 (15)\t–\t\nPigmentation\t0\t1\t0\t0\t1 (5)\t1 (5)\t0 (0)\t\nSkin rash\t0\t0\t0\t0\t0 (0)\t0 (0)\t0 (0)\t\nCutaneous symptoms of the hands and feet\t0\t0\t0\t0\t0 (0)\t0 (0)\t0 (0)\t\nAnorexia\t7\t6\t3\t0\t16 (80)\t9 (45)\t3 (15)\t\nConstipation\t0\t0\t0\t0\t0 (0)\t0 (0)\t0 (0)\t\nDiarrhea\t7\t1\t2\t0\t10 (50)\t3 (15)\t2 (10)\t\nNausea\t3\t2\t1\t0\t6 (30)\t3 (15)\t1 (5)\t\nInfection (accompanied by neutropenia)\t0\t0\t6\t0\t6 (30)\t6 (30)\t6 (30)\t\nEdema\t1\t1\t0\t0\t2 (10)\t1 (5)\t0 (0)\t\nNeuropathy (motor)\t0\t0\t0\t0\t0 (0)\t0 (0)\t0 (0)\t\nNeuropathy (sensory)\t1\t0\t0\t0\t1 (5)\t0 (0)\t0 (0)\t\nWatery eyes\t0\t0\t0\t0\t0 (0)\t0 (0)\t0 (0)\t\nLeucopenia\t–\t9\t6\t3\t–\t18 (90)\t9 (45)\t\nNeutropenia\t–\t3\t10\t5\t–\t18 (90)\t15 (75)\t\nAnemia\t–\t2\t0\t0\t–\t2 (10)\t0 (0)\t\nThrombocytopenia\t–\t0\t0\t0\t–\t0 (0)\t0 (0)\t\n\n\n\nThe objective response rate to chemotherapy\nThe objective response rate to chemotherapy was 66.7% [CR, n = 2 (11.1%); PR, n = 10 (55.6%); SD, n = 6 (33.3%); and PD, n = 0 (0%)]. The responses in the completion group were CR [n = 1 (8.3%)], PR [n = 7 (58.3%)], SD [n = 4 (33.3%)], and PD [n = 0 (0%)]. The responses in the non-completion group were CR [n = 1 (16.7%)], PR [n = 3 (50%)], SD [n = 2 (33.3%)], and PD [n = 0 (0%)]. There was no significant difference between the patients who could and could not complete the ED (p = 1.000). Surgical resection was performed in 18 patients. One patient selected observation rather than surgery because a CR was attained, and 1 patient died after chemotherapy. No postoperative complications were observed, and the administration of the ED did not interfere with any of the planned operations.\n\nDiscussion\nIn the present study, 14 of the 20 patients (70%) completed taking an orally administered ED at a dose of 2 packs (160 g)/day during chemotherapy.\n\nBesides taste and satiety, there may be several reasons why the orally administered ED was or was not completed. First, there is likely to be a difference in the completion rate due to anorexia. Although there was no significant difference between the loss or withdrawal of the ED and anorexia, a relationship between these factors was suggested in the present study. Second, the patients in whom the antitumor effect was poor, and in whom stenosis worsened, could not take the ED. However, there was no significant difference in the objective response rate to chemotherapy between the patients who could and could not complete the ED. Third, there is likely to be a relationship between poor compliance and the development of oral pain from OM. We did not refrain from administering analgesics. In fact, 2 patients (15.4%) with grade ≥ 2 OM completed the oral administration of the ED, and 2 patients (33.3%) without grade ≥ 2 OM could not complete the oral administration of the ED. Still, we are of the opinion that it is important to consider administering an ED with DCF chemotherapy. Although the number of cases was small, the incidence of OM in the ED completion group was significantly suppressed in comparison to the non-completion group.\n\nNishimura et al. reported that the incidence of OM (grade ≥ 1) was the highest during chemotherapy for breast cancer (76.5%), followed by head and neck cancer (67.7%), colorectal cancer (63%), and esophageal cancer (57.8%). When classified by chemotherapy regimen, the incidence of OM (grade ≥ 1) was the highest among those receiving DCF (85.7%), followed by those receiving 5-FU/leucovorin/irinotecan (80%) and 5-FU/cyclophosphamide/adriamycin (78.8%). Moreover, the incidence of grade ≥ 2 OM among patients receiving DCF was approximately 40% [22].\n\nThe exact objective incidence of OM may not be known because its incidence is described according to complaints of the patient or assessment by general physicians or medical staff members who are not specialists in the oral environment; thus, its incidence may often be underestimated. A thorough examination of the intraoral condition with instruments specific to the oral cavity can only be conducted by oral and maxillofacial surgeons, dentists, and their teams. We therefore constructed the CRS to assess the oral environment.\n\nThe grade ≥ 2 OM rate in previous DCF report was 28% [10] and all the grade ≥ 2 OM rate in this study was 31.6%. In our previous study including FP and triplet regimen, OM of grade ≥ 2 was occurred in 10% with Gln plus an ED group [17]. The incidence of grade ≥ 2 OM in the 2 packs (160 g/day) of ED completion group was in 15.4% that was significantly lower than non-completion group. Although the OM suppression effect in this study seems to be low, it is doubtful whether the oral cavity was completely evaluated in those previous studies.\n\nIn this study, based on the results of the CRS, OM of Grade ≥ 1 was actually observed in all patients (100%). Thus, the judgment of OM by general clinicians might be lower than that by dental specialists, which suggests that in the clinical setting the actual incidence of OM among patients undergoing chemotherapy for cancer may be greater than clinicians realize.\n\nFor this reason, we focused on the following characteristics of EDs. An ED is a specialized formula containing a blend of proteins as amino acids. Because of its nature, little digestion is necessary, and it shows high absorption efficiency. Thus, EDs are frequently used for patients with inflammatory bowel disease, in particular patients with Crohn’s disease (CD).\n\nThe effects of EDs in CD have been widely reported [18, 23]; in particular, the induction of remission [24] and sustained remission [25] from CD has been reported. An ED has been shown to have a clear suppressive effect on clinical activity and on inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) [23]. Moreover, histidine inhibited the production of TNF-α and IL-6 by mouse macrophages [18]. Current studies have shown that amino acids themselves can protect the mucosa and have anti-inflammatory effects [18, 26]. The administration of an ED during cancer chemotherapy has been reported to have the potential prevent OM [17, 21]. Chemotherapy damages DNA through the production of reactive oxygen species, the induction of apoptosis through the upregulation of the expression of intracellular molecules, and the production of several cytokines, such as IL-1β, IL-6, and TNF-α [27, 28].\n\nBecause OM is reported to be caused by chemotherapy-induced mucosal damage [17], we measured the mucosal integrity on the basis of DAO activity. As a result, we found that the integrity of the intestinal mucosa tended to be maintained in the ED completion group. The previous report also showed that chemotherapy reduced the integrity of the intestinal mucosa and that a combination of an ED and Gln maintained the integrity to a significantly greater extent than Gln alone during chemotherapy, indicating a possible connection with the environment of the oral cavity [17]. Previous reports have shown that amino acids might be more absorbable—even during chemotherapy—from the viewpoints of efficacy in maintaining the mucosal integrity and their easy digestibility. In addition it has been hypothesized that an ED might also offer a mucosal protective effect in chemotherapy-induced mucositis via mechanisms that are similar to those that provide a suppressive effect against inflammatory cytokines in CD.\n\nThe high completion rate of the orally administered 2 packs of ED (160 g/day) suggested the possibility of decreased OM. The factors that may affect expression of grade ≥ 2 OM were compared, but no significant difference was observed between the two population except compliance of ED (Table 4).Table 4 Logistic regression analysis of factors affecting expression of oral mucositis ≥ Grade 2\n\nFactors\tOral mucositis ≥ Grade 2\tOdds ratio (95% CI)\tp value\t\n−\t+\t\nAge\t\t\n < 70\t6\t3\t\t\t\n ≥ 70\t5\t3\t1.20 (0.16–8.80)\t0.8577\t\nPerformance status\t\n 0\t5\t2\t\t\t\n 1\t7\t4\t1.43 (0.18–11.09)\t0.7330\t\nBody mass index\t\n < 22\t6\t3\t\t\t\n ≥ 22\t7\t3\t0.86 (0.12–5.94)\t0.8760\t\nHistopathology\t\n Squamous cell carcinoma\t12\t5\t\t\t\n Adenocarcinoma\t1\t1\t2.40 (0.12–46.39)\t0.5624\t\nLocation\t\n Upper Middle esophagus\t8\t4\t\t\t\n Lower esophagus\t5\t2\t0.80 (0.10–6.10)\t0.8296\t\nMacroscopic type\t\n Bulging type\t2\t1\t\t\t\n Ulceration type\t11\t5\t0.91 (0.07–12.52)\t0.9432\t\nWall depth degree\t\n T1, T2\t2\t3\t\t\t\n T3\t11\t3\t0.18 (0.02–1.64)\t0.1285\t\nLymph node metastasis\t\n N0, N1\t6\t2\t\t\t\n N2 ,N3\t7\t4\t1.71 (0.23–12.89)\t0.6006\t\nCancer stage\t\n II\t1\t2\t\t\t\n III\t12\t4\t0.17 (0.01–2.37)\t0.1857\t\nUnderlying disease\t\n Negative\t7\t1\t\t\t\n Positive\t6\t5\t5.83 (0.52–64.79)\t0.1512\t\nPast illness\t\n Negative\t5\t4\t\t\t\n Positive\t6\t2\t0.42 (0.05–3.31)\t0.4074\t\nAlbumin (g/dl)\t\n ≤ 3.7\t6\t1\t\t\t\n > 3.7\t7\t5\t4.29 (0.39–47.62)\t0.2362\t\nPrealbumin (mg/dl)\t\n ≤ 20\t8\t1\t\t\t\n > 20\t5\t5\t8.00 (0.71–90.00)\t0.0922\t\nRetinol binding protein (mg/dl)\t\n ≤ 3\t6\t1\t\t\t\n > 3\t7\t5\t4.29 (0.39–47.62)\t0.2362\t\nFerritin (ng/ml)\t\n ≤ 100\t3\t3\t\t\t\n > 100\t10\t3\t0.30 (0.04–2.34)\t0.2510\t\nTransferrin (mg/dl)\t\n ≤ 200\t4\t1\t\t\t\n > 200\t9\t5\t2.22 (0.19–25.72)\t0.5228\t\nCRP (mg/dl)\t\n ≤ 0.3\t7\t3\t\t\t\n ≫ 0.3\t6\t3\t1.17 (0.17–8.09)\t0.8760\t\nPlasma diamine oxidase activity (U/ml)\t\n ≤ 5\t8\t1\t\t\t\n > 5\t3\t4\t10.67 (0.82–138.22)\t0.0701\t\nIgA (mg/dl)\t\n ≤ 200\t6\t2\t\t\t\n > 200\t6\t4\t2.00 (0.26–15.38)\t0.5056\t\nCompliance of 160 g/day of elemental diet\t\n Non-completion\t2\t4\t\t\t\n Completion\t11\t2\t0.09 (0.01–0.88)\t0.0384※\t\n※p < 0.05\n\n\n\n\nIn the present study, the combination of the ED with esophageal cancer chemotherapy did not increase the rate of adverse digestive events in comparison to the historical data of another report on DCF therapy [8] (Table 5).Table 5 Comparison of digestive adverse events with historical data Fisher’s exact test\n\n\tEPOC study (n = 20)\tHistorical dataa (n = 42)\tp value\t\nAll grade\tGrade 3 ≤ \tAll grade\tGrade 3 ≤ \tAll grade\tGrade 3 ≤ \t\nAnorexia\t16 (80%)\t3 (15%)\t39 (92.9%)\t3 (7.1%)\t0.1986\t0.3773\t\nDiarrhea\t10 (50%)\t2 (10%)\t16 (38.1%)\t0 (0%)\t0.4186\t0.1005\t\nNausea\t6 (30%)\t1 (5%)\t28 (66.7%)\t0 (0%)\t0.013\t0.3226\t\naHara et al. [8]\n\n\n\n\nThe intention behind initiating the oral intake of the ED from 1 week before chemotherapy was to prevent the occurrence of pain from OM. Without the pain of OM, patients can eat regular meals and continue taking the ED through the chemotherapy cycle. In addition, when enteral nutrients are administered orally, poor compliance due to taste becomes a serious problem. Flavoring agents or a jelly mix may be good choices to make it easier for the patient to accept the taste of the ED. Measures against satiety are also important. By avoiding both increases in the caloric intake up to 1 h before a meal and uncontrolled increases in blood sugar throughout the day [29], the patients who received the ED over a period of 3 h at the same start time for breakfast and dinner tended to be able to receive the ED at a dose of 160 g/day throughout the course of chemotherapy in the present study. Another report also showed the possibility of orally administering an ED at a dose of 160 g/day [30].\n\nThe present study is associated with several limitations. First, it would be preferable to use more than one judge to assess OM in the CRS. Second, compliance to the ED should be investigated in two groups in a larger-scale study. In the present study, we wanted to determine how much of the ED could be administered orally to patients undergoing DCF chemotherapy and to investigate the differences in physiological activity according to compliance to the ED. Thus, we set the dose of the ED to 160 g/day and assessed patient compliance, adverse events, and other parameters for use in a future phase III study.\n\nConclusion\nOur multi-institutional study revealed that 14 of 20 (70%) patients with esophageal cancer completed the oral administration of an ED at a dose of 2 packs (160 g/day) during DCF chemotherapy. The CRS was useful for determining the precise incidence of OM. An ED might be a one of the test treatment to reduce the incidence of OM and should be evaluated in further randomized study. We have, therefore, begun a prospective multi-institutional phase III trial using the CRS.\n\n\nElectronic supplementary material\nBelow is the link to the electronic supplementary material.\nSupplementary material 1 (TIFF 605 kb)\n\n \n\nAcknowledgements\nThis study was partly supported by Grants from the Clinical Trial Program for Cancer 2016 in the Japan Society of Clinical Oncology, and was partly funded by EA Pharma Co., Ltd., Tokyo, Japan. We would like to thank Rise Japan for providing editorial assistance and Medical Edge K.K. for analyzing the data.\n\nAuthor contributions\nKY and YK conceived the study concept, and planned the design as the principal investigator. YT interpreted the results, and wrote the manuscript draft. KY revised the manuscript draft by adding intellectual insights and provided critical advice. TU, NY, YA, HT, HB, HM,YK and KY obtained the data and provided their critical comments to improve the manuscript and gave final approval of the final version for submission.\n\nEthical statement\nThis work conforms to the guidelines set forth in the Helsinki Declaration of 1975, as revised in 2000 (5), concerning Human and Animal Rights, and the authors followed the policy concerning Informed Consent.\n\nConflict of interest\nDr. Yoshida reports Grants, personal fees and non-financial support from EA Pharma Co., Ltd., Grants, personal fees and non-financial support from Sanofi, Grants, personal fees and non-financial support from Yakult Honsha Co., Ltd., Grants from Kyowa Hakko Kirin Co., Ltd., Grants, personal fees and non-financial support from Chugai Pharm. Co., Ltd., Grants, personal fees and non-financial support from Taiho Pharm. Co., Ltd., Grants, personal fees and non-financial support from Takeda Pharm. Co., Ltd., Grants, personal fees and non-financial support from Eli Lilly Japan K.K., Grants, personal fees and non-financial support from Daiichi Sankyo Co., Ltd., Grants, personal fees and non-financial support from Ono Pharm. Co., Ltd., Grants, personal fees and non-financial support from Merck Serono Co., Ltd., Grants, personal fees and non-financial support from Novartis Pharma K.K., outside of the submitted work. Dr. Kitagawa reports Grants and honoraria from Yakult Honsha Co., Ltd., Taiho Pharm. Co., Ltd., Grants from Kyowa Hakko Kirin Co., Ltd., honoraria from Sanofi K.K., Phizer Co., Ltd., Nippon Kayaku Co., Ltd. and Bristol-Myers Squibb, outside of the submitted work. Dr. Matsubara reports Grants from EA Pharma Co., Ltd., Yakult Honsha co., Ltd., Kyowa Hakko Kirin Co., Ltd. and Taiho Pharma Co., Ltd., outside of the submitted work. 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Tanaka Y Takahashi T Yamaguchi K Osada S Shimokawa T Yoshida K Elemental diet plus glutamine for the prevention of mucositis in esophageal cancer patients receiving chemotherapy: a feasibility study Support Care Cancer 2016 24 2 933 941 10.1007/s00520-015-2864-9 26266659 \n18. Andou A Hisamatsu T Okamoto S Chinen H Kamada N Kobayashi T Hashimoto M Okutsu T Shimbo K Takeda T Matsumoto H Sato A Ohtsu H Suzuki M Hibi T Dietary histidine ameliorates murine colitis by inhibition of proinflammatory cytokine production from macrophages Gastroenterology 2009 136 564 574 10.1053/j.gastro.2008.09.062 19027739 \n19. Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. 2003.\n20. Therasse P Arbuck SG Eisenhauer EA Wanders J Kaplan RS Rubinstein L Verweij J Van Glabbeke M van Oosterom AT Christian MC Gwyther SG New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada J Natl Cancer Inst 2009 92 205 216 10.1093/jnci/92.3.205 \n21. Ogata Y Ishibashi N Yamaguchi K Uchida S Kamei H Nakayama G Hirakawa H Tanigawa M Akagi Y Preventive effects of amino-acid-rich elemental diet Elental® on chemotherapy-induced oral mucositis in patients with colorectal cancer: a prospective pilot study Support Care Cancer 2016 24 2 783 789 10.1007/s00520-015-2844-0 26266658 \n22. Nishimura N Nakano K Ueda K Kodaira M Yamada S Mishima Y Yokoyama M Terui Y Takahashi S Hatake K Prospective evaluation of incidence and severity of oral mucositis induced by conventional chemotherapy in solid tumors and malignant lymphomas Support Care Cancer 2012 20 2053 2059 10.1007/s00520-011-1314-6 22116139 \n23. Yamamoto T Nakahigashi M Saniabadi AR Iwata T Maruyama Y Umegae S Matsumoto K Impacts of long-term enteral nutrition on clinical and endoscopic disease activities and mucosal cytokines during remission in patients with Crohn’s disease: a prospective study Inflamm Bowel Dis 2007 13 1493 1501 10.1002/ibd.20238 17879280 \n24. Okada M Maeda K Yao T Iwashita A Nomiyama Y Kitahara K Minute lesions of the rectum and sigmoid colon in patients with Crohn’s disease Hepatogastroenterology 1991 37 3 319 324 \n25. Takagi S Utsunomiya K Kuriyama S Yokoyama H Takahashi S Iwabuchi M Takahashi H Takahashi S Kinouchi Y Hiwatashi N Funayama Y Sasaki I Tsuji I Shimosegawa T Effectiveness of an ‘half elemental diet’ as maintenance therapy for Crohn’s disease: a randomized-controlled trial Aliment Pharmacol Ther 2006 24 9 1333 1340 10.1111/j.1365-2036.2006.03120.x 17059514 \n26. Ameho CK Adjei AA Harrison EK Takeshita K Morioka T Arakaki Y Ito E Suzuki I Kulkarni AD Kawajiri A Yamamoto S Prophylactic effect of dietary glutamine supplementation on interleukin 8 and tumour necrosis factor á production in trinitrobenzene sulphonic acid induced colitis Gut 1997 41 487 493 10.1136/gut.41.4.487 9391247 \n27. Sonis ST The pathobiology of mucositis Nat Rev Cancer 2004 4 277 284 10.1038/nrc1318 15057287 \n28. Bossi P Bergamini C Miceli R Cova A Orlandi E Resteghini C Locati L Alfieri S Imbimbo M Granata R Mariani L Iacovelli NA Huber V Cavallo A Licitra L Rivoltini L Salivary cytokine levels and oral mucositis in head and neck cancer patients treated with chemotherapy and radiation therapy Int J Radiat Oncol Biol Phys 2016 96 5 959 966 10.1016/j.ijrobp.2016.08.047 27745982 \n29. Anderson GH Woodend D Consumption of sugars and the regulation of short-term satiety and food intake Am J Clin Nutr 2003 78 4 843S 849S 10.1093/ajcn/78.4.843S 14522748 \n30. Kataoka K Sakagami J Hirota M Masamune A Shimosegawa T Effects of oral ingestion of the elemental diet in patients with painful chronic pancreatitis in the real-life setting in Japan Pancreas 2014 43 3 451 457 10.1097/MPA.0000000000000038 24622078\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1612-9059",
"issue": "15(4)",
"journal": "Esophagus : official journal of the Japan Esophageal Society",
"keywords": "Central review system; Chemotherapy; DCF; Esophageal carcinoma; Oral mucositis",
"medline_ta": "Esophagus",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D004938:Esophageal Neoplasms; D005240:Feasibility Studies; D005260:Female; D005526:Food, Formulated; D006801:Humans; D015994:Incidence; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D009367:Neoplasm Staging; D011446:Prospective Studies; D013280:Stomatitis",
"nlm_unique_id": "101206627",
"other_id": null,
"pages": "239-248",
"pmc": null,
"pmid": "30225745",
"pubdate": "2018-10",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "19027739;20878160;17059514;26887378;17236223;27745982;10655437;20193900;21879261;14522748;23155307;9391247;9762946;28476132;26896963;2070982;17154160;15057287;20068567;17879280;21778771;24622078;23152361;21345693;26266659;23991649;22116139;26266658",
"title": "The effect of an elemental diet on oral mucositis of esophageal cancer patients treated with DCF chemotherapy: a multi-center prospective feasibility study (EPOC study).",
"title_normalized": "the effect of an elemental diet on oral mucositis of esophageal cancer patients treated with dcf chemotherapy a multi center prospective feasibility study epoc study"
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"companynumb": "JP-INGENUS PHARMACEUTICALS, LLC-INF201806-000623",
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"activesubstancename": "DOCETAXEL"
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"abstract": "Aromatic antiepileptic drugs (AEDs) are among the drugs most frequently involved in severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reactions with eosinophilia and systemic symptoms (DRESS). This study investigated the associations between the genetic polymorphisms of HLA class-I and AED-induced SCARs in the Spanish population. HLA class-I genotypes were determined in AED (phenytoin[PHT],lamotrigine[LTG],carbamazepine[CBZ],phenobarbital[PB])-induced SJS/TEN (n=15) or DRESS (n=12) cases included in the Spanish SCAR registry, PIELenRed. There were 3 control groups: (A)tolerant to a single AED, (B)tolerant to any AED, and (C)Spanish population controls. For SJS/TEN, concomitant HLA-A*02:01/Cw15:02 alleles were significantly associated with PHT-cases compared to control groups B and C [(B)odds ratio(OR):14.75, p=0.009;(C)OR:27.50, p<0.001], and were close to significance with respect to control group A (p=0.060). The genotype frequency of the HLA-B*38:01 was significantly associated with PHT-LTG-cases compared with the 3 groups of controls [(A)OR:12.86, p=0.012;(B)OR:13.81; p=0.002;(C)OR:14.35, p<0.001], and with LTG-cases [(A)OR:147.00, p=0.001;(B)OR:115.00, p<0.001;(C)OR:124.70, p<0.001]. We found the HLA-B*15:02 allele in a Spanish Romani patient with a CBZ-case. The HLA-A*11:01 was significantly associated with CBZ-cases [(A)OR:63.89, p=0.002;(B)OR:36.33, p=0.005;(C)OR:28.29, p=0.007]. For DRESS, the HLA-A*24:02 genotype frequency was statistically significant in the PHT-LTG-cases [(A)OR:22.56, p=0.003;(B)OR:23.50. p=0.001; (C)OR:33.25, p<0.001], and in the LTG-cases [(A),OR:49.00, p=0.015;(B)OR:27.77, p=0.005; (C)OR:34.53, p=0.002]. HLA-A*31:01 was significantly associated with the CBZ-cases [(A)OR:22.00, p=0.047;(B)OR:29.50, p=0.033;(C)OR:35.14, p=0.006]. In conclusion, we identified several significant genetic risk factors for the first time in the Spanish Caucasian population: HLA-A*02:01/Cw*15:02 combination as a risk factor for PHT-induced SJS/TEN, HLA-B*38:01 for LTG- and PHT- induced SJS/TEN, HLA-A*11:01 for CBZ-induced SJS/TEN, and HLA-A*24:02 for LTG- and PHT- induced DRESS. The strong association between HLA*31:01 and CBZ-DRESS in Europeans was confirmed in this study.",
"affiliations": "Department of Clinical Pharmacology, La Paz University Hospital-Carlos III, IdiPAZ, School of Medicine, Autonomous University of Madrid, Madrid, Spain. Electronic address: elena.ramirez@inv.uam.es.;Institute for Health Research, La Paz University Hospital, IdiPAZ, Madrid, Spain.;Department of Clinical Pharmacology, La Paz University Hospital-Carlos III, IdiPAZ, School of Medicine, Autonomous University of Madrid, Madrid, Spain.;Department of Clinical Pharmacology, La Paz University Hospital-Carlos III, IdiPAZ, School of Medicine, Autonomous University of Madrid, Madrid, Spain.;Clinical Pharmacology Unit, Príncipe de Asturias University Hospital, Department of Biomedical Sciences (Pharmacology), University of Alcalá, Madrid, Spain.;Clinical Pharmacology Unit, Príncipe de Asturias University Hospital, Department of Biomedical Sciences (Pharmacology), University of Alcalá, Madrid, Spain.;Immunology Department, Ramón y Cajal University Hospital, Madrid, Spain.;Immunology Department, Ramón y Cajal University Hospital, Madrid, Spain.;Allergy Department, La Paz University Hospital-Carlos III, IdiPAZ, Madrid, Spain.;Allergy Department, La Paz University Hospital-Carlos III, IdiPAZ, Madrid, Spain.;Dermatology Department, La Paz University Hospital-Carlos III, IdiPAZ, Madrid, Spain.;Dermatology Department, La Paz University Hospital-Carlos III, IdiPAZ, Madrid, Spain.;Intensive Care Department, La Paz University Hospital-Carlos III, IdiPAZ, Madrid, Spain.;Dermatology Department, Getafe University Hospital, Madrid, Spain.;Dermatology Department, Getafe University Hospital, Madrid, Spain.;Pathological Anatomy Department, Getafe University Hospital, Madrid, Spain.;Clinical Pharmacology Unit, Geriatric Department, Getafe University Hospital, Madrid, Spain.;Department of Clinical Pharmacology, La Paz University Hospital-Carlos III, IdiPAZ, School of Medicine, Autonomous University of Madrid, Madrid, Spain.;Department of Clinical Pharmacology, La Paz University Hospital-Carlos III, IdiPAZ, School of Medicine, Autonomous University of Madrid, Madrid, Spain.;Department of Clinical Pharmacology, La Paz University Hospital-Carlos III, IdiPAZ, School of Medicine, Autonomous University of Madrid, Madrid, Spain. Electronic address: jesus.frias@uam.es.",
"authors": "Ramírez|Elena|E|;Bellón|Teresa|T|;Tong|Hoi Y|HY|;Borobia|Alberto M|AM|;de Abajo|Francisco J|FJ|;Lerma|Victoria|V|;Moreno Hidalgo|Miguel A|MA|;Castañer|José L|JL|;Cabañas|Rosario|R|;Fiandor|Ana|A|;González-Ramos|Jessica|J|;Herranz|Pedro|P|;Cachafeiro|Lucía|L|;González-Herrada|Carlos|C|;González|Olga|O|;Aramburu|José A|JA|;Laosa|Olga|O|;Hernández|Rafael|R|;Carcas|Antonio J|AJ|;Frías|Jesús|J|",
"chemical_list": "D000927:Anticonvulsants",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.phrs.2016.11.027",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1043-6618",
"issue": "115()",
"journal": "Pharmacological research",
"keywords": "Aromatic antiepileptic drugs; Carbamazepine (PubChem CID: 2554); Drug reaction with eosinophilia and systemic symptoms; Human leukocyte antigen; Lamotrigine (PubChem CID: 3878); Phenobarbital (PubChem CID: 4763); Phenytoin (PubChem CID: 1775); Severe cutaneous adverse drug reactions; Stevens-Johnson syndrome; Toxic epidermal necrolysis",
"medline_ta": "Pharmacol Res",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants; D002648:Child; D002675:Child, Preschool; D063926:Drug Hypersensitivity Syndrome; D005260:Female; D005805:Genes, MHC Class I; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012307:Risk Factors; D013030:Spain; D013262:Stevens-Johnson Syndrome; D044465:Whites; D055815:Young Adult",
"nlm_unique_id": "8907422",
"other_id": null,
"pages": "168-178",
"pmc": null,
"pmid": "27888155",
"pubdate": "2017-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Significant HLA class I type associations with aromatic antiepileptic drug (AED)-induced SJS/TEN are different from those found for the same AED-induced DRESS in the Spanish population.",
"title_normalized": "significant hla class i type associations with aromatic antiepileptic drug aed induced sjs ten are different from those found for the same aed induced dress in the spanish population"
} | [
{
"companynumb": "ES-MYLANLABS-2017M1010107",
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"occurcountry": "ES",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PHENYTOIN"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nAnalysis of cross-reactivity is necessary for prescribing safe cephalosporins for penicillin allergic patients. Amoxicillin (AX) is the betalactam most often involved in immediate hypersensitivity reactions (IHRs), and cefadroxil (CX) the most likely cephalosporin to cross-react with AX, since they share the same R1 side chain, unlike cefuroxime (CO), with a structurally different R1. We aimed to analyse cross-reactivity with CX and CO in patients with confirmed IHRs to AX, including sIgE recognition to AX, CX, CO, and novel synthetic determinants of CX.\n\n\nMETHODS\nFifty-four patients with confirmed IHRs to AX based on skin test (ST) and/or drug provocation test (DPT) were included. Serum sIgE to AX and benzylpenicillin was determined by Radioallergosorbent test (RAST). Two potential determinants of CX, involving intact or modified R1 structure, with open betalactam ring, were synthesised and sIgE evaluated by RAST inhibition assay.\n\n\nRESULTS\nTolerance to CX (Group A) was observed in 64.8% cases and cross-reactivity in 35.2% cases (Group B). Cross-reactivity with CO was only found in 1.8% cases from Group B. ST to CX showed a negative predictive value of 94.6%. RAST inhibition assays showed higher recognition to CX as well as to both synthetic determinants (66% of positive cases) in Group B.\n\n\nCONCLUSIONS\nCross-reactivity with CX in AX allergic patients is 35%, being ST not enough for prediction. R1, although critical for recognition, is not the unique factor. The synthetic determinants of CX, 1-(HOPhG-Ser-Bu) and 2-(pyrazinone) are promising tools for determining in vitro cross-reactivity to CX in AX allergic patients.",
"affiliations": "Allergy Research Group, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Civil, 29009, Málaga, Spain.;Allergy Research Group, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Civil, 29009, Málaga, Spain.;Allergy Research Group, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Civil, 29009, Málaga, Spain.;Allergy Research Group, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Civil, 29009, Málaga, Spain.;Allergy Research Group, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Civil, 29009, Málaga, Spain.;Allergy Research Group, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Civil, 29009, Málaga, Spain.;Allergy Research Group, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Civil, 29009, Málaga, Spain.;Allergy Research Group, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Civil, 29009, Málaga, Spain.;Allergy Research Group, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Civil, 29009, Málaga, Spain.;Allergy Research Group, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Civil, 29009, Málaga, Spain.;Allergy Research Group, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Civil, 29009, Málaga, Spain. mjtorresj@uma.es.;Allergy Research Group, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Civil, 29009, Málaga, Spain.",
"authors": "Bogas|Gador|G|;Mayorga|Cristobalina|C|;Martín-Serrano|Ángela|Á|;Fernández-Santamaría|Rubén|R|;Jiménez-Sánchez|Isabel M|IM|;Ariza|Adriana|A|;Barrionuevo|Esther|E|;Posadas|Teresa|T|;Salas|María|M|;Fernández|Tahía Diana|TD|;Torres|María José|MJ|;Montañez|María Isabel|MI|http://orcid.org/0000-0001-6641-5979",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s13601-020-00368-1",
"fulltext": "\n==== Front\nClin Transl Allergy\nClin Transl Allergy\nClinical and Translational Allergy\n2045-7022 BioMed Central London \n\n368\n10.1186/s13601-020-00368-1\nResearch\nPenicillin and cephalosporin cross-reactivity: role of side chain and synthetic cefadroxil epitopes\nBogas Gador 12 Mayorga Cristobalina 123 Martín-Serrano Ángela 13 Fernández-Santamaría Rubén 1 Jiménez-Sánchez Isabel M. 13 Ariza Adriana 1 Barrionuevo Esther 12 Posadas Teresa 12 Salas María 12 Fernández Tahía Diana 14 Torres María José mjtorresj@uma.es 1235 http://orcid.org/0000-0001-6641-5979Montañez María Isabel maribel.montanez@ibima.eu 13 1 grid.452525.1Allergy Research Group, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Civil, 29009 Málaga, Spain \n2 grid.411457.2Allergy Unit, Hospital Regional Universitario de Málaga, Hospital Civil, 29009 Málaga, Spain \n3 Nanostructures for Diagnosing and Treatment of Allergic Diseases Laboratory, Andalusian Center for Nanomedicine and Biotechnology-BIONAND, Parque Tecnológico de Andalucía, 29590 Málaga, Spain \n4 grid.10215.370000 0001 2298 7828Departamento de Biología Celular, Genética y Fisiología, Universidad de Málaga, 29071 Málaga, Spain \n5 grid.10215.370000 0001 2298 7828Departamento de Medicina, Universidad de Málaga, Facultad de Medicina, 29071 Málaga, Spain \n4 12 2020 \n4 12 2020 \n2020 \n10 5710 10 2020 27 11 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nAnalysis of cross-reactivity is necessary for prescribing safe cephalosporins for penicillin allergic patients. Amoxicillin (AX) is the betalactam most often involved in immediate hypersensitivity reactions (IHRs), and cefadroxil (CX) the most likely cephalosporin to cross-react with AX, since they share the same R1 side chain, unlike cefuroxime (CO), with a structurally different R1. We aimed to analyse cross-reactivity with CX and CO in patients with confirmed IHRs to AX, including sIgE recognition to AX, CX, CO, and novel synthetic determinants of CX.\n\nMethods\nFifty-four patients with confirmed IHRs to AX based on skin test (ST) and/or drug provocation test (DPT) were included. Serum sIgE to AX and benzylpenicillin was determined by Radioallergosorbent test (RAST). Two potential determinants of CX, involving intact or modified R1 structure, with open betalactam ring, were synthesised and sIgE evaluated by RAST inhibition assay.\n\nResults\nTolerance to CX (Group A) was observed in 64.8% cases and cross-reactivity in 35.2% cases (Group B). Cross-reactivity with CO was only found in 1.8% cases from Group B. ST to CX showed a negative predictive value of 94.6%. RAST inhibition assays showed higher recognition to CX as well as to both synthetic determinants (66% of positive cases) in Group B.\n\nConclusions\nCross-reactivity with CX in AX allergic patients is 35%, being ST not enough for prediction. R1, although critical for recognition, is not the unique factor. The synthetic determinants of CX, 1-(HOPhG-Ser-Bu) and 2-(pyrazinone) are promising tools for determining in vitro cross-reactivity to CX in AX allergic patients.\n\nKeywords\nAmoxicillinBetalactamCephalosporinCross-reactivityDrug allergyAntigenic determinantSpecific IgEhttp://dx.doi.org/10.13039/501100004587Instituto de Salud Carlos IIIPI12/02529, PI15/01206, PI18/00095, RETIC ARADYAL RD16/0006/0001CP15/00103, PI17/01237JR18/00054CD17/0146Bogas Gador Ariza Adriana Torres María José Montañez María Isabel Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía (ES)CTS-06603Torres María José http://dx.doi.org/10.13039/501100010566Consejería de Salud, Junta de AndalucíaC-0044-2012 SAS2013PI-0699-2011, PI-0179-2014PE-0172-2018PE-0172-2018Mayorga Cristobalina Fernández-Santamaría Rubén Torres María José Montañez María Isabel issue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nBetalactams (BLs) are the drugs most frequently involved in immediate (IgE-mediated) hypersensitivity reactions (IHRs) [1–3], which could be explained by their ability to act as haptens due to their high chemical reactivity against proteins [4, 5]. BL chemical structure is formed by a 4-membered ring (the so-called BL ring) that in penicillins is fused to a 5-membered thiazolidine ring, and in cephalosporins to a 6-membered dihydrothiazine ring (Fig. 1). These drugs have a side chain (R1) bound to the BL ring; besides, cephalosporins have a second side chain (R2) bound to the dihydrothiazine ring, whose chemical structures distinguish the different compounds [6, 7].Fig. 1 Chemical structures of betalactam antibiotics involved in the study: amoxicillin (AX), cefadroxil (CX), and cefuroxime (CO); with indication of the different parts of the structures\n\n\n\nPenicillins are the most consumed antibiotics in Europe, representing 37% of total consumption, followed by cephalosporins with a 15% of total antibiotic consumption [8]. Among them, amoxicillin (AX) is the most consumed and the most often involved in IHRs to BLs followed by cephalosporins [3, 9] which include the following: cefuroxime (CO), ceftriaxone, cefatrizin, cefaclor, and cefadroxil (CX) [10, 11], with different percentage of cross-reactivity between them [6], highly related to their chemical structure [12–14]. Cross-reactivity rate with cephalosporins in penicillin-allergic patients with IgE-mediated reactions ranges from 0% to almost 40% depending on the chemical structure of the BL involved [15–22], specifically on similarity in the R1 side chain [23, 24]. In this context, AX, which shares the same amino R1 side chain with CX (Fig. 1), could have a high cross reactivity [19–21]. Conversely, CO, with a different R1 side chain, has shown tolerance in patients with IHRs to penicillins [16–19] and, more recently, similar results have been found with cefazolin and ceftibuten [22, 25].\n\nCross-reactivity has important clinical implications, especially for searching safe alternative for further treatments, and an accurate diagnosis based on skin testing (ST) is recommended, being the role of drug provocation tests (DPT) controversial [3, 9, 26]. In vitro evaluation of cross-reactivity to BLs, mainly based on immunoassays, is limited by the difficulty for studying the structure of cephalosporin-protein conjugates [27]. Although several reports have addressed this issue [28–30], the antigenic determinants of cephalosporins are currently not well-known [31].\n\nTo our knowledge, structure–activity relationship (SAR) studies have been the unique successful approach for investigating cephalosporin epitopes [28–30, 32]. In this context, we have elucidated precise epitope structures through synthesis and immunologic evaluation of well-defined structures proposed as antigenic determinants for cephalosporins with different R1, bearing different functionalities at the C-6 of the cephalosporin (methyl, hydroxymethyl, aldehyde, mercaptomethyl) and without involvement of the remaining dihydrothiazine ring [29, 30]. Moreover, we have identified a novel synthetic pyrazinone structure as an antigenic determinant of cefaclor [28], formed after reaction of the amino group in the R1 with the likely aldehyde functionality at C-6 of the original cephalosporin [28, 32]. CX is another aminocephalosporin that could follow the same fragmentation and reactivity pathways as cefaclor [32].\n\nIn this study we have evaluated the in vivo degree of cross-reactivity with CX and CO in patients with confirmed IHR to AX and the immunological recognition of AX and these cephalosporins by serum specific IgE (sIgE). The ultimate aim of this study was to evaluate if synthetic structures, proposed as potential antigenic determinants mimicking the fragment of CX, which would remain coupled to the protein, can help get insight into the structure responsible for CX allergies and, therefore, study cross-reactivities between AX and CX.\n\nMethods\nPatients\nThe studied group was obtained from the Regional University Hospital of Málaga Drug Allergy Database. This prospective cohort includes all patients with confirmed drug allergy from 1984 to 2019 after an allergological workup including clinical history, ST, and DPT.\n\nPatients with IHR to AX (allergic to the whole penicillin group or AX selective reactors with good tolerance to penicillin V (PV)) were diagnosed following the European Academy of Allergy and Clinical Immunology (EAACI) recommendations [9, 33]. Tolerance to CX and CO was evaluated and, based on CX tolerance, patients were classified into: Group A with tolerance (demonstrated by negative ST and DPT) and Group B with cross-reactivity (demonstrated by positive ST or DPT) (Fig. 2).Fig. 2 a The diagnostic algorithm includes skin tests (STs) to PPL/BP-OL, MDM/DM and amoxicillin (AX) and if negative drug provocation tests (DPT) to penicillin V (PV) and AX. Patients were classified into two groups, allergic to the whole group of penicillins or selective reactors to AX. b Cross reactivity to cefadroxil (CX) was analysed by STs and DPT and AX-allergic patients classified into two groups: Group A with good tolerance and Group B with cross-reactivity. In all cases cross-reactivity with cefuroxime (CO) was also analysed by ST and DPT\n\n\n\nSkin test\nSkin prick (SPT) and, if negative, intradermal tests (IDT) were performed as described [9, 33], using benzylpenicilloyl-poly-L-lysine (PPL, DAP, Diater, Leganés, Spain) at 1.07·10–2 M, minor determinant mixture (MDM: benzylpenicillin, benzylpenicilloate, and benzylpenilloate) at 1.5 M and AX (Diater laboratories, Madrid, Spain); CX (Lilly SA, Madrid) and CO (GlaxoSmithKline S.A, Madrid) all at 20 mg/mL. Since May 2011 DAP composition has changed and includes the major determinant benzylpenicilloyl-octa-L-lysine (BP-OL) at 0.04 mg/mL, equivalent to 8.64·10–5 M concentration of the benzylpenicilloyl (BPO) moiety, and the minor determinant (MD) at 0.5 mg/mL, equivalent to 1.5·10–3 M concentration of sodium benzylpenilloate. Cephalosporin reagents were prepared according to Romano [19, 34].\n\nReadings were done after 20 min and considered positive: (i) In SPT, if a wheal larger than 3 mm surrounded by erythema appeared, with a negative response to the control saline; (ii) In IDT, if the increase in diameter of the wheal area marked initially was greater than 3 mm surrounded by erythema. Positive data expressed as the mean diameter recorded by measuring the largest and the smallest diameters at right angles to each other [35].\n\nDrug provocation test\nIn subjects with negative ST to PPL/BP-OL and MDM/MD, oral DPT with PV was performed at incremental dose (50, 100, 100, 150 mg) each 40-min until reaching the total cumulative dose (TCD) of 400 mg, followed by a 2 day therapeutic course of PV of 400 mg/8-h at home [33]. If DPT with PV and ST to AX was negative, oral DPT with AX was performed (50, 100, 150, 200 mg) until TCD of 500 mg, followed by a 2 day therapeutic course of AX 500 mg/8-h at home. For cross-reactivity analysis, if ST was negative, CX was orally administered (50, 100, 150, 200 mg) until TCD of 500 mg, followed by a 2 day therapeutic course of CX 500 mg/8-h. Finally, CO was administered following this procedure.\n\nPatients were carefully monitored during DPT and for 2 h after the last dose, complete equipment for cardiopulmonary resuscitation was available [36].\n\nIn vitro sIgE determination by radioallergosorbent test (RAST)\nIt was done using BP and AX conjugated to Poly-L-Lysine (PLL) (Sigma, St. Louis, MO) resulting in BPO-PLL and AXO-PLL in the solid phase, as described [37, 38], and radiolabeled anti-IgE antibody (kindly provided by Thermo Fisher Scientific and radiolabelled in our laboratory) [28]. Samples were considered positive if they were higher than 2.5% of label uptake, which was the mean + 2SD of a negative control group.\n\nSynthesis of chemical structures\nThe molecule 1 (HOPhG-Ser-Bu) (Fig. 3a) was synthesised as described [30].Fig. 3 a Degradation hypothesis of cefadroxil (CX) after nucleophilic opening of betalactam ring by protein amino groups, leading to the cephalosporoyl intermediate, which degrades through dihydrotiazine fragmentation, and leading different functionality at carbon 6, hydroxyl and aldehyde respectively, and eventually resulting in the proposed antigenic determinants. Those equivalent synthetic structures for further immunological evaluation are represented in the square. b Synthesis of pyrazinone (molecule 2), pyrazin-2(1H)-one, proposed as CX determinant, through Ugi/Deprotect/Cyclize strategy\n\n\n\nThe molecule 2 (pyrazinone) (Fig. 3a) was synthesised following the Ugi/Desprotect/Cyclize strategy (Fig. 3b) [39], adapting protocols from cefaclor pyrazinone synthesis [28]. The synthetic methodology and characterisation of the pure compound can be found in this article's Additional file 1.\n\nRAST inhibition assay\nThis was done as described [38], incubating sera from patients with RAST values higher than 7% with different BLs (AX, CX, and CO) and the synthetic determinants of CX (1 and 2) in two ten-fold decreasing concentrations (100 mM and 10 mM) for 18 h at room temperature. After this, the AXO-PLL disc was added, followed by the previous described RAST procedure. The results were expressed as percentage inhibition with respect to the non-inhibited serum. Comparison of the inhibition capacity of the different inhibitors was made at 50% inhibition.\n\nStatistical analysis\nDescription of quantitative variable included the median, mean, standard deviation (SD), and interquartile range (IR). Differences in percentage between the groups were compared by Chi-square analysis, numeric demographic data by Student t test. Comparisons for variables without a normal distribution were performed by the Mann–Whitney test for non-related samples and by Friedman test for related samples. All statistical analyses were done using the software package GraphPad PRISM v7. A P < 0.05 was considered statistically significant.\n\nResults\nFrom 1393 patients with confirmed BL hypersensitivity evaluated from 1984 to 2019, 994 subjects were confirmed with IHRS to AX, from which we randomly selected 54 patients, whose cross-reactivity to CX and CO was evaluated and flow-charts analysed (Fig. 2). The mean age was 41.7 ± 12.04 years; 35 (64.8%) were males; 51 (94.4%) had 1 episode and 3 (5,6%) two; in 32 (56.1%) episodes AX-CLV was the culprit and in 25 (43.9%) AX. The main symptoms were anaphylaxis in 40 (70.2%) cases, urticaria in 13 (22.8%), and anaphylactic shock in 4 (7%). The mean time interval between drug administration and development of symptoms was 26.1 ± 19.2 min and between last reaction and study 132.4 ± 131.4 days (Table 1).Table 1 Demographic and clinical data of patients included in the study\n\nPat\tGroup\tSex\tAge\tDrug\tEpi\tReaction\tIDR (min)\tIRS (d)\t\n1\tA\tM\t55\tAX-CLV\t1\tAnaphylaxis\t60\t180\t\n2\tB\tM\t44\tAX-CLV\t1\tAnaphylaxis\t20\t60\t\n3\tA\tM\t46\tAX\t1\tAnaphylaxis\t30\t30\t\n4\tB\tM\t55\tAX\t1\tUrticaria\t30\t300\t\n5\tA\tM\t62\tAX-CLV\t1\tAnaphylaxis\t60\t90\t\n6\tB\tF\t45\tAX-CLV\t1\tAnaphylaxis\t10\t30\t\n7\tB\tM\t24\tAX\t1\tAnaphylaxis\t10\t30\t\n8\tB\tF\t45\tAX\t1\tAnaphylaxis\t20\t90\t\n9\tA\tM\t47\tAX\t2\tUrticaria\n\nAnaphylaxis\n\n\t40\n\n10\n\n\t477\n\n365\n\n\t\n10\tA\tF\t46\tAX-CLV\t1\tAnaphylaxis\t30\t120\t\n11\tA\tM\t43\tAX-CLV\t1\tAnaphylaxis\t45\t60\t\n12\tB\tF\t40\tAX/AX-CLV\t2\tUrticaria\n\nAnaphylaxis\n\n\t30\n\n5\n\n\t112\n\n109\n\n\t\n13\tA\tF\t16\tAX-CLV\t1\tUrticaria\t60\t30\t\n14\tA\tM\t27\tAX-CLV\t1\tAnaphylactic shock\t5\t21\t\n15\tA\tM\t66\tAX\t1\tAnaphylaxis\t60\t365\t\n16\tB\tM\t44\tAX\t1\tAnaphylaxis\t10\t365\t\n17\tA\tF\t50\tAX-CLV\t1\tAnaphylaxis\t15\t30\t\n18\tA\tM\t44\tAX-CLV\t1\tAnaphylaxis\t10\t280\t\n19\tA\tM\t25\tAX-CLV\t1\tUrticaria\t60\t120\t\n20\tB\tF\t33\tAX-CLV\t1\tAnaphylaxis\t15\t6\t\n21\tB\tF\t36\tAX-CLV\t1\tAnaphylaxis\t30\t60\t\n22\tA\tM\t30\tAX\t1\tAnaphylaxis\t5\t20\t\n23\tB\tM\t45\tAX-CLV\t1\tAnaphylactic shock\t5\t30\t\n24\tA\tM\t30\tAX-CLV\t1\tAnaphylaxis\t30\t210\t\n25\tB\tM\t57\tAX-CLV\t1\tAnaphylaxis\t5\t60\t\n26\tA\tM\t49\tAX\t1\tAnaphylaxis\t10\t120\t\n27\tA\tF\t39\tAX\t1\tUrticaria\t40\t40\t\n28\tA\tF\t39\tAX-CLV\t1\tUrticaria\t60\t95\t\n29\tA\tF\t21\tAX-CLV\t1\tAnaphylaxis\t15\t230\t\n30\tA\tM\t46\tAX-CLV\t1\tAnaphylaxis\t2\t137\t\n31\tB\tM\t49\tAX\t1\tAnaphylaxis\t5\t180\t\n32\tB\tF\t37\tAX-CLV\t1\tAnaphylaxis\t20\t30\t\n33\tA\tF\t57\tAX\t1\tAnaphylaxis\t30\t90\t\n34\tB\tM\t26\tAX\t1\tAnaphylaxis\t20\t10\t\n35\tB\tM\t48\tAX-CLV\t1\tAnaphylaxis\t60\t146\t\n36\tA\tM\t23\tAX-CLV\t1\tAnaphylaxis\t50\t60\t\n37\tB\tF\t42\tAX\t1\tAnaphylaxis\t5\t120\t\n38\tB\tM\t57\tAX-CLV\t1\tAnaphylaxis\t30\t28\t\n39\tB\tM\t30\tAX-CLV\t1\tUrticaria\t10\t730\t\n40\tA\tF\t37\tAX-CLV\t1\tAnaphylaxis\t5\t30\t\n41\tA\tF\t14\tAX-CLV\t1\tAnaphylaxis\t10\t90\t\n42\tA\tM\t44\tAX\t1\tUrticaria\t30\t120\t\n43\tA\tM\t28\tAX\t2\tAnaphylaxis\n\nAnaphylaxis\n\n\t20\n\n25\n\n\t230\n\n180\n\n\t\n44\tA\tM\t63\tAX-CLV\t1\tAnaphylaxis\t10\t30\t\n45\tA\tM\t51\tAX\t1\tUrticaria\t60\t30\t\n46\tA\tM\t35\tAX\t1\tUrticaria\t30\t90\t\n47\tA\tM\t32\tAX\t1\tAnaphylaxis\t45\t180\t\n48\tA\tM\t53\tAX\t1\tAnaphylaxis\t30\t90\t\n49\tA\tM\t44\tAX\t1\tUrticaria\t45\t120\t\n50\tA\tF\t38\tAX-CLV\t1\tAnaphylaxis\t10\t30\t\n51\tA\tM\t54\tAX-CLV\t1\tAnaphylactic shock\t5\t90\t\n52\tA\tF\t62\tAX-CLV\t1\tUrticaria\t60\t210\t\n53\tB\tM\t49\tAX-CLV\t1\tAnaphylaxis\t30\t120\t\n54\tA\tF\t44\tAX\t1\tAnaphylactic shock\t5\t240\t\nPatients were classified into Group A (Good tolerance to cefadroxil) or Group B (Cross-reactivity with cefadroxil)\n\nPat, Patients; M, Male; F, Female; AX-CLV, Amoxicillin-clavulanic; AX, Amoxicillin; Epi, Number of episodes; IDR (min), Interval drug administration and development of symptoms in minutes; IRS (d), Interval last reaction and allergological study in days\n\n\n\nAllergological work-up\nFifty (92.6%) patients were diagnosed by ST and 4 (7.4%) by DPT (Tables 2 and 3). Regarding ST, 2 (4%) cases were positive to PPL/BP-OL (both by IDT), 4 (8%) to MDM/MD (all by IDT), and to AX 27 (54%) by SPT and 23 (46%) by IDT (Table 2). Moreover, P37 and P39 developed immediate generalised pruritus and wheals 20 and 30 min respectively after ST with AX.Table 2 Skin tests and RAST results in patients from Group A (Good tolerance to cefadroxil) and Group B (Cross-reactivity with cefadroxil)\n\nPat\tGroup\tSkin test\tRAST\tAX-PLL\t\nPPL/BP-OL\tMDM/MD\tAX\tCX\tCO\tBPO-PLL\t\n1\tA\tNeg\tNeg\tNeg\tNeg\tNeg\tND\tND\t\n2\tB\tNeg\tNeg\tSPT + (5 x 5)\tID + (2x2)\tNeg\t0\t3.42\t\n3\tA\tNeg\tNeg\tSPT+(5 x 5)\tNeg\tNeg\t0.15\t3.24\t\n4\tB\tNeg\tNeg\tSPT+(4 x 5)\tSPT + (4 x 4)\tNeg\t0\t0\t\n5\tA\tNeg\tNeg\tNeg\tNeg\tNeg\t0\t0\t\n6\tB\tNeg\tNeg\tSPT + (5 x 5)\tIDT + (1 x 1)\tNeg\tND\tND\t\n7\tB\tNeg\tNeg\tSPT + (6 x 6)\tSPT + (3 x 3)\tNeg\t0.34\t14.59\t\n8\tB\tNeg\tNeg\tSPT + (8 x 1)\tSPT + (5 x 5)\tNeg\t0\t3.51\t\n9\tA\tNeg\tNeg\tSPT + (5 x 5)\tNeg\tNeg\t0\t0\t\n10\tA\tNeg\tNeg\tIDT + (3 x 2)\tNeg\tNeg\t0\t0\t\n11\tA\tNeg\tNeg\tIDT + (2 x 2)\tNeg\tNeg\t0\t0\t\n12\tB\tNeg\tNeg\tIDT + (3 x 3)\tIDT + (2x2)\tNeg\t0.2\t0.46\t\n13\tA\tNeg\tNeg\tIDT + (4 x 4)\tNeg\tNeg\tND\tND\t\n14\tA\tNeg\tNeg\tSPT + (3 x 3)\tNeg\tNeg\t0\t0\t\n15\tA\tNeg\tNeg\tIDT + (2 x 3)\tNeg\tNeg\tND\tND\t\n16\tB\tNeg\tNeg\tSPT + (4 x 5)\tIDT + (2 x 2)\tNeg\t1.72\t11.71\t\n17\tA\tNeg\tNeg\tIDT + (2 x 3)\tNeg\tNeg\t0\t0\t\n18\tA\tNeg\tNeg\tIDT + (3 x 4)\tNeg\tNeg\t0\t0\t\n19\tA\tNeg\tNeg\tNeg\tNeg\tNeg\tND\tND\t\n20\tB\tNeg\tNeg\tIDT + (2 x 2)\tIDT + (2 x 1)\tNeg\t0\t3.2\t\n21\tB\tNeg\tNeg\tSPT + (5 x 6)\tIDT + (1 x 2)\tNeg\tND\tND\t\n22\tA\tIDT+(2x1)\tIDT+(1x1)\tSPT + (3 x 3)\tNeg\tNeg\t3.2\t6.79\t\n23\tB\tNeg\tIDT+(2x2)\tSPT + (6 x 6)\tSPT + (3 x 3)\tNeg\t23.54\t29.83\t\n24\tA\tNeg\tNeg\tSPT + (2 x 3)\tNeg\tNeg\t0\t3.03\t\n25\tB\tNeg\tNeg\tSPT + (5 x 6)\tIDT + (2 x 2)\tNeg\t1.22\t7.55\t\n26\tA\tNeg\tNeg\tNeg\tNeg\tNeg\t0\t0\t\n27\tA\tNeg\tNeg\tIDT + (3 x 3)\tIDT + (2 x 2)\tNeg\t0.2\t0.46\t\n28\tA\tNeg\tNeg\tIDT + (3 x 4)\tNeg\tNeg\t2.15\t8.32\t\n29\tA\tNeg\tNeg\tIDT + (4 x 4)\tNeg\tNeg\t0.09\t0.54\t\n30\tA\tNeg\tNeg\tSPT + (5 x 6)\tNeg\tNeg\t0\t1.14\t\n31\tB\tNeg\tNeg\tSPT + (5 x 5)\tSPT+(2+3)\tNeg\t0\t22.54\t\n32\tB\tNeg\tNeg\tSPT + (3 x 3)\tIDT+(2 x 3)\tNeg\t0\t15.56\t\n33\tA\tNeg\tNeg\tSPT + (4 x 5)\tNeg\tNeg\t1.28\t2.31\t\n34\tB\tNeg\tNeg\tSPT + (6 x 6)\tIDT + (2 x 3)\tNeg\t1.87\t3.36\t\n35\tB\tNeg\tIDT + (2x2)\tSPT + (7 x 8)\tSPT + (3 x 4)\tNeg\t6.15\t26.09\t\n36\tA\tNeg\tNeg\tIDT + (2 x 2)\tNeg\tNeg\t0\t25.56\t\n37\tB\tNeg\tNeg\tIDT + (1 x 2)\tNeg\tNeg\t0.37\t0.13\t\n38\tB\tNeg\tNeg\tSPT + (5 x 6)\tIDT + (3 x 4)\tNeg\t1.65\t21.8\t\n39\tB\tNeg\tNeg\tIDT + (2 x 2)\tNeg\tNeg\t0\t0.92\t\n40\tA\tNeg\tNeg\tSPT + (2 x 3)\tNeg\tNeg\t0\t0.7\t\n41\tA\tNeg\tNeg\tIDT + (5 x 6)\tNeg\tNeg\t0\t1.93\t\n42\tA\tNeg\tNeg\tIDT + (2 x 2)\tNeg\tNeg\t0\t0.37\t\n43\tA\tNeg\tNeg\tIDT + (3 x 3)\tNeg\tNeg\t0\t1.24\t\n44\tA\tNeg\tNeg\tIDT + (4 x 5)\tNeg\tNeg\t0.23\t0\t\n45\tA\tNeg\tNeg\tIDT + (2 x 2)\tNeg\tNeg\t0\t23.2\t\n46\tA\tNeg\tNeg\tSPT + (4 x 4)\tNeg\tNeg\t0\t0\t\n47\tA\tNeg\tID + (2x2)\tSPT + (5 x 6)\tNeg\tNeg\t0.84\t1.12\t\n48\tA\tID + (2x2)\tNeg\tSPT + (4 x 5)\tNeg\tNeg\t8.13\t13.87\t\n49\tA\tNeg\tNeg\tIDT + (2 x 2)\tNeg\tNeg\t0\t0.14\t\n50\tA\tNeg\tNeg\tSPT + (5 x 4)\tNeg\tNeg\t0.54\t0.41\t\n51\tA\tNeg\tNeg\tIDT + (5 x 7)\tNeg\tNeg\t0\t14.68\t\n52\tA\tNeg\tNeg\tIDT + (3 x 4)\tNeg\tNeg\t0\t7.93\t\n53\tB\tNeg\tNeg\tSPT + (4 x 5)\tNeg\tNeg\t0\t16.84\t\n54\tA\tNeg\tNeg\tIDT + (3 x 2)\tNeg\tNeg\t0.06\t33.02\t\nPat, Patients; PPL/BPO-OL, Benzylpenicilloyl-poly-L-lysine/benzylpenicilloyl-octa-L-lysine; MDM/MD, Minor determinant mixture/minor determinant; AX, Amoxicillin; CX, Cefadroxil; CO, Cefuroxime; BPO-PLL, Benzylpenicilloyl-poly-L-lysine; AXO-PLL, Amoxicilloyl-poly-L-lysine; SPT, Skin prick test; IDT, Intradermal test; Neg, Negative; ND, Not done\n\nTable 3 Drug provocation test results in patients from Group A (Good tolerance to cefadroxil) and Group B (Cross-reactivity with cefadroxil)\n\nPat\tGroup\tDrug\tReaction\tIDR (min)\tTCD (mg)\t\n1\tA\tAX\tUrticaria\t160\t500\t\nPV/CX/CO\tGood tolerance\t–\t–\t\n2\tB\tPV/CO\tGood tolerance\t–\t–\t\n3\tA\tPV/CX/CO\tGood tolerance\t–\t–\t\n4\tB\tPV/CO\tGood tolerance\t–\t–\t\n5\tA\tAX\tAnaphylaxis\t15\t50\t\nPV/CX/CO\tGood tolerance\t–\t–\t\n6\tB\tPV/CO\tGood tolerance\t–\t–\t\n7\tB\tPV/CO\tGood tolerance\t–\t–\t\n8\tB\tPV\tAnaphylaxis\t45\t150\t\nCO\tGood tolerance\t–\t–\t\n9\tA\tPV/CX/CO\tGood tolerance\t–\t–\t\n10\tA\tPV/CX/CO\tGood tolerance\t–\t–\t\n11\tA\tPV/CX/CO\tGood tolerance\t–\t–\t\n12\tB\tPV/CO\tGood tolerance\t–\t–\t\n13\tA\tPV/CX/CO\tGood tolerance\t–\t–\t\n14\tA\tPV/CX/CO\tGood tolerance\t–\t–\t\n15\tA\tPV/CX/CO\tGood tolerance\t–\t–\t\n16\tB\tPV/CO\tGood tolerance\t–\t–\t\n17\tA\tPV/CX/CO\tGood tolerance\t–\t–\t\n18\tA\tPV/CX/CO\tGood tolerance\t–\t–\t\n19\tA\tAX\tUrticaria\t140\t500\t\nPV/CX/CO\tGood tolerance\t–\t–\t\n20\tB\tPV/CO\tGood tolerance\t–\t–\t\n21\tB\tPV/CO\tGood tolerance\t–\t–\t\n22\tA\tCX/CO\tGood tolerance\t–\t–\t\n23\tB\tCO\tGood tolerance\t–\t–\t\n24\tA\tPV/CX/CO\tGood tolerance\t–\t–\t\n25\tB\tPV/CO\tGood tolerance\t–\t–\t\n26\tA\tAX\tGeneralized pruritus and erythema\t60\t150\t\nPV/CX/CO\tGood tolerance\t–\t–\t\n27\tA\tPV/CO\tGood tolerance\t–\t–\t\n28\tA\tPV/CX/CO\tGood tolerance\t–\t–\t\n29\tA\tPV/CX/CO\tGood tolerance\t–\t–\t\n30\tA\tPV/CX/CO\tGood tolerance\t–\t–\t\n31\tB\tPV/CO\tGood tolerance\t–\t–\t\n32\tB\tPV/CO\tGood tolerance\t–\t–\t\n33\tA\tPV/CX/CO\tGood tolerance\t–\t–\t\n34\tB\tPV\tGood tolerance\t–\t–\t\nCO\tUrticaria\t25\t50\t\n35\tB\tCO\tGood tolerance\t–\t–\t\n36\tA\tPV/CX/CO\tGood tolerance\t–\t–\t\n37\tB\tPV/CO\tGood tolerance\t–\t–\t\nCX\tUrticaria\t50\t150\t\n38\tB\tPV/CO\tGood tolerance\t–\t–\t\n39\tB\tPV/CX/CO\tGood tolerance\t–\t–\t\n40\tA\tPV/CX/CO\tGood tolerance\t–\t-\t\n41\tA\tPV/CX/CO\tGood tolerance\t–\t-\t\n42\tA\tPV/CX/CO\tGood tolerance\t–\t–\t\n43\tA\tPV/CX/CO\tGood tolerance\t–\t–\t\n44\tA\tPV/CX/CO\tGood tolerance\t–\t–\t\n45\tA\tPV/CX/CO\tGood tolerance\t–\t–\t\n46\tA\tPV/CX/CO\tGood tolerance\t–\t–\t\n47\tA\tCX/CO\tGood tolerance\t–\t–\t\n48\tA\tCX/CO\tGood tolerance\t–\t–\t\n49\tA\tPV/CX/CO\tGood tolerance\t–\t–\t\n50\tA\tPV/CX/CO\tGood tolerance\t–\t–\t\n51\tA\tPV/CX/CO\tGood tolerance\t–\t–\t\n52\tA\tPV/CX/CO\tGood tolerance\t–\t–\t\n53\tB\tPV/CO\tGood tolerance\t–\t–\t\nCX\tAnaphylaxis\t30\t50\t\n54\tA\tPV/CX/CO\tGood tolerance\t–\t–\t\nTime Interval and Total cumulative dose drug administration and the development of symptoms\n\nPat, Patients; AX, Amoxicillin; PV, Penicillin V; CX, Cefadroxil; CO, Cefuroxime; IDR (min), Interval between drug administration and development of symptoms in minutes; TCD, Total cumulative dose in mg\n\n\n\nP1, P5, P19, and P26 were diagnosed by DPT, with 2 cases developing urticaria, 1 anaphylaxis, and 1 generalised pruritus and erythema after AX administration (Table 3). P8 developed anaphylaxis after PV administration. Based on ST and DPT, patients were diagnosed as selective reactors to AX (N = 48, 88.9%) or allergic to the whole group of penicillins (N = 6, 11.6%).\n\nIn all cases, ST with CX was done, with 37 (68.5%) cases negative and 17 (31.5%) positive (6 (35.3) by SPT and 11 (64.7%) by IDT) (Table 2). From the 37 cases with negative ST to CX, DPT was done with this cephalosporin, being positive in 2 (5.4%) (Table 3). P37 developed urticaria in trunk 50 min after 150 mg of CX and needed antihistamines and corticosteroids, and P53 developed anaphylaxis 30 min after 50 mg of CX and needed epinephrine.\n\nTolerance to cefadroxil happens in 65% of AX allergic patients\nBased on CX study, 35 (64.8%) cases showed tolerance (Group A) and 19 (35.2%) cross-reactivity (Group B). Comparisons of the clinical characteristics of both groups showed no differences regarding type of the original reaction to penicillins, time interval between drug administration and symptom development, or time between last reaction and study. Comparisons of ST to AX showed that in Group A, 12 (34.3%) cases were positive by SPT, 19 (54.3%) by IDT and 4 (11.4%) negative whereas in Group B 15 (78.9%) cases were positive by SPT, 4 (21.1%) by IDT, and 0 (0%) negative, being differences statistically significant (p = 0.006).\n\nThe allergological study to CO showed negative STs in all cases (Table 2) and tolerance was also confirmed in all cases by DPT (Table 3) but only P34 (Group B) developed urticaria in trunk and arms 25 min after 50 mg of CO. Symptoms resolved 2 h after antihistamine administration. Therefore, cross-reactivity with CO was 1.8%, although a concomitant sensitisation rather than a cross-reactivity could be hypothesized.\n\nSignificant differences of recognition are only found at the lower concentration of cefadroxil\nThe analysis of sIgE results indicated that the mean value of RAST to BPO-PLL and AXO-PLL was 1.12 ± 3.65 and 6.8 ± 9.4 respectively, with 4 out of 48 (8.3%) cases positive to BPO-PLL and 24 out of 48 (50%) to AXO-PLL (Table 2). Comparisons between groups A and B showed higher differences, although not discriminating, in terms of mean levels to AXO-PLL and the percentage of positive cases (76.5% vs 35.5%;) for AXO-PLL in Group B (p = 0.038 and p = 0.007, respectively).\n\nTo study CX specific recognition, we performed RAST inhibition assays on 6 cases from each group (Fig. 4a). As inhibitors, we included AX, CX, and CO at two concentrations, 10 and 100 mM (Fig. 4b). Results with AX showed, as expected, a high percentage of inhibition at both concentrations in all cases. Regarding CX, the percentage of inhibition was above 50% in most of patients at 100 mM, 5 out of 6 patients in each group, similarly to levels obtained with AX. However, these percentages decrease at 10 mM, being lower than those observed with AX especially Group A (Fig. 4a). In fact, comparison analysis of the percentage of inhibition between groups only shows significant differences for CX at 10 mM (p = 0.034) (Fig. 4c). Only one case (P38, Group B) showed a percentage above 50% with CO.Fig. 4 Immunological recognition of different BLs evaluated by RAST Inhibition using AXO-PLL as solid phase. a Graphs show the percentage of inhibition produced by different BLs, including amoxicillin, cefadroxil, and cefuroxime at two concentrations 10 and 100 mM in 6 individual sera from Group A (left) and 6 individual sera from group B (right). b Chemical structures of BLs, amoxicillin, cefadroxil and cefuroxime, used in the fluid phase. c Mean of the percentage of inhibition induced by Amoxicillin (AX) and Cefadroxil (CX) at two different concentrations in sera from AX-allergic patients from Groups A and B. Statistical analysis for non-related samples was performed by Mann–Whitney U test and significance considered for p < 0.05\n\n\n\nSynthetic determinants of cefadroxil showed better sIgE recognition in Group B\nThe design of the two synthetic determinants of CX was based on our degradation hypothesis of the aminocephalosporin-protein conjugate, using butylamine as a model nucleophile emulating protein lysine (Fig. 3a). After covalent protein conjugation through BL ring, the dihydrothiazine ring is unstable and could degrade producing structures in which carbon 6 presents different functionalities. Two relevant candidates, according to previous immunological recognition results [30], are structures bearing hydroxyl and aldehyde functionality in carbon 6. In the case of hydroxyl functionality, it would generate the molecule 1 as determinant; whereas the aldehyde functionality can react with the amino group of R1 side chain generating the pyrazinone 2 as a novel determinant. The synthesis of the molecule 2 was achieved following the Ugi/Deprotect/Cyclize strategy (Fig. 3b) [39]. First, starting reagents (an isocyanide, a protected amine, a protected aldehyde, and a N-protected aminoacid) were assembled by following the one-pot Ugi four-component reaction to produce the Ugi adduct. The latter acid-mediated-cleavage of the protected groups may result in the amino-functionalised aldehyde intermediate that cyclises, through intramolecular imine formation, and aromatises affording target pyrazinone (2). This method allowed the straightforward synthesis of 2, for which other procedures resulted unsuccessful. Compounds 1 and 2 were purified and well-characterised, allowing the immunological recognition study of precise chemical structures.\n\nRAST inhibition assays were performed using CX and the two synthetic structures (1 and 2), as inhibitors (Fig. 5b), in two cases from Group A and 6 from Group B. There was no inhibition with these structures in Group A (Fig. 5a). Higher percentages of inhibition were observed in Group B, being greater than 50% in 4 out of 6 cases at 100 mM, in which similar levels of inhibition to those obtained with CX were observed (Fig. 5a). However, significant lower percentage of inhibition with these synthetic structures was observed performing the RAST inhibition at 10 mM (p = 0.0022 for both) (Fig. 5c).Fig. 5 Immunological evaluation results with cefadroxil (CX) and its synthetic antigenic determinants. a RAST inhibition assays performed with sera from AX-allergic patients, 2 from Group A and 6 patients from Group B. b Chemical structure of inhibitors, synthetic compounds HOPhG-Ser-Bu (1), Pyrazinone (2) and native CX, and solid phase (amoxicilloyl-poly-L-Lysine, AXO-PLL). c Bars represent mean of percentage of inhibition for the three inhibitors at 100 and 10 mM concentrations in Group B. Statistical comparisons among related samples by Friedman test for related samples being significant with p values < 0.05\n\n\n\nDiscussion\nBLs are the most widely used antibiotics and the drugs most frequently involved in IHR [1] in adults and children [40–42]. All BL compounds can potentially induce a specific immunological response and, due to their wide prescription, BL allergy is nowadays a worldwide health issue with relevant implications [43–45]. One of the main issues is establishing the risk of developing an allergic reaction to cephalosporins prescribed in patients previously diagnosed of penicillin IHR, with different unsolved questions like if this risk can be predicted by ST and/or DPT, or the role of the chemical structure, specifically the side chain, in this recognition [10, 46–49]. The main difficulty is that, despite efforts [28–30], the antigenic determinants of cephalosporins are unknown [31]. In this study we have found that, for predicting cross-reactivity, ST is not enough and, R1 side chain, although critical for recognition, is not the unique factor. Moreover, the use of chemical tools for SAR study is a promising approach for elucidating the chemical structures involved in these IHRs.\n\nIn this study we have found that the cross-reactivity of IHRs to AX with CX, a cephalosporin with the same R1, was 35% and with CO, cephalosporin with different R1, figures decrease to 1.8%. Results with CX are in agreement with those by Romano [19] reporting that 39.3% of patients with IHR to penicillins had positive tests for cephalosporins, with 37.7% positive to aminocephalosporins, including CX and/or cefamandole. These results are similar to our previous data, with 38% of cross-reactivity between AX and CX using DPT [21]. Relevantly, we did not detect differences in cross-reactivity to CX among those selective to AX compared to those reacting to the whole group, confirming that R1 is not the only factor influencing cross-reactivity. Regarding CO tolerance, all patients had negative ST and only one had a positive DPT, showing a high degree of CO tolerance, in line with previous data [16–19, 25].\n\nComparisons of SPT results to AX between Group A and B (cross-reactivity to CX) showed a higher percentage of positivity (78.9 vs 34.3%) in the group tolerant to CX (Group A). These results agree with those by Romano [19] estimating an odds ratio of ST positivity to ampicillin for cross-reacting to at least one cephalosporin of 2.5 (CI, 1.4–4.5). Moreover, the analysis of the sIgE results showed significantly higher levels and positivity to AXO-PLL in Group B. This seems to indicate that patients that cross-react with cephalosporins have a high degree of reactivity, taking into account that the two cases that developed systemic symptoms after ST with penicillins belong to Group B and that patients reacted to small amount of CX (50 and 150 mg) and CO (50 mg) in DPT.\n\nRegarding the role of ST for predicting cross-reactivity, a positive cephalosporin ST in patients allergic to penicillins may indicate not only cross-reactivity but also concomitant sensitivity. Of note, P34 with cross-reaction to CO also reacted to CX. Whether this patient has cross-reacting or co-existing antibodies was something we cannot clarify in the present study as the RAST level was not enough for performing RAST inhibition with both drugs. However, cross-reactivity is more probable since this patient had not been previously treated with cefuroxime or any cephalosporin. This percentage is in agreement with previous data [18] that found 2.9% of cross-reactivity with CO in patients with prior histories involving only a penicillin. If a negative cephalosporin ST predicts good tolerance is controversial [50]. Different studies showed that patients with a well-established IgE-mediated allergy to penicillin and with ST negative to cephalosporins tolerate cephalosporins [15–17]. However, others demonstrated that less than 3% of cases can have a DPT positive with cephalosporin despite having negative ST [18, 19]. In this study 2 out of 37 patients (5.4%) with ST negative to CX and 1 out of 54 patients (1.8%) with ST negative to CO had a positive DPT to CX and CO respectively, indicating a negative predictive value (NPV) of 94.6% for CX and 98.1% for CO. That means that although NPV are high, a negative ST does not mean tolerance even if R1 are different.\n\nOur immunological study by RAST inhibition assays agrees with previous results on cross-reactivity between penicillins and cephalosporins, showing that AX presented a better recognition, followed by CX [21]. Data showed a discriminating capacity of the test between Group A and B using lower drug concentrations, 10 mM, observing a significantly lower recognition of CX in patients with good tolerance to CX (Group A).\n\nRegardless of this discriminative capacity, these data indicate that, although important for IgE recognition, the R1 is not per se the only structure involved in the immunological response, as structural modifications or some fragments of the nuclear structure may be involved in the antigenic determinant. In penicillins, the penicilloyl structure formed after protein conjugation is stable and, therefore, the thiazolidine ring could also play a role in the antigenic determinant [51–53]. On the contrary, the equivalent cephalosporyl structure is unstable, thus the R2 substituent is expulsed [54, 55] and the dihydrothiazine ring suffers different fragmentations, producing a complex mixture in which structures are difficult to elucidate [29, 31]. We have addressed this issue, by using chemical tools, for performing SAR studies in which precisely defined structures, consisting on the R1 side chain coupled to the open BL ring with the carbon 6 of the original drug represented by a methyl group, were recognised by sIgE from patients with IHR to the cephalosporin containing either the same R1 or one structurally similar [29]. Further SAR studies involved similar synthetic determinants but with different functionalisation in such carbon 6, finding that hydroxymethyl and aldehyde functionality, compared with methyl group, increased recognition [30]. Based on these results, synthetic determinants of CX, involving the whole intact R1 or a modified R1 side chain, have been immunologically evaluated, showing higher-recognition by sIgE from patients cross-reactive to CX (Group B).\n\nThe structure 1 (HPhG-Ser-Bu), consisting on the R1 side chain of CX and open BL ring with hydroxymethyl functionality at carbon 6 [30], was not previously evaluated with sIgE to aminocephalosporins. These determinants containing the intact corresponding aminocephalosporins R1 have been immunologically evaluated in a recent study with cefaclor-allergic patients (12% of positive cases) [28], and in the present study with AX- and/or CX-allergic patients (66% of positive cases at the maximum concentration), showing different extent of recognition depending on R1.\n\nThe pyrazinone 2 has been synthesised and immunologically evaluated in this study for the first time. Its structure derives from intramolecular reaction between the R1 amino group and the aldehyde at carbon 6. Inhibition results in six cases of Group B show that the pyrazinone 2, at 100 mM concentration, is recognised in 66% of cases, in agreement with IgE recognition observed for pyrazinones derived from cefaclor, with 63% of positive cases for the equivalent pyrazinone to that described here [28], and 60% of patients for an equivalent analog developed by Venemalm [32].\n\nThese synthetic determinants (1 and 2) were not recognised by the two selected patients with tolerance to CX (Group A). Importantly, greater differences in recognition between CX and the synthetic structures were observed in Group A than in Group B, using the higher concentration.\n\nOne could think that AX presents the amino group in R1 for the formation of additional determinants, as diketopiperazine, considered as a minor determinant of AX [56]. However, it did not show sIgE recognition in previous studies [57], which is consistent with its lack of reactivity with proteins [56].\n\nConclusions\nWe have confirmed that cross-reactivity between penicillin and cephalosporins occurs when the R1 side chain is identical as previously reported, and that negative ST is not enough for predicting tolerance, being DPT necessary. The primary determinant of immunochemical recognition of aminocephalosporins rested, with the structure of the R1, intact (molecule 1) or in its cyclised form as pyrazinone (molecule 2), although other parts of the molecule (excluding R2 substituents and most of the dihydrothiazine) are necessary for the formation of the antigenic determinant. These structures represent useful and safe alternatives for determining in vitro cross-reactivity to CX in AX-allergic patients. We think that other determinants, involving different patterns of recognition, could also participate in CX-allergic reactions; and more research is needed in this regard.\n\nSupplementary Information\n\nAdditional file 1: Figure S1. Nuclear Magenteic Resonance (NMR) characterization of structure 2. (A) 1H-NMR (CH3OD)spectrum, (B) 13C-NMR (CH3OD) spectrum, and (C) heteronuclear single quantum coherence (HSQC) experiment with gradient pulse. Bidimensional NMR spectrum (left) and signal assignation (right).\n\n \n\nAbbreviations\nAXAmoxicillin\n\nAXOAmoxicilloyl\n\nBLBetalactam\n\nBPBenzylpenicillin\n\nBPOBenzylpenicilloyl\n\nBP-OLBenzylpenicilloyl-octa-L-lysine\n\nCOCefuroxime\n\nCXCefadroxil\n\nDPTDrug provocation test\n\nEAACIEuropean Academy of Allergy and Clinical Immunology\n\nIDTIntradermal tests\n\nIHRImmediate hypersensitivity reactions\n\nIRInterquartile range\n\nMDMinor determinant\n\nMDMMinor determinant mixture\n\nNPVNegative predictive value\n\nPPLBenzylpenicilloyl-poly-L-lysine\n\nPLLPoly-L-Lysine\n\nPVPenicillin V\n\nRASTRadioallergosorbent test\n\nSARStructure–activity relationship\n\nsIgESpecific IgE\n\nSTSkin testing\n\nSDStandard deviation\n\nSPTSkin prick test\n\nTCDTotal cumulative dose\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nGador Bogas and Cristobalina Mayorga, María José Torres and María Isabel Montañez contributed equally to this work\n\nSupplementary Information\nThe online version contains supplementary material available at 10.1186/s13601-020-00368-1.\n\nWe thank Ms Claudia Corazza for her help with the English version of the manuscript.\n\nAuthors’ contributions\nConcepts, Design, Definition of intellectual content—GB, CM, TDF, MIM, MJT. Literature search—GB, CM, AM-S, RF-S, TDF, AA, MIM, MJT. Clinical studies: GB, EB, TP, MS, MJT. Clinical data analysis—GB, CM, TDF, MS, MJT. Immunoassay studies and data analysis—CM, AM-S, RF-S, AA, IMJ-S, MIM. Chemical synthesis and structural elucidation—AM-S, MIM. Statistical analysis—CM, TDF, MJT. Manuscript preparation and editing—GB, CM, MIM, MJT. All authors have read and approved the final manuscript.\n\nFunding\nThe present study has been supported by the Institute of Health ‘‘Carlos III’’ (ISCIII) of MINECO (Grants cofunded by ERDF: ‘‘Una manera de hacer Europa’’: Grant ns. PI12/02529, PI15/01206, CP15/00103, PI17/01237, PI18/00095, RETIC ARADYAL RD16/0006/0001, Euronanomed Program AC19/00082; Andalusian Regional Ministry of Economy and Knowledge (Grants cofunded by ERDF: ‘‘Andalucía se mueve con Europa’’: Grant No. CTS-06603); Andalusian Regional Ministry of Health (Grant Nos. PI-0699–2011, PI-0179–2014, PE-0172–2018 cofunded by ERDF); and ‘‘Premio UNICAJA a la innovación en biomedicina y salud.’’ C.M. holds ‘Nicolas Monardes’ research contract by Andalusian Regional Ministry Health (Grant No. C-0044–2012 SAS2013). G.B. holds a “Juan Rodes” Grant (JR18/00054), M.I.M. holds a ‘‘Miguel Servet I’’ Grant (CP15/00103), and A.A. holds a ‘‘Sara Borrell’’ Grant (CD17/0146), all by ISCIII of MINECO (grants cofunded by European Social Fund: ‘‘El FSE invierte en futuro’’). R.F.S. holds a predoctoral Grant (PE-0172–2018) cofunded by ERDF.\n\nAvailability of data and materials\nAll data generated or analysed during this study are included in this published article and its supplementary Additional file 1.\n\nEthics approval and consent to participate\nThe studied group was obtained from the Regional University Hospital of Málaga Drug Allergy Database. The study was approved by the institutional review board, and informed consent for all procedures was obtained from all patients.\n\nCompeting interests\nThe group collaborates in research grants with Diater Laboratories (Madrid, Spain). The authors declare no other relevant conflicts of interest.\n==== Refs\nReferences\n1. Doña I Barrionuevo E Blanca-López N Torres M Fernandez T Mayorga C Trends in hypersensitivity drug reactions: more drugs, more response patterns, more heterogeneity J Investig Allergol Clin Immunol 2014 24 3 143 153 25011351 \n2. Demoly P Adkinson NF Brockow K Castells M Chiriac AM Greenberger PA International consensus on drug allergy Allergy 2014 69 4 420 437 10.1111/all.12350 24697291 \n3. Torres MJ Celik GE Whitaker P Atanaskovic-Markovic M Barbaud A Bircher A A EAACI drug allergy interest group survey on how European allergy specialists deal with beta-lactam allergy Allergy 2019 74 6 1052 1062 10.1111/all.13721 30637768 \n4. 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Gomes ER Brockow K Kuyucu S Saretta F Mori F Blanca-Lopez N Drug hypersensitivity in children: report from the pediatric task force of the EAACI Drug Allergy Interest Group Allergy 2016 71 2 149 161 10.1111/all.12774 26416157 \n42. Torres MJ Blanca M The complex clinical picture of β-lactam hypersensitivity: penicillins, cephalosporins, monobactams, carbapenems, and clavams Med Clin North Am 2010 94 4 805 820 10.1016/j.mcna.2010.04.006 20609864 \n43. Mayorga C Fernandez TD Montañez MI Moreno E Torres MJ Recent developments and highlights in drug hypersensitivity Allergy 2019 74 12 2368 2381 10.1111/all.14061 31557314 \n44. Stone CA Jr Trubiano J Coleman DT Rukasin CRF Phillips EJ The challenge of de-labeling penicillin allergy Allergy 2020 75 2 273 288 10.1111/all.13848 31049971 \n45. Sousa-Pinto B Blumenthal KG Macy E Bavbek S Benić MS Alves-Correia M Diagnostic testing for penicillin allergy: a survey of practices and cost perceptions Allergy 2020 75 2 436 441 10.1111/all.13951 31230367 \n46. Romano A Gaeta F Arribas Poves MF Valluzzi RL Cross-reactivity among beta-lactams Curr Allergy Asthma Rep 2016 16 3 24 10.1007/s11882-016-0594-9 26898316 \n47. Picard M Robitaille G Karam F Daigle JM Bédard F Biron É Cross-reactivity to cephalosporins and carbapenems in penicillin-allergic patients: two systematic reviews and meta-analyses J Allergy Clin Immunol Pract 2019 7 8 2722 38.e5 10.1016/j.jaip.2019.05.038 31170539 \n48. Mirakian R Leech SC Krishna MT Richter AG Huber PA Farooque S Management of allergy to penicillins and other beta-lactams Clin Exp Allergy 2015 45 2 300 327 10.1111/cea.12468 25623506 \n49. Yang M-S Kang DY Seo B Park HJ Park S-Y Kim M-Y Incidence of cephalosporin-induced anaphylaxis and clinical efficacy of screening intradermal tests with cephalosporins: a large multicenter retrospective cohort study Allergy 2018 73 9 1833 1841 10.1111/all.13435 29517808 \n50. Blanca M Romano A Torres MJ Férnandez J Mayorga C Rodriguez J Update on the evaluation of hypersensitivity reactions to betalactams Allergy 2009 64 2 183 193 10.1111/j.1398-9995.2008.01924.x 19133923 \n51. Ariza A Garzon D Abánades DR de Ríos V Vistoli G Torres MJ Protein haptenation by amoxicillin: High resolution mass spectrometry analysis and identification of target proteins in serum J Proteomics. 2012 77 504 20 10.1016/j.jprot.2012.09.030 23041134 \n52. Torres MJ Montañez MI Ariza A Salas M Fernandez TD Barbero N The role of IgE recognition in allergic reactions to amoxicillin and clavulanic acid Clin Exp Allergy 2016 46 2 264 274 10.1111/cea.12689 26662186 \n53. Ariza A Mayorga C Salas M Doña I Martín-Serrano Á Pérez-Inestrosa E The influence of the carrier molecule on amoxicillin recognition by specific IgE in patients with immediate hypersensitivity reactions to betalactams Sci Rep 2016 6 35113 10.1038/srep35113 27731424 \n54. Pratt RF Faraci WS Direct observation by 1H-NMR of cephalosporoate intermediates in aqueous solution during the hydrazinolysis and β-lactamasecatalized hydrolysis of cephalosporin with 3´ leaving groups: kinetics and equilibria of the 3´ elimination reaction J Am Chem Soc 1986 108 5328 5333 10.1021/ja00277a044 \n55. Montañez MI, Martín-Serrano A, Mayorga C, Barrionuevo E, Pérez N, Romano A, et al. Reply. J Allergy Clin Immunol. 2020.\n56. Pajares MA Zimmerman T Sánchez-Gómez FJ Ariza A Torres MJ Blanca M Amoxicillin inactivation by thiol-catalyzed cyclization reduces protein haptenation and antibacterial potency Front Pharmacol. 2020 11 189 10.3389/fphar.2020.00189 32210804 \n57. Torres MJ Ariza A Fernández J Moreno E Laguna JJ Montañez MI Role of minor determinants of amoxicillin in the diagnosis of immediate allergic reactions to amoxicillin Allergy 2010 65 5 590 596 10.1111/j.1398-9995.2009.02245.x 19968633\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2045-7022",
"issue": "10(1)",
"journal": "Clinical and translational allergy",
"keywords": "Amoxicillin; Antigenic determinant; Betalactam; Cephalosporin; Cross-reactivity; Drug allergy; Specific IgE",
"medline_ta": "Clin Transl Allergy",
"mesh_terms": null,
"nlm_unique_id": "101576043",
"other_id": null,
"pages": "57",
"pmc": null,
"pmid": "33292516",
"pubdate": "2020-12-04",
"publication_types": "D016428:Journal Article",
"references": "27731424;8828545;19968633;31821817;25623506;15238366;31034613;11112903;15985814;16461141;30829415;30843233;12911412;31680067;31749148;30637768;16164453;32210804;16867046;29517808;11260156;26991315;31049971;25011351;27319758;26416157;12833570;23041134;31170539;11459649;20609864;26662186;11991289;25898690;8172357;30216468;21425867;17156341;32145403;8837660;26898316;30028512;31557314;23741979;23551216;29408440;31230367;22092779;19133923;20357485;29017833;24697291",
"title": "Penicillin and cephalosporin cross-reactivity: role of side chain and synthetic cefadroxil epitopes.",
"title_normalized": "penicillin and cephalosporin cross reactivity role of side chain and synthetic cefadroxil epitopes"
} | [
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"companynumb": "ES-TEVA-2021-ES-1872073",
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"activesubstancename": "PENICILLIN V"
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{
"abstract": "Calcium channel blockers (CCBs) have seen an increase in rate of non-therapeutic exposure that is both accidental and intentional in nature. Patients experiencing the toxic effects of a CCB overdose are resource intensive and can quickly outstrip the capabilities of local health systems, necessitating transfer to larger tertiary or quaternary care centers. We present a case of intentional non-dihydropyridine CCB overdose and toxicity in a 20-year-old patient requiring initial stabilization at a referring critical access emergency department with continuation of treatment and support during a 60-minute rotor wing transport from the referring hospital to an academic quaternary care center. Emphasis is placed on the unique challenges in resuscitation and ongoing critical care administration during the transport phase of care. Proper stabilization of patients, planning, and consideration of potential problems associated with transport can help minimize stresses and risk of the transport, improving the outcome of extremely ill patients even under challenging circumstances.",
"affiliations": "Survival Flight, Michigan Medicine, Ann Arbor, MI. Electronic address: wdsadler@umich.edu.;Survival Flight, Michigan Medicine, Ann Arbor, MI.;Survival Flight, Michigan Medicine, Ann Arbor, MI.;Survival Flight, Michigan Medicine, Ann Arbor, MI.;Survival Flight, Michigan Medicine, Ann Arbor, MI.;Survival Flight, Michigan Medicine, Ann Arbor, MI; Department of Emergency Medicine, Division of Critical Care, Michigan Medicine, Ann Arbor, MI; Michigan Center for Integrative Research in Critical Care, Michigan Medicine, Ann Arbor, MI.",
"authors": "Sadler|William David|WD|;Hunt|Nathanial|N|;Nelson|Kris|K|;Adelmann|Edward|E|;Mazurek|Paul|P|;Bassin|Benjamin S|BS|",
"chemical_list": "D002121:Calcium Channel Blockers; D004364:Pharmaceutical Preparations",
"country": "United States",
"delete": false,
"doi": "10.1016/j.amj.2020.11.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1067-991X",
"issue": "40(1)",
"journal": "Air medical journal",
"keywords": null,
"medline_ta": "Air Med J",
"mesh_terms": "D000328:Adult; D002121:Calcium Channel Blockers; D003422:Critical Care; D062787:Drug Overdose; D004636:Emergency Service, Hospital; D006801:Humans; D004364:Pharmaceutical Preparations; D055815:Young Adult",
"nlm_unique_id": "9312325",
"other_id": null,
"pages": "69-72",
"pmc": null,
"pmid": "33455631",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Calcium Channel Blocker Intoxication: A Critical Care Transport Perspective.",
"title_normalized": "calcium channel blocker intoxication a critical care transport perspective"
} | [
{
"companynumb": "US-MICRO LABS LIMITED-ML2021-00478",
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{
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"activesubstance": {
"activesubstancename": "VERAPAMIL HYDROCHLORIDE"
},
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"abstract": "Tramadol is an opioid used in the treatment of moderate to moderately severe pain. Tramadol's use during pregnancy is generally avoided and may cause some reversible withdrawal effects in neonates, and its use during lactation is not licensed by the manufacturer. A small clinical trial reported infants were exposed to <3% of a mother's tramadol dose through breast milk with no evidence of harmful effects. Presented is a case study of breast milk, neonatal urine, and neonatal oral fluid for the analysis of tramadol and its metabolites, along with the validation of a method for the analysis of tramadol, O-desmethyltramadol, and N-desmethyltramadol in breast milk. Tramadol and its metabolites were extracted by solid-phase extraction after saponification of breast milk to remove lipids. Samples were analyzed by ultra-pressure liquid chromatography-tandem mass spectrometry. To the author's knowledge, this is the first report of tramadol and its metabolites in neonatal oral fluid. The breast milk concentrations were 63, 22, and 76 ng/mL for the analysis of tramadol, O-desmethyltramadol, and N-desmethyltramadol, respectively, on day of life 12. On day of life 20, the breast milk concentrations were 1,254, 388, and 937 ng/mL for the analysis of tramadol, O-desmethyltramadol, and N-desmethyltramadol, respectively. Oral fluid concentrations were 1,011, 1,499, and 406 ng/mL for the analysis of tramadol, O-desmethyltramadol, and N-desmethyltramadol, respectively, on day of life 20. Oral fluid concentrations were similar to breast milk for tramadol, almost four times higher for O-desmethyltramadol, and less than half for N-desmethyltramadol. The absolute infant dose was calculated to be 10 μg/kg/day and 294 μg/kg/day for tramadol on day of life 12 and 20, respectively.",
"affiliations": "Integrative Life Sciences Doctoral Program, Virginia Commonwealth University, 1000 W Cary St, Richmond, VA 23284, USA.;Department of Forensic Science, Virginia Commonwealth University, 1015 Floyd Ave, Richmond, VA 23284, USA.;Departments of Pathology, Virginia Commonwealth University, 1001 E Marshall St, Richmond, VA 23284, USA.;Departments of Pathology, Virginia Commonwealth University, 1001 E Marshall St, Richmond, VA 23284, USA.;Division of Neonatal Medicine, Department of Pediatrics, Children's Hospital of Richmond at VCU, School of Medicine, Virginia Commonwealth University, 1000 E Broad St, Richmond, VA 23284, USA.;Division of Neonatal Medicine, Department of Pediatrics, Children's Hospital of Richmond at VCU, School of Medicine, Virginia Commonwealth University, 1000 E Broad St, Richmond, VA 23284, USA.;Departments of Pharmacology and Toxicology, Virginia Commonwealth University, 1112 E Clay St, Richmond, VA 23284, USA.",
"authors": "Gesseck|Ashley M|AM|0000-0002-3400-5745;Peace|Michelle R|MR|;Nanco|Carrol R|CR|;Wolf|Carl E|CE|;Hendricks-Muñoz|Karen D|KD|;Xu|Jie|J|;Poklis|Justin L|JL|0000-0001-5470-5717",
"chemical_list": "D000701:Analgesics, Opioid; D014147:Tramadol",
"country": "England",
"delete": false,
"doi": "10.1093/jat/bkab055",
"fulltext": null,
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"issn_linking": "0146-4760",
"issue": "45(8)",
"journal": "Journal of analytical toxicology",
"keywords": null,
"medline_ta": "J Anal Toxicol",
"mesh_terms": "D000701:Analgesics, Opioid; D002853:Chromatography, Liquid; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008895:Milk, Human; D009035:Mothers; D011247:Pregnancy; D014147:Tramadol",
"nlm_unique_id": "7705085",
"other_id": null,
"pages": "840-846",
"pmc": null,
"pmid": "34037761",
"pubdate": "2021-09-17",
"publication_types": "D016428:Journal Article",
"references": "12899994;16105270;21394525;9233209;7892138;27131494;20386886;11360033;20854338;21785611;31436289;26648652;12706545;29462321;18043469;9700556;27145974;17370066;30248201;29599166;29419722;12598495;9987460;24927721;6879643;24944422;23979084;24061447;8990259;22317891;18294329;25565668;32591773;6204626;21819795",
"title": "Neonatal Exposure to Tramadol through Mother's Breast Milk.",
"title_normalized": "neonatal exposure to tramadol through mother s breast milk"
} | [
{
"companynumb": "US-AUROBINDO-AUR-APL-2021-052661",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRAMADOL"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nPhlebosclerotic colitis is a rare condition with a high mortality. It has been seen almost exclusively in Asian patients who are ≥ 60 years old, with a slight male predominance. Although it predominantly affects the right colon and seems to be related in some cases to using natural herbal medicines, neither its etiology nor its pathogenesis are known.\n\n\nMETHODS\nWe present an extremely rare case of a 62-year-old Spanish white man patient of non-Asian ethnicity with no history of using natural medications, who was diagnosed with phlebosclerotic colitis of submucosal veins.\n\n\nCONCLUSIONS\nTo date, this is the only case reported in Spain, and only the second reported for Europe, in the literature. Due to the nonspecific symptoms and insidious radiological findings of this disease (both in early and mild stages) as well as exclusive submucosal involvement presented here, it is necessary that the treating physician has a high level of suspicion for its diagnosis.",
"affiliations": "Pathology Unit, Hospital Universitario Virgen del Rocío, Seville, Spain. javi5r@hotmail.com.;Radiology Unit, Hospital Universitario Virgen del Rocío, Seville, Spain.;Pathology Unit, Hospital Universitario Virgen del Rocío, Seville, Spain.",
"authors": "Mohigefer|J|J|;Gómez-Millán|P|P|;Borrero|J J|JJ|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s13256-021-02930-2",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947\nBioMed Central London\n\n2930\n10.1186/s13256-021-02930-2\nCase Report\nPhlebosclerotic colitis in a non-Asian patient: a case report\nMohigefer J. javi5r@hotmail.com\n\n1\nGómez-Millán P. 2\nBorrero J. J. 1\n1 grid.411109.c 0000 0000 9542 1158 Pathology Unit, Hospital Universitario Virgen del Rocío, Seville, Spain\n2 grid.411109.c 0000 0000 9542 1158 Radiology Unit, Hospital Universitario Virgen del Rocío, Seville, Spain\n18 7 2021\n18 7 2021\n2021\n15 34916 12 2020\n25 5 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\nPhlebosclerotic colitis is a rare condition with a high mortality. It has been seen almost exclusively in Asian patients who are ≥ 60 years old, with a slight male predominance. Although it predominantly affects the right colon and seems to be related in some cases to using natural herbal medicines, neither its etiology nor its pathogenesis are known.\n\nCase presentation\n\nWe present an extremely rare case of a 62-year-old Spanish white man patient of non-Asian ethnicity with no history of using natural medications, who was diagnosed with phlebosclerotic colitis of submucosal veins.\n\nConclusion\n\nTo date, this is the only case reported in Spain, and only the second reported for Europe, in the literature. Due to the nonspecific symptoms and insidious radiological findings of this disease (both in early and mild stages) as well as exclusive submucosal involvement presented here, it is necessary that the treating physician has a high level of suspicion for its diagnosis.\n\nKeywords\n\nPhlebosclerotic colitis\nSubmucosal veins\nIschemic colitis\nCalcification\nCase report\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nPhlebosclerotic colitis is a type of ischemic colitis whose etiopathogenesis is yet to be determined [1]. It is characterized by calcification and obstruction of the submucosal and mesenteric veins of the large intestine, causing chronic ischemia. The treating physician must have a high level of suspicion, as both endoscopic and radiological findings can go unnoticed [2]. Phlebosclerotic changes are frequent in patients with venous insufficiency of the lower limbs [3]. However, it was not until 1989 that this was described to be intestinal [4]. The etiology of colitis is highly varied and can include heart failure, emboli, coagulopathies, infections, medical drugs, and physical trauma. However, unlike other types of colitis, phlebosclerotic colitis is not caused by any of these [1]. Here, we present a case of a non-Asian Spanish patient who was diagnosed with phlebosclerotic colitis of submucosal veins, who was a smoker, had a history of alcohol abuse, and presented a mild factor XII deficiency. To our knowledge, this is the first described case in Spain in the literature, and only the second in Europe [2].\n\nCase presentation\n\nA 62-year-old non-Asian Spanish man was admitted to the emergency room for abdominal pain of epigastric origin, which evolved over the next 3 days to diffuse pain with constipation, but with no fever or vomiting. He had a 32-pack-year smoking history and had completed disulfiram treatment for alcohol cessation 10 years previously. He had residual pain in lower limbs after lumbar disc herniation surgery 15 years previously, for which he was taking naproxen, and had a medical history of a mild factor XII deficiency. He had no other relevant medical, surgical, or family history. On physical examination, palpation showed he had a contracted abdomen, with lividity and signs of peritonism but with no signs of deep vein thrombosis in the lower limbs. Blood pressure was 112/88 mmHg, heart rate 122 beats per minute, and temperature 35.8 ℃. There were no other findings on physical and neurological examination. A thoracoabdominal computed tomography (CT) scan revealed “findings suggestive of intestinal perforation (probably in the upper hemiabdomen), without being able to clearly identify the point of perforation.” Laboratory parameters in the emergency room showed glucose 123 mg/dL, urea 238 mg/dL, creatinine 4.29 mg/dL (previously, normal), total bilirubin 1.45 mg/dL (conjugated 0.91 mg/dL), and amylase 111 mg/dL. Sodium and potassium were in normal range, and the hemogram was also normal. Intravenous fluid resuscitation and empiric antimicrobial therapy with piperacillin–tazobactam 3.375 g/8 hours intravenous for 10 days, fluconazole 400 mg/24 hours for 6 days, and vancomycin 1 g/12 hours for 4 days were started. The patient underwent urgent surgical intervention, which revealed generalized peritonitis, perforation at the pylorus, necrosis of the greater omentum, and an abundance of free fluid in all abdominal quadrants (surgical intervention consisted of pyloric suture and resection of the greater omentum). The pathology report revealed “pyloric wall with signs of perforation and epiplon with adiponecrosis, microabscesses and exudative-fibrinoid serositis.” In the immediate postoperative period, the patient had a low level of consciousness and saturation of up to 80%, with acute lung edema observed on the CT scan (“extensive bilateral pulmonary consolidations associated with bilateral pleural effusion and evidence of anasarca due to probable fluid overload/decompensated heart failure”). The patient was intubated to achieve oxygen saturation > 98% with an FiO2 of 0.4. The patient was sedated and on analgesic, responding to painful stimuli. Hemodynamically, he was mostly stable with a need for norepinephrine at 0.3 mg/kg/minute and tension readings of 123/73 and 90 beats per minute. However, liver function progressively worsened, reaching total bilirubin levels of 4.15 mg/dL. Likewise, the patient was in acute renal failure AKIN III, with diuresis dependent on furosemide at 30 mg/hour, creatinine levels > 4 mg/dL, and urea > 290 mg/dL. The patient presented poor postoperative course, with progressively higher fluid outflow through abdominal drains and abdominal sepsis, as revealed by symptoms and microbiology (Klebsiella pneumoniae was isolated in blood culture; Enterococcus faecalis and Escherichia coli in the drains; E. coli and Streptococcus anginosus in the surgical wound), which raised suspicion of perforation of the previous surgical suture. As intraabdominal pressure increased progressively, the patient underwent a second surgical intervention at 9 days after the first surgery, which revealed a biliopurulent contamination in the peritoneal cavity caused by a previous dehiscence from a pyloric suture line. Therefore, based on intraoperative findings, duodenal exclusion was performed by gastric antrectomy followed by retrocolic Roux-en-Y (end-to-side) gastrojejunostomy and jejunojejunal distal (side-to-side) anastomosis. Cholecystectomy was then followed by external drainage of the common bile duct by placement of a T-tube, to prevent cholecystitis. Splenectomy was performed because of intraoperative bleeding.\n\nThe patient remained intubated and sedated, maintaining good saturation. He also had hemodynamic stability without vasoactive amines. However, total bilirubin levels continued to rise (from 4.15 to 6.8 mg/dl), and the patient continued to exhibit anuria, with urea 291 mg/dl, creatinine 4.02 mg/dl; pH 7.35, HCO3- 26.5 mmol/L, pCO2 47 mmHg, and normal anion gap (AG). The patient began treatment with an infusion of caspofungin for 13 days at 50 mg/24 hours, meropenem for 21 days at 1 g/8 hours, and again with vancomycin for 6 days. As the patient again presented very poor postoperative evolution, with fecal contamination of the abdominal drainage, a third surgery was performed 4 days after the second one, in which the patient underwent partial colectomy (due to the intraoperative ischemic appearance of the colon) and resuture of the pyloric repair. Pathological anatomy showed gastric and duodenal dehiscence, with an ischemic appearance of the transverse colon and perforations, foci of hemorrhagic necrosis (both mucosal and submucosal), secondary gangrenous inflammation, and multiple intestinal ulcerations related to calcified phlebosclerosis of the submucosal vessels. After the third intervention, the patient was in stable but serious condition. Hemodynamically, the patient was stable, with some hypertensive peaks (160/70 mmHg). Bilirubin levels improved, down to 2.19 mg/dl; however, the patient continued to have poor kidney function that required hemodialysis sessions at 6 days after the third surgery. Due to the improvement in respiratory function, extubation was carried out but failed due to weakness in the musculature. For this reason, a tracheostomy was performed at 29 days after admission. Teicoplanin was delivered at 3 days after the third surgery, at 400 mg/12 hours for 6 days by isolation in surgical wound exudate of Enterococcus gallinarum. An infusion of ertapenem and ampicillin at 1 g/24 hours and 1 g/6 hours, respectively, was started at 16 days after the third surgery but was suspended because of a skin rash. Linezolid infusion (600 mg/12 hours) was also started at 20 days after the last intervention in order to treat for Gram-positive bacteria. In the last days of life, the patient showed increased overall deterioration, with disconnection to his environment, oscillation between normothermia and hypothermia, and systolic blood pressure < 70 mmHg, which forced hemodialysis to be suspended. Furthermore, despite hemodialysis, creatinine peaks continued at 8.11 mg/dl, and urea at 190 mg/dl. After receiving palliative care, the patient died, 35 days after admission. No autopsy was requested.\n\nDiscussion and conclusions\n\nPhlebosclerotic colitis is an extremely rare condition in Europe: it occurs almost exclusively in patients of Asian descent and is practically an unknown disease in Spain, with only one European case described to date in the literature [2]. The current case exemplifies this rarity very well: a patient without Asian descent who was admitted to the hospital because of a perforation secondary to sclerosis and calcification exclusively of the submucosal veins of the colon (phlebosclerotic colitis) who died after a torpid evolution.\n\nThe disease etiology is unknown. In 2014, Fang et al. [5] suggested that factors that lead to an increase in intraluminal pressure also lead to both compromised capillaries and a retention of toxic material in the colon (and especially on the right side, which has a longer retention time), which would increase their absorption and produces sclerosis, fibrosis, calcification, and hyalinization of the mesenteric and submucosal colic veins [5, 6].\n\nPhlebosclerotic colitis presents with nonspecific symptoms (abdominal pain, diarrhea, intestinal obstruction, nausea, and vomiting are the most frequent) and can be either acute or chronic [7, 8]. While imaging tests are essential for its diagnosis, there must also be a high level of suspicion on the part of the physicians, as the alterations can easily go unnoticed, especially in early and mild stages. CT scans typically show a thickening of the colic wall together with punctate or serpiginous calcifications of the mesenteric veins, arranged perpendicular to the longitudinal axis of the colon [9, 10]. However, the absence of these findings does not rule out the diagnosis, especially in our case, as in addition to having few calcifications at the radiological level, the patient had an exclusive submucosal involvement that did not involve mesenteric vessels (Fig. 1) [6]. Angiography in the arterial phase shows a tortuous vasa recta and the marginal arteries of the colon; in the venous phase, it shows a decreased perfusion, although this is difficult to quantify [11]. Endoscopically, a purplish and friable colic mucosa with segmental distribution is observed, with erosions, ulcers, and hemorrhagic nodules, which can be seen using a barium enema for digital imaging [12]. However, this last diagnostic test could contribute to the worsening of the disease in the acute phase due to an increase in intracolic pressure [7].Fig. 1 A–D Contrast-enhanced computed tomography (CECT) of the patient. A Three-dimensional (3D) vascular reconstruction that shows multiple atherosclerotic calcifications (triangles) but no severe stenosis in the main abdominal branches of the aorta. The CECT also displayed permeability of all veins. B Sagittal view of CECT, showing nonspecific linear hyperdensities of the colonic wall that could be related to incipient calcifications (arrow). C Coronal view of CECT, showing features of small bowel ischemia affecting the jejunum (circle), which led to a diagnosis of nonocclusive mesenteric ischemia. No ischemic changes in the colon were identified. D Axial view of CECT, showing that a moderate amount of intraperitoneal fluid was also present (thick arrow)\n\nHistological examinations can reveal mucosal ulceration, with foci of hemorrhagic necrosis in both mucosal and submucosal layers. The submucosal layer can show thickening due to fibrosis and hyalinization, with sclerosis, calcification, and luminal narrowing of the mesenteric and submucosal veins (the arteries are not affected). In our case, the only vessel alterations were observed in the submucosal vessels (Fig. 2). Note that mucosal atrophy and inflammation are also frequent histological findings [13].Fig. 2 Hematoxylin and eosin (H&E)-stained tissue findings of the colon. A H&E image (at 4×) in which several submucosal vessels can be observed, with an important eccentric parietal calcification and a mucous ulceration that is already reepithelialized. B Detail (at 20×) of intense parietal calcification of a colonic submucosal vessels. C Magnification (10×) of images, showing intense epithelial denudation caused by vascular ischemia\n\nDisease treatment varies depending on each patient's condition. Less severe conditions can be treated conservatively with follow-up, while patients with severe conditions (e.g., perforation, bleeding, and persistent intestinal obstruction) or patients whose symptoms do not remit with treatment require surgery (either subtotal or total colectomy), with a relatively good prognosis [11, 14]. In our case, given the severity and negative evolution of the patient's condition, surgery was fully indicated.\n\nIn summary, an extensive differential diagnosis is required for phlebosclerotic colitis, especially to distinguish it from other infrequent pathologies, such as idiopathic myointimal hyperplasia of the mesenteric veins, Buerger’s disease (thromboangiitis obliterans with involvement of the mesenteric vasculature), enterocolic lymphocytic phlebitis, and some types of vasculitis, such as allergic granulomatous angiitis or Behcet’s disease [13, 15]. In the case presented here, colitis could have been associated with nonsteroidal antiinflammatory drugs (NSAIDs) (given the chronic intake of naproxen); however, there was not an increased number of epithelial apoptotic bodies. Microbiological isolation of several bacteria (but not Clostridioides difficile or E. coli O157: H7) and antibiotic treatment (such as ampicillin) make it necessary to rule out pseudomembranous colitis, though pseudomembranes and fibrin thrombi were not observed (note that the submucosal veins showed calcification and sclerosis). Furthermore, the patient was treated with vancomycin. The colon was affected but with skip areas; however, we did not observe histological findings, such as lymphoid aggregates, transmural involvement, or poorly formed granulomas typical of Crohn’s disease. Finally, the differential diagnosis with calcifying uremic arteriolopathy could also be proposed, because of the similarity to the histopathological findings, but it does not fit with the previous normal kidney function and the clinical characteristics of the patient (absence of diabetes, hyperphosphatemia, obesity, dialysis, hypercoagulative states, hypoalbuminemia, dialysis, or dermal alterations).\n\nPhlebosclerotic colitis is already a very rare disease, and its submucosal involvement even more so, with only one case reported to date. It occurs almost exclusively in people of Asian ethnicity. Due to the nonspecific symptoms and insidious radiological findings in early and mild stages as well as involvement only of the submucosal veins, it is necessary that the physician has a high suspicion to diagnose it. Angiographic and CT images show very characteristic findings of the disease; together with the endoscopic and pathological findings, they define this pathology, which has a poor prognosis. Given the low prevalence of this condition, further investigations are necessary to better understand the pathogenesis, as it is not yet clear.\n\nAcknowledgements\n\nThe authors thank Veronica A. Raker for translating this case report for publication.\n\nAuthors’ contributions\n\nJM and PG-M analyzed and interpreted the patient data and conducted the systematic review of the literature. JJB reviewed and corrected the manuscript. JM wrote the manuscript. All authors read and approved the final manuscript.\n\nFunding\n\nNo funding.\n\nAvailability of data and materials\n\nNot applicable. All data are included in the article.\n\nDeclarations\n\nEthics approval and consent to participate\n\nThis study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.\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. Feuerstadt P Brandt LJ Colon ischemia: recent insights and advances Curr Gastroenterol Rep 2010 12 383 90 10.1007/s11894-010-0127-y 20690005\n2. Klein S Buchner D Chang DH Büttner R Drebber U Fries JWU Exclusive phlebosclerosis of submucosal veins leading to ischemic necrosis and perforation of the large bowel: first European case Case Rep Gastroenterol 2018 12 1 137 142 10.1159/000488195 29805356\n3. Tepelenis K Papathanakos G Barbouti A Paraskevas G Kitsouli A Alexandra Kefala M Phlebosclerosis in lower extremities veins—a systematic review Vasa. 2020 49 349 10.1024/0301-1526/a000868 32323629\n4. Iwashita A Summary of the monthly meeting of the Research Society for Early Gastric Cancer (in Japanese) Stomach Intestine (Tokyo) 1989 24 421 422\n5. Fang YL Hsu HC Chou YH Wu CC Chou YY Phlebosclerotic colitis: a case report and review of the literature Exp Ther Med 2014 7 3 583 586 10.3892/etm.2014.1492 24520249\n6. Mathew RP Girgis S Wells M Low G Phlebosclerotic colitis—an enigma among ischemic colitis J Clin Imaging Sci. 2019 9 18 1 4 30788185\n7. Nishimura G Surgery G Nagai N Ninomiya I Kitagawa H Fujimura T Chronic ischemic lesions of the colon caused by phlebosclerosis of ileocolic mesenteric vein Dig Endosc 2004 16 2 169 171 10.1111/j.1443-1661.2003.00334.x\n8. Liu YC Lee WJ An unusual cause of intestinal obstruction: phlebosclerotic colitis Int Emerg Med 2020 15 335 6 10.1007/s11739-019-02241-x\n9. Markos V Kelly S Yee WC Davis JE Cheifetz RE Alsheikh A Case report: phlebosclerotic colitis: imaging findings of a rare entity AJR 2005 184 1584 1586 10.2214/ajr.184.5.01841584 15855120\n10. Pan X Wang CH A case of phlebosclerotic colitis Clin Res Hepatol Gastroenterol 2015 39 6 651 652 10.1016/j.clinre.2015.06.013 26206576\n11. Chen W Zhu H Chen H Shan G Xu G Chen L Phlebosclerotic colitis: our clinical experience of 25 patients in China Medicine (United States). 2018 97 43 e12824\n12. Maruyama Y Watanabe F Kanaoka S Kanamaru H Yoshino G Koda K A case of phlebosclerotic ischemic colitis: a distinct entity Endoscopy 1997 29 4 334 10.1055/s-2007-1004207 9255548\n13. Chang K-H New histologic findings in idiopathic mesenteric: clues to its pathogenesis and etiology—probably ingested toxic agent-related J Chin Med Assoc 2007 70 6 227 235 10.1016/S1726-4901(09)70364-8 17591581\n14. Yu CJ Wang HH Chou JW Lai HC Huang WH Peng CY Phlebosclerotic colitis with nonsurgical treatment Int J Colorectal Dis. 2009 24 1241 2 10.1007/s00384-009-0707-1 19390857\n15. Rosen N Sommer I Knobel B Intestinal Buerger’s disease Arch Pathol Lab Med. 1985 109 10 962 3 3840010\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "15(1)",
"journal": "Journal of medical case reports",
"keywords": "Calcification; Case report; Ischemic colitis; Phlebosclerotic colitis; Submucosal veins",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D003092:Colitis; D006801:Humans; D008297:Male; D008875:Middle Aged; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "349",
"pmc": null,
"pmid": "34274012",
"pubdate": "2021-07-18",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20690005;9255548;26206576;32323629;3840010;15855120;24520249;19390857;29805356;17591581;31782055;30412073;31448169",
"title": "Phlebosclerotic colitis in a non-Asian patient: a case report.",
"title_normalized": "phlebosclerotic colitis in a non asian patient a case report"
} | [
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"companynumb": "ES-TEVA-2022-ES-2016748",
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"abstract": "Nocardia thyroid abscess with pneumonia is a rare clinical presentation. We reported a liver transplant recipient with Nocardia thyroiditis and pneumonia after receiving high dose immunosuppressants to preserve his graft. The patient is a 50-year-old male who developed hepatitis C virus-related liver cirrhosis and received a liver transplant. Seven months post-transplantation the patient developed graft rejection, which was treated with 3 days pulse dose methyl-prednisolone followed by an increased dose of his tracolimus, mycophenolate and prednisolone. He presented to the hospital with a 2 week history of fever, tenderness in his anterior neck and dry cough. On admission his temperature was 39.5°C. The right wing of his thyroid gland was swollen to 3 cm in size, fluctuant and tender. On auscultation of his lungs there were fine crepitations and increased vocal resonance in the right middle lung field. On laboratory testing, a complete blood count (CBC) revealed leukocytosis (19,900/mm3) with neutrophils (97%). A chest X-ray showed an patchy infiltrates and round circumscribed densities in the superior segment of the right lower lobe of his lung. A CT scan of his neck revealed a diffusely enlarged right wing of the thyroid gland, 3.8 cm in diameter that had an abnormal hyposignal area. A CT of his chest revealed consolidation of the superior segment of the right lower lobe and necrotic right paratracheal lymph nodes with inflamed strap muscles. Fine needle aspiration of the right lobe of thyroid gland was performed. Modified acid-fast bacilli (MAFB) staining showed partially acid-fast beaded branching filamentous organisms and a culture grew out Nocardia asteroides. He was treated with trimethoprim-sulfamethoxazole for 6 months. He improved clinically and his chest X-ray also cleared.",
"affiliations": null,
"authors": "Reechaipichitkul|Wipa|W|;Thanasatirakul|Pachara|P|",
"chemical_list": "D007166:Immunosuppressive Agents; D011239:Prednisolone; D009173:Mycophenolic Acid; D016559:Tacrolimus",
"country": "Thailand",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0125-1562",
"issue": "46(6)",
"journal": "The Southeast Asian journal of tropical medicine and public health",
"keywords": null,
"medline_ta": "Southeast Asian J Trop Med Public Health",
"mesh_terms": "D000038:Abscess; D005334:Fever; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D009617:Nocardia Infections; D018410:Pneumonia, Bacterial; D011239:Prednisolone; D016559:Tacrolimus; D013966:Thyroiditis",
"nlm_unique_id": "0266303",
"other_id": null,
"pages": "1055-62",
"pmc": null,
"pmid": "26867364",
"pubdate": "2015-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "NOCARDIOSIS REVEALED BY THYROID ABSCESS AND PNEUMONIA IN A LIVER TRANSPLANT RECIPIENT.",
"title_normalized": "nocardiosis revealed by thyroid abscess and pneumonia in a liver transplant recipient"
} | [
{
"companynumb": "TH-VISTAPHARM, INC.-VER201706-000137",
"fulfillexpeditecriteria": "1",
"occurcountry": "TH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditi... |
{
"abstract": "BACKGROUND\nThe potential combination of diuretics- angiotensin-converting enzyme inhibitors- Non-steroidal anti-inflammatory drugs (diuretics-ACEIs-NSAIDs), the so-called 'triple whammy', to produce clinically significant nephrotoxicity in chronic kidney disease (CKD) is often unrecognized. In 2013, in the British Medical Journal, we described accelerated post-operative acute kidney injury (AKI) in CKD patients concurrently on 'triple whammy' medications, a new syndrome that we aptly named 'quadruple whammy'.\n\n\nMETHODS\nTwo case reports.\n\n\nRESULTS\nI. A 59-year-old Caucasian male, hypertensive CKD III, serum creatinine (SCr) 1.42 mg/dL, developed accelerated oliguric AKI after elective right nephrectomy. Outpatient medications included Lisinopril-Hydrochlorothiazide and Nabumetone (NSAID). SCr rapidly more than doubled with metabolic acidosis and hyperkalemia within 24 hours, peaking at 4.02 mg/dL. 'Triple whammy' medications were promptly stopped and the hypotension was corrected. SCr was 1.64 mg/dL and stable, after three months. II. A 46-year-old Caucasian male, hypertensive CKD II, SCr 1.21 mg/dL, developed accelerated AKI after elective right hip arthroplasty. Outpatient medications included Lisinopril and Hydrochlorothiazide. Celecoxib (200 mg) was given pre-operatively. Within 36 hours, SCr rapidly more than doubled to 2.58 mg/dL, with metabolic acidosis. 'Triple whammy' medications were promptly stopped and the hypotension was corrected. SCr was 0.99 mg/dL, and stable, after one month.\n\n\nCONCLUSIONS\nWe have described two cases of preventable accelerated AKI following post-operative hypotension in CKD patients concurrently on 'triple whammy' medications. We dubbed this new syndrome \"Quadruple Whammy\". It is not uncommon. 'Renoprevention', the pre-emptive withholding of (potentially nephrotoxic) medications, including 'triple whammy' medications, pre-operatively, in CKD patients, together with the simultaneous avoidance of peri-operative hypotension would help reduce, if not eliminate such AKI - a call for more pharmacovigilance.",
"affiliations": "Mayo Clinic College of Medicine, Rochester, Minnesota; Department of Nephrology, Mayo Clinic Health System, Eau Claire, Wisconsin, USA, .",
"authors": "Onuigbo|M A|MA|;Agbasi|N|N|",
"chemical_list": "D000959:Antihypertensive Agents; D002074:Butanones; D052246:Cyclooxygenase 2 Inhibitors; D004338:Drug Combinations; D011720:Pyrazoles; D013449:Sulfonamides; C091365:hydrochlorothiazide, lisinopril drug combination; D006852:Hydrochlorothiazide; D017706:Lisinopril; D000068579:Celecoxib; D000077430:Nabumetone",
"country": "India",
"delete": false,
"doi": "10.4103/1119-3077.141440",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "17(5)",
"journal": "Nigerian journal of clinical practice",
"keywords": null,
"medline_ta": "Niger J Clin Pract",
"mesh_terms": "D058186:Acute Kidney Injury; D000959:Antihypertensive Agents; D019644:Arthroplasty, Replacement, Hip; D002074:Butanones; D000068579:Celecoxib; D052246:Cyclooxygenase 2 Inhibitors; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D006801:Humans; D006852:Hydrochlorothiazide; D017706:Lisinopril; D008297:Male; D008875:Middle Aged; D000077430:Nabumetone; D009392:Nephrectomy; D011183:Postoperative Complications; D011720:Pyrazoles; D051436:Renal Insufficiency, Chronic; D013449:Sulfonamides; D013577:Syndrome; D014922:Wisconsin",
"nlm_unique_id": "101150032",
"other_id": null,
"pages": "649-54",
"pmc": null,
"pmid": "25244280",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "\"Quadruple whammy\"- a preventable newly described syndrome of post-operative AKI in CKD II and CKD III patients on combination \"Triple whammy\" medications: a Mayo Clinic Health System, Eau Claire, Wisconsin experience.",
"title_normalized": "quadruple whammy a preventable newly described syndrome of post operative aki in ckd ii and ckd iii patients on combination triple whammy medications a mayo clinic health system eau claire wisconsin experience"
} | [
{
"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2014-01815",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HYDROCHLOROTHIAZIDE"
},
"drug... |
{
"abstract": "A case of massive accidental triiodothyronine intoxication (1000-fold the usual therapeutic dose, for 8 days) is reported with important disturbances of cardiovascular and central nervous systems that required intensive care support. Serum free triiodothyronine levels were 4789 pmol L(-1) on admittance (normal values, 3.5-6.5 pmol x L(-1)). In the absence of a specific treatment, hemoperfusions were performed but failed to accelerate significantly the decay of blood levels of free triiodothyronine (apparent half-life 25.9 hours; 95% confidence interval: 19.8-37.4 hours). The patient, a young woman, made a satisfactory recovery, in spite of important clinical complications.",
"affiliations": "Endocrinology Department, University Hospital Dr. Peset, University of Valencia, Valencia, Spain.",
"authors": "Solá|Eva|E|;Gómez-Balaguer|Marcelino|M|;Morillas|Carlos|C|;Garzón|Sandra|S|;García|Santiago|S|;Morcillo|Esteban J|EJ|;Hernández-Mijares|Antonio|A|",
"chemical_list": "D014284:Triiodothyronine",
"country": "United States",
"delete": false,
"doi": "10.1089/105072502320288528",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1050-7256",
"issue": "12(7)",
"journal": "Thyroid : official journal of the American Thyroid Association",
"keywords": null,
"medline_ta": "Thyroid",
"mesh_terms": "D000328:Adult; D002318:Cardiovascular Diseases; D002493:Central Nervous System Diseases; D003422:Critical Care; D005260:Female; D006464:Hemoperfusion; D006801:Humans; D011041:Poisoning; D014284:Triiodothyronine",
"nlm_unique_id": "9104317",
"other_id": null,
"pages": "637-40",
"pmc": null,
"pmid": "12193311",
"pubdate": "2002-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Massive triiodothyronine intoxication: efficacy of hemoperfusion?",
"title_normalized": "massive triiodothyronine intoxication efficacy of hemoperfusion"
} | [
{
"companynumb": "ES-BAUSCH-BL-2018-032536",
"fulfillexpeditecriteria": "2",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LIOTHYRONINE"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nTo determine the etiologic factors, circumstances of diagnosis, obstetrical management and complications of eclampsia and to value the maternal and perinatal outcomes.\n\n\nMETHODS\nWe conducted a retrospective descriptive study, from January 1996 to December 2006 in a maternity type IIB.\n\n\nRESULTS\nSixteen cases of eclampsia were studied. The prevalence of eclampsia over the study period was 8.1 per 10,000 births, without annual change in the incidence. The mean age of the patients was 27.8+/-6.7 years. The major risk factor was the primipaternity (87.5%). The eclampsia occurred in ante-, peri- and post-partum in 56, 6 and 38% of the cases, respectively. In cases of eclampsia, 75% of the patients had elevated blood pressure, 93% presented headache, but 62% presented with an atypical form with less than three functional symptoms (headache, visual trouble, hyperreflexia). Various treatments had been started: antihypertensive treatment (75%), antiepileptic treatment (69%) and magnesium sulphate (94%). Eleven patients had developed complications, mainly HELLP syndrome (10 patients). No maternal death was noted. The mean birth weight was 2366+/-818 g, 43.8% of children had birth weight less than the 10th percentile, and 87.5% of children were girls. One fetal and one perinatal death at day 19 had been noted.\n\n\nCONCLUSIONS\nNowadays, the physiopathology of eclampsia remains misunderstood. It is difficult to establish risk factors, the primipaternity being certainly one of these. Eclampsia may occur in an atypical and unforeseeable form in well followed patients, without risk factor. The diagnosis should be done quickly for an adapted treatment and obstetrical management.",
"affiliations": "Service de chirurgie gynécologique et d'obstétrique, CHU Jean-Verdier, Assistance publique-Hôpitaux de Paris, université Paris-XIII, Bondy, France. g.ducarme@gmail.com",
"authors": "Ducarme|G|G|;Herrnberger|S|S|;Pharisien|I|I|;Carbillon|L|L|;Uzan|M|M|",
"chemical_list": "D000959:Antihypertensive Agents",
"country": "France",
"delete": false,
"doi": "10.1016/j.gyobfe.2008.11.011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1297-9589",
"issue": "37(1)",
"journal": "Gynecologie, obstetrique & fertilite",
"keywords": null,
"medline_ta": "Gynecol Obstet Fertil",
"mesh_terms": "D000328:Adult; D000959:Antihypertensive Agents; D004461:Eclampsia; D005260:Female; D017359:HELLP Syndrome; D006801:Humans; D015994:Incidence; D007226:Infant Mortality; D007231:Infant, Newborn; D008297:Male; D008428:Maternal Mortality; D011247:Pregnancy; D011256:Pregnancy Outcome; D012189:Retrospective Studies; D012307:Risk Factors; D055815:Young Adult",
"nlm_unique_id": "100936305",
"other_id": null,
"pages": "11-7",
"pmc": null,
"pmid": "19119047",
"pubdate": "2009-01",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Eclampsia: retrospective study about 16 cases.",
"title_normalized": "eclampsia retrospective study about 16 cases"
} | [
{
"companynumb": "PHHY2017FR102237",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "NICARDIPINE"
},
"drugadditional": null,
"dru... |
{
"abstract": "BACKGROUND\nCervical radiculopathy is a common condition affecting many people each year. The efficacy of cervical epidural steroid injection for patients that have not responded to conservative treatment has been demonstrated. Even with confirmatory radiocontrast dispersion indicating correct presence in the epidural space, there still may be rostral spread of steroid and local anesthetic resulting in an unusual presentation of symptoms and potentially life threatening complications.\n\n\nMETHODS\nWe present the case of a 52-year-old male presenting for a right sided C6-C7 epidural steroid injection. The epidural space was identified and a Tuohy needle was advanced using loss of resistance technique. Isovue contrast was used for needle localization and after confirmation of the presence of the contrast in the epidural space, dexamethasone and lidocaine were injected to the area without any complications. Five minutes after arrival to the PACU, the patient developed a constellation of symptoms including inability to swallow, vertigo, and horizontal nystagmus which required reassurance and vigilant monitoring.\n\n\nCONCLUSIONS\nInterventional pain physicians must be cognizant that even with confirmatory epidural radiocontrast dispersion, there still may be inadvertent uptake of steroid and local anesthetic rostrally resulting in an unusual presentation of symptoms and potentially life threatening complications. Potential reasons for the rostral spread include inadvertent subdural or intrathecal injection.",
"affiliations": "Miami Beach Anesthesiology Associates, Inc., Department of Anesthesiology, Mount Sinai Medical Center, Miami Beach, Florida.;Miami Beach Anesthesiology Associates, Inc., Department of Anesthesiology, Mount Sinai Medical Center, Miami Beach, Florida.;Miami Beach Anesthesiology Associates, Inc., Department of Anesthesiology, Mount Sinai Medical Center, Miami Beach, Florida.;Department of Pain Medicine, Mount Sinai Medical Center, Miami Beach, Florida.",
"authors": "Viswanath|Omar|O|;Suthar|Rekha|R|;Kannan|Murlikrishna|M|;Baskin|Michael|M|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.5812/aapm.44636",
"fulltext": "\n==== Front\nAnesth Pain MedAnesth Pain Med10.5812/aapm.KowsarAnesthesiology and Pain Medicine2228-75232228-7531Kowsar 10.5812/aapm.44636Case ReportPost Procedural Complication following Cervical Epidural Local Anesthetic Injection: A Case Report Viswanath Omar 1Suthar Rekha 1Kannan Murlikrishna 1*Baskin Michael 21 Miami Beach Anesthesiology Associates, Inc., Department of Anesthesiology, Mount Sinai Medical Center, Miami Beach, Florida2 Department of Pain Medicine, Mount Sinai Medical Center, Miami Beach, Florida* Corresponding author: Murlikrishna Kannan, Department: Department of Anesthesiology, Institution: Mt. Sinai Medical Center (Miami Beach, Florida), Mailing address: 4300 Alton Road, Suite 1401, Dept of Anesthesiology, Mount Sinai Medical Center, Miami Beach, FL 33140. Tel: +1-3056742742, E-mail: murli_31@yahoo.com01 2 2017 4 2017 7 2 e4463610 12 2016 14 1 2017 20 1 2017 Copyright © 2017, Iranian Society of Regional Anesthesia and Pain Medicine (ISRAPM)2017This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.Introduction\nCervical radiculopathy is a common condition affecting many people each year. The efficacy of cervical epidural steroid injection for patients that have not responded to conservative treatment has been demonstrated. Even with confirmatory radiocontrast dispersion indicating correct presence in the epidural space, there still may be rostral spread of steroid and local anesthetic resulting in an unusual presentation of symptoms and potentially life threatening complications.\n\nCase Presentation\nWe present the case of a 52-year-old male presenting for a right sided C6-C7 epidural steroid injection. The epidural space was identified and a Tuohy needle was advanced using loss of resistance technique. Isovue contrast was used for needle localization and after confirmation of the presence of the contrast in the epidural space, dexamethasone and lidocaine were injected to the area without any complications. Five minutes after arrival to the PACU, the patient developed a constellation of symptoms including inability to swallow, vertigo, and horizontal nystagmus which required reassurance and vigilant monitoring.\n\nConclusions\nInterventional pain physicians must be cognizant that even with confirmatory epidural radiocontrast dispersion, there still may be inadvertent uptake of steroid and local anesthetic rostrally resulting in an unusual presentation of symptoms and potentially life threatening complications. Potential reasons for the rostral spread include inadvertent subdural or intrathecal injection.\n\nEpidural InjectionPost Procedure ComplicationSubdural InjectionNystagmusLocal Anesthetic Toxicity\n==== Body\n1. Introduction\nCervical radiculopathy is a common condition affecting 83 per 100,000 persons each year (1). Presenting symptoms include cervical pain with or without radiculopathic upper extremity pain, deep tendon reflex depression, headache, weakness, or vertigo. Duration and severity of symptoms directs selection of treatment modality. Common conservative treatment consists of nonsteroidal anti-inflammatory drugs (NSAIDs), anticonvulsants, muscle relaxants, and physical therapy (2). The efficacy of cervical epidural steroid injection for patients that have not responded to conservative treatment has been demonstrated (3-5). If the patient’s symptoms continue to persist after this interventional procedure, then surgical interventions may be considered.\n\nDerby et al. report that the overall rate of complication following cervical epidural steroid injections as 5 per 1000 injections (6). Complications described as minor include vasovagal episodes, headache, rashes, worsening pain, pain, and new paresthesia. Major complications, although rare, include direct spinal cord trauma, epidural hematoma or abscess, transection of vertebral artery, and injection of the particulate steroid into a radiculomedullary artery or vertebral artery resulting in spinal cord or posterior cerebellar embolic infarction (7, 8). Subdural injection of local anesthetic and steroid represents a rare but potentially life threatening complication (2). The incidence of subdural injection is 0.8% with lumbar epidural injection and surprisingly high 1.6% - 3.2% during diagnostic myelography (9, 10).\n\n2. Case Presentation\nA 52-year-old male presented to the ambulatory surgery center for a scheduled right sided C6 - C7 interlaminar epidural steroid injection. The patient had been dealing with neck pain for the last few years, with decreased range of motion predominantly on extension, positive Spurling’s sign on the right side, decreased sensation to light touch in the C6 - C7 nerve distribution, and normal reflexes that were elicited on physical examination. He had minimal relief with medication, including NSAIDs and tramadol, and physical therapy. MRI of the cervical spine showed a posterior disc osteophyte complex that was causing mild to moderate spinal canal stenosis with severe right and moderate to severe left neural foraminal narrowing. The radiologic findings along with the positive physical exam findings were evidence that the patient could potentially benefit from a cervical epidural block.\n\nAfter informed consent was obtained, the patient was placed on the fluoroscopy table in the prone position with the neck in the neutral position. The right C6 - C7 epidural space was identified using fluoroscopy and a 22-gauge, 3.5 inch Tuohy was advanced to the epidural space using loss of resistance technique. Isovue contrast was used for needle localization and after confirmation of the presence of the contrast in the epidural space (Figure 1), 10 mg of dexamethasone and 2 mL of preservative free 1% lidocaine were injected.\n\nFigure 1. Posterolateral View of the Cervical Spine with contrast injection showing the typical Contrast Pattern for Epidural Injection with Limited Cephalocaudal Spread and Outlining of Nerve Roots\nThe patient was then taken from the OR to the post anesthesia care unit (PACU) for observation. About five minutes after arrival into the PACU, the patient was noted to be anxious and hypertensive, with the systolic pressure running in the 180s mmHg and the diastolic pressure in the 100s mmHg. The patient was normotensive prior to the procedure with a blood pressure of 134/82 mmHg. In addition to the elevated blood pressure, the patient reported that he was unable to swallow and was having a subjective sensation of dizziness, and concurrent horizontal nystagmus. All other vital signs, including pulse oximetry, heart rate, respiratory rate, and temperature were all within normal limits.\n\nThe patient was reassured and after thirty minutes from the initial presentation the symptoms resolved. The patient was observed in the PACU for another thirty minutes and then was transferred to phase two of PACU and from there was discharged home with no further issues or complications. Prior to discharge, the patient did report that his neck pain felt much better at this time than before the procedure.\n\n3. Discussion\nComplications from epidural injections can present in dramatic clinical fashion. Our patient’s constellation of symptoms, including difficulty swallowing, vertigo, and horizontal nystagmus points to possible local anesthetic spread rostrally to the brainstem and lower midbrain levels. These symptoms are the likely precipitant of anxiety in our patient and the resultant hypertension, which normalized concurrently with the dissipation of those symptoms. The swallowing difficulty, horizontal nystagmus, and vertigo in our patient may be due to the effect of local anesthetic on the glossopharyngeal, abducens, and vestibulocochlear cranial nerves respectively. The glossopharyngeal cranial nerve innervates the stylopharyngeus muscle whose functions include elevating both the larynx and pharnx and dilating the pharynx which promotes swallowing (11). The vestibulocochlear cranial nerve splits into the vestibular and cochlear nerve. The vestibular nerve is responsible for innervating the vestibules and semicircular canal of the inner ear, which are structures that transmits information about balance (12). The abducens cranial nerve innervates the lateral rectus muscle which is responsible for abduction of the eyeball in the lateral direction away from the midline of the body (13). The presentation of hypertension is likely secondary to the aniety.\n\nDuring the pain procedure, epidural placement of the needle is confirmed by a radiocontrast dye. However, when complications arise, the possibility of inadvertent subdural or intrathecal spread of the medication must be considered in amongst other causes in the differential diagnosis given the close geographic proximity of the anatomical structures of the spinal cord. The spinal cord and the spinal nerve proximal to the dorsal root ganglion are surrounded by a trilaminar structure that is composed of an outer layer of dense fibrous dura mater, a middle arachnoid layer of thin nonvascular tissue, and an inner pial layer of thick vascular connective tissue. As the subdural space is larger in the cervical region compared to the lumbar region, the risk for inadvertent subdural injections may also be greater in the cervical region. The subdural space typically extends from the inferior border of the second sacral vertebra into the intracranial space unlike the epidural space which typically terminates at the foramen magnum (2).\n\nThe greatest hazard of subdural injection is the small volume of local anesthetic solution required to spread cephalad leading to significant neurological and hemodynamic complications including loss of consciousness, severe hypotension, bradycardia, and cardiac arrest (14, 15).\n\nEven with appropriate confirmation with radiocontrast dye, seemingly unrelated symptomology may potentially manifest in the patient. Although the cause may not be initially apparent, interventional pain physicians must be vigilant to the possibility of inadvertent spread of local anesthetic even after a confirmatory presence of radiographic contrast in the epidural space. Supportive treatment including hemodynamic and ventilatory support may be required.\n\nAuthors’ Contribution:Omar Viswanath, Direct patient care, literature review, draft production, review/edit draft; Rekha Suthar, Literature review, draft production, review/edit draft; Murlikrishna Kannan, Direct Patient Care, literature review, review draft, edit draft; Michael Baskin: Direct Patient Care, literature review, review draft, edit draft.\n\nConflict of Interest:None.\n\nFunding/Support:No funding.\n==== Refs\nReferences\n1 Huston CW Cervical epidural steroid injections in the management of cervical radiculitis: interlaminar versus transforaminal. A review. Curr Rev Musculoskelet Med. 2009 2 1 30 42 10.1007/s12178-008-9041-4 19468916 \n2 Sadacharam K Petersohn JD Green MS Inadvertent Subdural Injection during Cervical Transforaminal Epidural Steroid Injection. Case Rep Anesthesiol. 2013 2013 847085 10.1155/2013/847085 24490089 \n3 Bush K Hillier S Outcome of cervical radiculopathy treated with periradicular/epidural corticosteroid injections: a prospective study with independent clinical review. Eur Spine J. 1996 5 5 319 25 10.1007/BF00304347 8915637 \n4 Strobel K Pfirrmann CW Schmid M Hodler J Boos N Zanetti M Cervical nerve root blocks: indications and role of MR imaging. Radiology. 2004 233 1 87 92 10.1148/radiol.2331030423 15317955 \n5 Bono CM Ghiselli G Gilbert TJ Kreiner DS Reitman C Summers JT et al. An evidence-based clinical guideline for the diagnosis and treatment of cervical radiculopathy from degenerative disorders. Spine J. 2011 11 1 64 72 10.1016/j.spinee.2010.10.023 21168100 \n6 Derby R Lee SH Kim BJ Chen Y Seo KS Complications following cervical epidural steroid injections by expert interventionalists in 2003. Pain Physician. 2004 7 4 445 9 16858486 \n7 Baker R Dreyfuss P Mercer S Bogduk N Cervical transforaminal injection of corticosteroids into a radicular artery: a possible mechanism for spinal cord injury. Pain. 2003 103 1-2 211 5 12749976 \n8 Brouwers PJ Kottink EJ Simon MA Prevo RL A cervical anterior spinal artery syndrome after diagnostic blockade of the right C6-nerve root. Pain. 2001 91 3 397 9 10.1016/S0304-3959(00)00437-1 11275398 \n9 Vandenabeele F Creemers J Lambrichts I Ultrastructure of the human spinal arachnoid mater and dura mater. J Anat. 1996 189 ( Pt 2) 417 30 8886963 \n10 Reina MA De Leon Casasola O Lopez A De Andres JA Mora M Fernandez A The origin of the spinal subdural space: ultrastructure findings. Anesth Analg. 2002 94 4 991 5 10.1097/00000539-200204000-00040 table of contents 11916810 \n11 Walker HK Walker HK Hall WD Hurst JW Cranial nerves IX and X: The glossopharyngeal and vagus nerves. 1990 3rd ed Clinical methods: The history, physical, and laboratory examinations. Boston Butterworths \n12 Kandel ER Schwartz JH Jessell TM Siegelbaum SA Hudspeth AJ Principles of neural science. 2013 5th ed 1019 36 Appleton and Lange: McGraw Hill \n13 Purves D Augustine GJ Fitzpatrick D Katz LC LeMantia A McNamara JO Neuroscience. 2001 2nd ed Sunderland (MA) Sinauer Associates \n14 Lehmann LJ Pallares VS Subdural injection of a local anesthetic with steroids: complication of epidural anesthesia. South Med J. 1995 88 4 467 9 10.1097/00007611-199504000-00018 7716603 \n15 Agarwal D Mohta M Tyagi A Sethi AK Subdural block and the anaesthetist. Anaesth Intensive Care. 2010 38 1 20 6 20191772\n\n",
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"issue": "7(2)",
"journal": "Anesthesiology and pain medicine",
"keywords": "Epidural Injection; Local Anesthetic Toxicity; Nystagmus; Post Procedure Complication; Subdural Injection",
"medline_ta": "Anesth Pain Med",
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"pubdate": "2017-04",
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"title": "Post Procedural Complication following Cervical Epidural Local Anesthetic Injection: A Case Report.",
"title_normalized": "post procedural complication following cervical epidural local anesthetic injection a case report"
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"abstract": "BACKGROUND\nAnticonvulsant hypersensitivity syndrome represents a rare but potentially fatal kind of adverse drug reaction. This clinical picture often hampers the flexibility with which alternative anticonvulsants or even other classes of drugs are prescribed in these patients, negatively affecting the efficacy of treatment and the course of the disease. The aim of this study was to analyse a group of six patients with severe cutaneous drug reactions induced by anticonvulsants and to report which alternative antiepileptic drugs and which drugs of other classes were tolerated.\n\n\nMETHODS\nA total of six patients (2 males and 4 females, age 11-73 years) are described in this study. In all the patients the onset of the severe cutaneous drug reactions was 2-4 weeks after initiating the anticonvulsant therapy: 2 out of 6 patients presented with a drug reaction with eosinophilia and systemic symptoms under therapy with phenytoin; 2 out of 6 presented with Stevens-Johnson syndrome under therapy with lamotrigine; and 2 out of 6 presented with a toxic epidermal necrolysis, one of them under therapy with valproic acid, and the other one under therapy with lamotrigine. Alternative anticonvulsants tolerated after the reaction were: clonazepam, levetiracetam, diazepam, delorazepam and lormetazepam.\n\n\nCONCLUSIONS\nIn our cases we observed that non aromatic anticonvulsants and benzodiazepines were well tolerated as alternative treatments in six patients with reactions to aromatic anticonvulsivants and that the risk of hypersensitivity reactions to other drug classes was not increased as compared to general population.",
"affiliations": "Department of Allergology and Immunology, Ospedale Metropolitano Niguarda Ca' Granda, Piazza Ospedale Maggiore, 3, 20162 Milan, Italy.;Department of Allergology and Immunology, Ospedale Metropolitano Niguarda Ca' Granda, Piazza Ospedale Maggiore, 3, 20162 Milan, Italy.;Department of Allergology and Immunology, Ospedale Metropolitano Niguarda Ca' Granda, Piazza Ospedale Maggiore, 3, 20162 Milan, Italy.;Department of Allergology and Immunology, Ospedale Metropolitano Niguarda Ca' Granda, Piazza Ospedale Maggiore, 3, 20162 Milan, Italy.;Department of Burn/Intensive Care, Ospedale Metropolitano Niguarda Ca' Granda, Milan, Italy.;Department of Allergology and Immunology, Ospedale Metropolitano Niguarda Ca' Granda, Piazza Ospedale Maggiore, 3, 20162 Milan, Italy.;Department of Allergology and Immunology, Ospedale Metropolitano Niguarda Ca' Granda, Piazza Ospedale Maggiore, 3, 20162 Milan, Italy.;Department of Allergology and Immunology, Ospedale Metropolitano Niguarda Ca' Granda, Piazza Ospedale Maggiore, 3, 20162 Milan, Italy.",
"authors": "De Luca|Fabrizio|F|;Losappio|Laura Michelina|LM|;Mirone|Corrado|C|;Schroeder|Jan Walter|JW|;Citterio|Antonella|A|;Aversano|Maria Gloria|MG|;Scibilia|Joseph|J|;Pastorello|Elide Anna|EA|",
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"fulltext": "\n==== Front\nClin Mol AllergyClin Mol AllergyClinical and Molecular Allergy : CMA1476-7961BioMed Central London 7210.1186/s12948-017-0072-5ReviewTolerated drugs in subjects with severe cutaneous adverse reactions (SCARs) induced by anticonvulsants and review of the literature De Luca Fabrizio fabrizio.deluca@unimi.it 1Losappio Laura Michelina lauramichelina.losappio@ospedaleniguarda.it 1Mirone Corrado corrado.mirone@ospedaleniguarda.it 1Schroeder Jan Walter jan.schroeder@ospedaleniguarda.it 1Citterio Antonella antonella.citterio@ospedaleniguarda.it 2Aversano Maria Gloria mariagloria.aversano@ospedaleniguarda.it 1Scibilia Joseph giuseppe.scibilia@ospedaleniguarda.it 1Pastorello Elide Anna +390264442751elide.pastorello@ospedaleniguarda.it 11 0000 0004 1757 8749grid.414818.0Department of Allergology and Immunology, Ospedale Metropolitano Niguarda Ca’ Granda, Piazza Ospedale Maggiore, 3, 20162 Milan, Italy 2 0000 0004 1757 8749grid.414818.0Department of Burn/Intensive Care, Ospedale Metropolitano Niguarda Ca’ Granda, Milan, Italy 4 10 2017 4 10 2017 2017 15 1628 4 2017 4 9 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\nAnticonvulsant hypersensitivity syndrome represents a rare but potentially fatal kind of adverse drug reaction. This clinical picture often hampers the flexibility with which alternative anticonvulsants or even other classes of drugs are prescribed in these patients, negatively affecting the efficacy of treatment and the course of the disease. The aim of this study was to analyse a group of six patients with severe cutaneous drug reactions induced by anticonvulsants and to report which alternative antiepileptic drugs and which drugs of other classes were tolerated.\n\nCase presentation\nA total of six patients (2 males and 4 females, age 11–73 years) are described in this study. In all the patients the onset of the severe cutaneous drug reactions was 2–4 weeks after initiating the anticonvulsant therapy: 2 out of 6 patients presented with a drug reaction with eosinophilia and systemic symptoms under therapy with phenytoin; 2 out of 6 presented with Stevens–Johnson syndrome under therapy with lamotrigine; and 2 out of 6 presented with a toxic epidermal necrolysis, one of them under therapy with valproic acid, and the other one under therapy with lamotrigine. Alternative anticonvulsants tolerated after the reaction were: clonazepam, levetiracetam, diazepam, delorazepam and lormetazepam.\n\nConclusions\nIn our cases we observed that non aromatic anticonvulsants and benzodiazepines were well tolerated as alternative treatments in six patients with reactions to aromatic anticonvulsivants and that the risk of hypersensitivity reactions to other drug classes was not increased as compared to general population.\n\nKeywords\nAnticonvulsantsDrug hypersensitivityAnticonvulsant hypersensitivity syndromeStevens–Johnson syndromeToxic epidermal necrolysisDrug reaction with eosinophilia and systemic symptomsSevere cutaneous adverse reactionsissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nAnticonvulsant hypersensitivity syndrome (AHS) represents a rare but potentially fatal kind of adverse drug reaction. The antiepileptic drugs (AEDs) most commonly involved are the aromatic anticonvulsants such as phenytoin, phenobarbital, carbamazepine, and lamotrigine; however, in the literature several cases induced by valproic acid are also reported [1–3]. Clinical presentations are highly variable and include either simple pruritic eruptions or severe forms such as Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) [4, 5]. SJS and TEN are characterized by detachment of the epidermis and erosions of mucous membranes and are considered to be the same disease, the only difference being the extent of skin detachment, < 10% of total body surface area in SJS, and > 30% in TEN [6]. DRESS is characterized by eosinophilia, skin rash, fever, lymphadenopathy, and visceral organ involvement [7]. The clinical symptoms usually develop from 1 to 8 weeks after starting the antiepileptic therapy; adults older than 64 years are at the highest risk for severe cutaneous adverse reactions (SCARs) [8]. The estimated incidence of mucocutaneous severe reactions to AEDs with internal organ involvement ranges from 1 in 1000 to 1 in 10,000 drug exposures [9]. In SJS/TEN necrosis of the skin and mucous membranes characterizes the disease; apoptosis of keratinocytes is mediated by the Fas–FasL interaction or through cytotoxic T-cell release of granulysin [10]. A genetic background confers an increased risk to develop severe forms of AHS in some ethnic groups, as demonstrated by several associations between HLA-A and -B haplotypes and severe anticonvulsant reactions, as reported in Table 1 [11–16].Table 1 Associations between HLA-A and -B haplotypes and severe anticonvulsant reactions\n\nDisease\tCulprit drug\tHLA haplotype\tPopulation\tAuthors (ref. number)\t\nSJS ⁄TEN\tCarbamazepine\tHLA-B*15:02\tAsians\t[11–13]\t\nSJS/TEN and DRESS\tCarbamazepine\tHLA-A*31:01\tEuropeans\t[14, 15]\t\nSJS/TEN and DRESS\tPhenytoin\tHLA-B*15:13 and -B*15:02\tMalaysians\t[16]\t\nSJS: Stevens Johnson syndrome, TEN: toxic epidermal necrolysis, DRESS: drug reaction with eosinophilia and systemic symptoms\n\n\n\n\nAs it has been demonstrated in the last decade, the T cell activation at the basis of SCARs is explainable by the so called “p-i mechanism” that does not imply any processing or metabolism of the drug, making thus reasonable a definite HLA restriction [17].\n\nInfections play an important role in the pathogenesis of these reactions through an aspecific activation of immunological response, so that, for example the human herpes virus 6 (HHV-6) reactivation in DRESS is considered a relevant diagnostic marker [18]. Moreover, viral infections as well as other cell damaging events such surgery or severe cardiac diseases, represent the so called ‘danger’ factors able to prepare the pathogenetic background favouring the appearance of SCARs. All these aspects are crucial points to address in order to evaluate the risk of hypersensitivity reactions to alternative anticonvulsants or other types of drug. However, more studies will be necessary to better define the kind of genetic/environmental interaction that are at the basis of these syndromes. As a result, SCARs often restrict the use of alternative anticonvulsants or of other classes of drugs that have to be prescribed in these patients, negatively affecting the efficacy of treatment and the course of the disease.\n\nThe aim of this study was to describe a group of six patients with SCARs induced by anticonvulsant drugs and to report which alternative antiepileptic drugs and drugs of other classes were tolerated.\n\nCase reports\nA total of 6 caucasian patients (2 males and 4 females, age 11–73 years), admitted to Niguarda Ca’ Granda Metropolitan Hospital for SCARs, are described in this study. In all of the patients the onset of the SCARs was 2–4 weeks after initiating the anticonvulsant therapy. For each patient we collected data regarding medical and pharmacological history. They were evaluated according to the diagnostic criteria based on RegiSCAR (Registry for Serious Cutaneous Reactions) classification (i.e. both clinical and histological features). In order to identify the inducing drug, we obtained a detailed and thorough medication history. Furthermore, a standard set of laboratory tests was performed including blood count, renal function, liver function, inflammatory markers, lactate dehydrogenase (LDH). Moreover, samples for antinuclear antibodies (ANA), and immunoglobulins against HHV-6, hepatitis virus B (HBV) and C (HCV), herpes simplex virus (HSV) type 1 and 2, human immunodeficiency virus (HIV), Epstein–Barr virus (EBV), and cytomegalovirus (CMV), blood cultures and urine cultures, were collected in order to exclude other diseases. Among the six cases, we found two cases of DRESS, two cases of SJS, and two cases of TEN. Tables 2 and 3 summarize the clinical characteristics of the study patients. Table 4 shows treatment, culprit and tolerated drugs after and during SCARs.Table 2 Demographics and risk factors\n\nPatient\tSex/age\tRisk factors\t\nP1\tM/11\tSurgery treatment of cerebral cancer\t\nP2\tF/32\tSurgery for rupture of middle cerebral artery aneurysm\t\nP3\tM/73\tSevere cachexia\t\nP4\tF/53\tAcute disseminated encephalomyelitis\t\nP5\tF/41\tHead trauma\t\nP6\tF/21\tNone\t\n\nTable 3 Clinical and laboratory data at the diagnosis\n\n\tP1\tP2\tP3\tP4\tP5\tP6\t\nEosinophils (%)\t12\t39\t5.1\t4.6\t2.3\t2.2\t\nLeukocytes (109/L)\t34.67\t40.23\t15.0\t16.0\t5.6\t4.7\t\nAtypical lymphocytes\t+\t+\t−\t−\t−\t−\t\nGOT/GPT (IU/L)\t1034/906\t1068/960\t56/50\t89/63\t510/702\t503/731\t\nCRP (mg/dL)\t9.2\t9.6\t13.6\t11.3\t1.1\t1.0\t\nLDH (IU/L)\t1780\t1890\t1230\t1360\t1450\t423\t\nHHV-6 infection\t+\t+\t−\t−\t−\t−\t\nHCV, HBV, CMV, HSV-1 and -2, EBV, HIV infection\t−\t−\tHSV-2\t−\t−\t\t\nBlood cultures\t−\t−\tCandida albicans\tMRSA\tStaphylococcus capitis\tMRSA\t\nUrine cultures\t−\t−\t−\t−\tEnterococcus faecalis\t−\t\nANA\t−\t−\t−\t−\t−\t−\t\nSkin biopsy\tAcantholytic cells, skin detachment, mild lymphocytic infiltration\tND\tND\tApoptotic keratinocytes, spongiosis, subepidermal blister and dermal inflammatory infiltrate\tDermal infiltrate of lymphocytes and monocytes\tApoptotic keratinocytes, epidermal necrosis and dermal infiltrate of lymphocytes\t\nCRP: C-reactive protein, GOT: glutamate oxaloacètique transaminase, GPT: glutamane pyruvate transaminase, LDH: lactate dehydrogenase, ANA: antinuclear antibodies, MRSA: methicillin-resistant Staphylococcus aureus, ND: not done, +: positive, −: negative\n\n\nTable 4 Treatment, culprit and tolerated drugs after and during SCARs\n\nPatient\tSCARs\tCulprit drug\tLatency (weeks)\tTreatment\tTolerated anticonvulsants\tOther tolerated drugs\t\nP1\tDRESS\tPhenytoin\t3\tMethylprednisolone for 3 months\tClonazepam\tIbuprofen, clarithromycin\t\nP2\tDRESS\tPhenytoin\t3\tPrednisone for 1 year\tLevetiracetam\tMetamizole, tramadol, amoxicillin, clarithromycin, ketoprofen, metoclopramide, rituximab, lercanidipine\t\nP3\tSJS\tLamotrigine\t4\tHydrocortisone bolus, prednisone for 1 month and immunoglobulin intravenously\tDelorazepam and lormetazepam\tEchinocandin\t\nP4\tSJS\tPhenytoin\t4\tHydrocortisone bolus, prednisone for 1 month and immunoglobulin intravenously\tDiazepam\tTeicoplanin, haloperidol\t\nP5\tTEN\tValproic acid\t2\tPrednisone for 1 month and immunoglobulin intravenously\tDiazepam and levetiracetam\tMeropenem\t\nP6\tTEN\tLamotrigine\t2\tPrednisone for 1 month and immunoglobulin intravenously\tDiazepam and levetiracetam\tTeicoplanin\t\nSCARs: severe cutaneous adverse reactions, SJS: Stevens–Johnson syndrome, DRESS: drug reaction with eosinophilia and systemic symptoms, TEN: toxic epidermal necrolysis\n\n\n\n\nCases of DRESS\nTwo patients, an 11-year old male (P1) and a 32-year old female (P2) presented SCARs and relevant eosinophilia after 3 weeks of therapy with phenytoin, prescribed as prophylactic anticonvulsant for surgical removal of glioblastoma in P1 and neurosurgery due to the rupture of a middle cerebral artery aneurysm in P2. Both patients developed generalized papular rash, fever, asthenia, lymphadenopathy, leukocytosis, eosinophilia, and signs of liver damage, as reported in Table 3. Eosinophilia, lymphadenopathy, skin biopsy in P1, and HHV-6 DNA positivity confirmed the diagnosis of DRESS. Other diagnostic tests were carried out to better characterize the extent of the organ involvement and possible complications. Abdominal ultrasound showed splenomegaly in P1 and was normal in P2. Positron emission tomography-computed tomography and cervical lymph node biopsy performed to investigate the relevant lymphoadenomegaly in P2 demonstrated only reactive lymphadenopathy, thus excluding a lymphoproliferative disorder. Anticonvulsants were discontinued in both the patients after the diagnosis and a treatment with methylprednisolone 40 mg daily for 40 days was given to P1; a complete and stable remission of symptoms was observed after a slow tapering of methylprednisolone over a period of 2 months. P2 underwent therapy with prednisone 70 mg daily for 10 days; glucocorticoid was then interrupted for a few days in order to perform lymph nodal biopsy that confirmed the reactive lymphadenopathy: a severe clinical relapse was observed characterized by macular papular rash, systemic lymphadenopathy, itching and asthenia. Prednisone was readministered at a dosage of 50 mg daily for 15 days, reduced to 25 mg and slowly tapered off 5 mg every 2 weeks under strict medical control. Normalization of inflammatory and necrosis markers was observed in P2 after 4 months from the beginning of glucocorticoid therapy; subsequently P2 showed relevant adverse effects: hypertension, headache, acne, hair loss and osteoporosis. In both cases a new anticonvulsant drug was necessary for a relapse of seizures. In P1 clonazepam was introduced after few days of glucocorticoid premedication treatment and was well tolerated in the following months. P2 underwent treatment with levetiracetam for seizure relapse and the drug was well tolerated in the following months. Other drugs were well tolerated after the reaction despite the fear of clinical relapse, such as ibuprofen and clarithromycin in P1; metamizole, tramadol, amoxicillin, clarithromycin, ketoprofen, lercanidipine, and metoclopramide in P2. One month after definitive suspension of glucocorticoids P2 manifested an abrupt increase in blood pressure, dysarthria, confusional state and headache not responsive to treatment. The patient was again hospitalized and the following blood values were observed: Hb 7.8 g/dL, platelets count 11,000 × 109/L, LDH 1560 IU/L, haptoglobin 10 mg/dL, the presence of schistocytes in peripheral blood, total bilirubin 2.2 mg/dL, and ADAMTS13 activity at 7%. After hospital admission the patient manifested purpuric lesions. Brain magnetic resonance imaging was carried out and showed micro hemorrhages. The diagnosis of thrombotic thrombocytopenic purpura (Moskowitz syndrome) was made so treatment with rituximab at dose of 375 mg/m2, i.e. once weekly for 4 weeks plus prednisone at 50 mg daily for 2 weeks with tapering after 1 month was instituted. The complete resolution of the clinical picture required a total of 14 months.\n\nCases of SJS\nTwo patients, a 73-year old male (P3) and a 53-year old female (P4) presented SCARs after 4 weeks of therapy with lamotrigine, prescribed to P3 for bipolar disorder with prevailing depressive symptoms in severe cachexia, and phenytoin prescribed to P4 as prophylaxis after acute disseminated encephalomyelitis. Both had developed diffuse maculopapular rash, fever, and 24 h later ulcerations of the oral mucosa, blistering skin lesions, epithelial detachment, conjunctivitis, and diffuse pain. HSV-2 IgM positivity was observed in P3. The clinical pictures and skin biopsy performed in P4 confirmed the diagnosis of SJS (Table 3). Abdominal ultrasound, echocardiogram and chest CT excluded organ involvement. After suspected SJS diagnosis, anticonvulsants were immediately discontinued; both P3 and P4 were treated with hydrocortisone 1 g bolus, followed by prednisone 50 mg/daily for 10 days tapered in the subsequent month. During the hospitalization the patients were treated with intravenous immunoglobulins (IV Ig) 0.4 g/kg daily for 5 days, and with topical agents. Enteral feeding and crystalloid were also required. New anticonvulsants were given: lormetazepam and diazepam in P3 and diazepam in P4. Moreover, P4 developed psychosis as an adverse effect of glucocorticoid therapy and was treated with haloperidol. Echinocandin and teicoplanin were administered for 2 weeks because of prolonged fever and positive blood cultures for Candida albicans and methicillin-resistant Staphylococcus aureus (MRSA) in P3 and P4, respectively. Both antibiotics were well tolerated by the patients and they were discharged after 3 weeks in good clinical conditions.\n\nCases of TEN\nTwo females, 41 year old (P5), and 21 year old (P6), presented SCARs after 2 weeks of therapy with valproic acid, given to P5 consequently to head trauma, and with lamotrigine, used in P6 for epilepsy. Both patients developed diffuse maculopapular rash and in addition P6 showed severe asthenia and conjunctivitis. Their clinical pictures progressed rapidly to TEN, showing epidermal detachment, mucosal involvement with severe bleeding requiring blood transfusions. In particular, epidermal detachment involved 45 and 95% of the body surface in P5 and P6, respectively. During the hospitalization, P6 developed respiratory distress requiring mechanical ventilation. Diagnostic routine work up on the diagnosis showed leukocytosis and sign of liver damage in both the patients. Infections were detected by urine cultures that showed Enterococcus faecalis in P5 and by blood cultures that were positive for Staphylococcus capitis and MRSA in P5 and in P6, respectively. Clinical pictures and skin biopsy confirmed the TEN diagnosis (Table 3). Ultrasound abdomen showed hepatomegaly in both patients, and echocardiograms were normal. Based on the diagnosis of TEN, anticonvulsants were stopped and the patients were treated with topical medications, IV Ig at 0.4/kg daily for 5 days and with prednisone 50 mg daily during 2 weeks of the hospitalization with slow tapering with complete remission after 1 month from the discharge. Meropenem and teicoplanin were administered for 2 weeks to treat secondary infections in P5 and P6 respectively and enteral feeding and crystalloid were also required. Antibiotics were perfectly tolerated also after glucocorticoid tapering. In both cases, new anticonvulsant were considered necessary and levetiracetam and diazepam were introduced in P5 and P6 respectively, a few days after the start of cortisone treatment, and were well tolerated in the following months.\n\nConclusions\nThe principal aim of this study was to describe the course of six patients affected by SCARs to anticonvulsants. These drugs, as well as allopurinol, have been already regarded as one of the most common causes of SCARs [19, 20]. The analysis of our clinical data allowed us to determine the tolerance to alternative anticonvulsants and to different drug classes that in the routine practice are often not administered for the fear of a relapse. According to a prospective RegiSCAR study, aromatic AEDs, in particular carbamazepine, phenytoin, and lamotrigine, were considered responsible for the reaction in the 35% of cases. Additional culprit drugs were allopurinol, sulfonamides and other antibiotics involved in another 41% of cases [19]. Two out of 6 SCARs from our study were induced by lamotrigine, three by phenytoin and one by valproic acid. In a recent review 172 cases of DRESS associated with 44 drugs were analyzed: the most frequently implicated was carbamazepine, followed by lamotrigine and phenytoin [21]. In SJS/TEN, an association with 12 “highly suspect” medication was reported that included anticonvulsants, mostly carbamazepine, oxcarbazepine, phenytoin and lamotrigine [20]. These observations confirmed previous clinical data [22, 23]. The reactions in our patients occurred on the first exposure to the drug, with a latency time from 2 to 4 weeks after the beginning of therapy, as already observed [1, 9]. Several potential risk factors for AED hypersensitivity were reported: previous history of AED-induced eruption [24], autoimmune diseases, treatment with corticosteroids, family history of SCARs [25], age below 12 years or above 64 associated with altered drug metabolism [8], head injury, surgery, genetic markers such as HLA-B*15:02 and HLA-A*31:01, and reactivation of HHV-6 and -7, EBV and CMV virus [26, 27].\n\nIn our patients we identified several of the above quoted risk factors, in particular: surgery (P1, P2), head trauma (P5), and herpes viral infections in P1, P2 (i.e. HHV-6), and in P3 (i.e. HSV 2); of note, this last patient also suffered from recurrent airway infections due to a cachectic state. All these situations have been reported to potentially determine severe distress and injury to cells that in turn can release internal molecules able to act as damage or danger signals stimulating toll-like receptors on antigen presenting cells activating thus the immune response.\n\nThe culprit drugs were identified only by clinical data as up to now no standardized diagnostic test has been adopted in delayed T-cell mediated drug allergy reactions except in contact dermatitis IVa type [28]. Although different skin tests (SPT, ID, patch tests) have been suggested as useful tools for the diagnosis of SCARs [29], more recently drug patch test was reported as the only convenient and safe tool for identifying culprit drugs in DRESS; on the contrary, this procedure was not recommended in SJS/TEN [30, 31]. We did not perform in vivo tests because our patients assumed only AEDs at the onset of SCARs. The clinical course worsened after discontinuation of the culprit drug, as already reported in DRESS [32]. Liver was the extracutaneous organ more frequently affected in our patients, as usually observed in DRESS (70–95%), and in SJS/TEN [33]. In DRESS, hepatic damage was more severe after phenytoin [34], as observed also in our two DRESS patients (P1 and P2). We observed no heart or kidney damage. Signs of renal damage were reported just in the 11% of DRESS patients, mainly, after allopurinol administration [19]. In P1 and P2, a diffuse lymphadenopathy was observed, as already reported in DRESS in nearly 75% of the cases [35]. In particular, in P2 lymph node biopsy showed a benign lymphoid hyperplasia, one of the two histological patterns reported in this syndrome, besides pseudolymphoma [7]. The most common complications we observed were secondary infections i.e. septicemia (4 out of 6 patients; 66%). A transient respiratory failure appeared in one case (P6). P2 developed an autoimmune disease, a sequelae already reported in DRESS especially if not treated with steroids [36]. However, in our patient a thrombotic thrombocytopenic purpura (Moskowitz syndrome) was developed nevertheless a previous high dose steroid therapy followed for several months. The time for complete resolution of the hypersensitivity reaction ranged from 2 to 12 months, compared to a period of 14–345 days reported by others [19, 36].\n\nIn respect to the culprit drugs, 5 out of 6 SCARs cases were induced by aromatic anticonvulsant drugs to confirm an increased risk of severe reactions to these molecules in comparison with other AEDs. In two cases (P3 and P6) the culprit drug was lamotrigine, a molecule already associated with a high risk of SJS and TEN [23], through a dose dependent effect [37]. Both lamotrigine and phenytoin, culprit drugs in P3, P4 and P6, were regarded as “highly suspect” compounds associated with SJS/TEN in a pharmacovigilance study [20]. Cross-reactivity between aromatic anticonvulsants ranged from 30 to 58% [38, 39], for this reason in our cases we selected non aromatic drugs, i.e. benzodiazepines and levetiracetam, as an alternative treatment. This choice relied on previous reports suggesting non aromatic AEDs, like gabapentin, as agents with low allergenic potential [39], in particular levetiracetam, was a drug associated with lower rash rates (0–6%) [24].\n\nSome authors advised against treatment with antibiotics or NSAIDs in the DRESS acute period, for unexplained cross-reactivity able to worsen the clinical picture [27]. However, alternative antimicrobials were administered without adverse effects in 16 out of 17 patients affected with antibiotic-related DRESS [40]. Our experience showed that in AED-induced SCARs the risk of hypersensitivity reactions to other drug classes was not increased in comparison with general population. Recently, a strict relationship between SCARs induced by allopurinol and carbamazepine and definite HLA-aplotypes has been identified. This observation might implicate a tight HLA restriction also in adverse reactions to different drugs and consequently a low risk of additional events [41]. In fact, other drugs tolerated were: ibuprofen, clarithromycin, amoxicillin, metamizole, tramadol, ketoprofen, metoclopramide, rituximab, lercanidipine, echinocandin, teicoplanin, haloperidoland meropenem. In our patients, we discontinued the culprit drug and administered steroid therapy at high dosage, a treatment suggested in other studies [42, 43]. High doses of steroid might have an immunosuppressive effect preventing a relapse due to other compounds [41]. The management of our patients differed according to the Unit in which they were admitted: DRESS subjects were treated in our Centre with high doses of steroids, while SJS/TEN subjects were treated in Burn Unit with IVIG, steroids and topic therapy. High doses of IVIG was effective in our SJS/TEN patients, as already reported in some studies [44], although this treatment was considered useless by other Authors [45]. The prognosis was good also as a consequence of careful supportive treatment conducted in specialized Burn Units.\n\nIn conclusion, on the basis of our case reports, we can suggest that non aromatic drugs, i.e. benzodiazepines and levetiracetam, are the most safe alternative treatment in SCARs due to the anticonvulsants. Moreover, we observed that drugs belonging to other classes were well tolerated in these patients confirming thus indirectly an HLA restriction for hypersensitivity reactions to other anticonvulsant drugs as well as to carbamazepine and phenytoin.\n\nAbbreviations\nAHSanticonvulsant hypersensitivity syndrome\n\nAEDsantiepileptic drugs\n\nSJSStevens–Johnson syndrome\n\nTENtoxic epidermal necrolysis\n\nDRESSdrug reaction with eosinophilia and systemic symptoms\n\nSCARssevere cutaneous adverse reactions\n\nRegiSCARRegistry for Serious Cutaneous Reactions\n\nLDHlactate dehydrogenase\n\nANAantinuclear antibodies\n\nHBVhepatitis virus B\n\nHCVhepatitis virus C\n\nHSVherpes simplex virus\n\nHIVhuman immunodeficiency virus\n\nEBVEpstein–Barr virus\n\nCMVcytomegalovirus\n\nAuthors’ contributions\nFDL collected data. LML wrote the draft paper and analyzed the data. CM, MGA wrote the draft paper. JWS followed clinical course of the patients. AC and JS revised the draft paper. EAP designed the study, wrote and revised the draft paper. All authors read and approved the final manuscript.\n\nAcknowledgements\nNot applicable.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAvailability of data and supporting materials\nData sharing not applicable to this article as no datasets were generated or analysed during the current study.\n\nConsent for publication\nInformed consent to clinical data collection and publication was obtained from all patients.\n\nEthics approval and consent to participate\nNot applicable in this retrospective clinical study.\n\nFunding\nNot applicable.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Knowles SR Shapiro LE Shear N Anticonvulsant hypersensitivity syndrome: incidence, prevention and management Drug Saf 1999 21 6 489 501 10.2165/00002018-199921060-00005 10612272 \n2. 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Sassolas B Haddan C Mockenhaupt M Dunat A Liss Y Bork K Haustein UF Vieluf D Roujeau JC Le Louet H ALDEN, an algorithm for assessment of drug causality in Stevens–Johnson Syndrome and toxic epidermal necrolysis: comparison with case-control analysis Clin Pharmacol Ther 2010 88 60 68 10.1038/clpt.2009.252 20375998 \n23. Mockenhaupt M Viboud C Dunand A Naldi L Halevy S Bouwer Bavinck HN Sidoroff A Schneck J Roujean JC Flahault A Stevens–Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study J Invest Dermatol 2008 128 35 44 10.1038/sj.jid.5701033 17805350 \n24. Arif H Burchsbaum R Weintraub D Koyfman S Salas-Humara C Bazil CW Resor SR Jr Hirsvh LJ Comparison and predictors of rash associated with 15 antiepileptic drugs Neurology 2007 68 20 1701 1709 10.1212/01.wnl.0000261917.83337.db 17502552 \n25. 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Barbaud A Skin testing and patch testing in non-IgE mediated drug allergy Curr Allergy Asthma Rep 2014 14 442 10.1007/s11882-014-0442-8 24740692 \n31. Barbaud A Collet E Milpied B Assier H Staumont D Avenel-Audran M Grange A Amarger S Girardin P Guinnepain MT Truchetet F Lasek A Waton J Toxidermies group of the French Society of Dermatology A multicentre study to determine the value and safety of drug patch tests for the three main classes of severe cutaneous adverse drug reactions Br J Dermatol 2013 168 3 555 562 10.1111/bjd.12125 23136927 \n32. Roujeau JC Stern RS Severe adverse cutaneous reactions to drugs New Engl J Med 1994 331 1272 1285 10.1056/NEJM199411103311906 7794310 \n33. Chave TA Mortimer NJ Sladden MJ Hall AP Hutchinson PE Toxic epidermal necrolysis: current evidence, practical management and future directions Br J Dermatol 2005 153 2 241 253 10.1111/j.1365-2133.2005.06721.x 16086734 \n34. 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Alvestad S Lydersen S Brodtkorb E Cross-reactivity pattern of rash from current aromatic antiepileptic drugs Epilepsy Res 2008 80 194 200 10.1016/j.eplepsyres.2008.04.003 18490142 \n39. Zaccara G Franciotta D Perucca E Idiosyncratic adverse reactions to antiepileptic drugs Epilepsia 2007 48 7 1223 1244 10.1111/j.1528-1167.2007.01041.x 17386054 \n40. Lin YF Yang CH Sindy H Lin JY Rosaline Hui CY Tsai YC Wu TS Huang CT Kao KC Hu HC Chiu CH Hung SI Chung WH Severe cutaneous adverse reactions related to systemic antibiotics Clin Infect Dis 2014 58 10 1377 1385 10.1093/cid/ciu126 24599767 \n41. Pichler WJ Daubner B Kawabata T Drug hypersensitivity: flare-up reactions, cross-reactivity and multiple drug hypersensitivity J Dermatol 2011 38 3 216 221 10.1111/j.1346-8138.2010.01142.x 21342222 \n42. 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Faye O Roujeay JC Treatment of epidermal necrolysis with high dose intravenous immunoglobulin (IVIg): clinical experience to date Drugs 2005 65 2085 2090 10.2165/00003495-200565150-00002 16225365\n\n",
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"keywords": "Anticonvulsant hypersensitivity syndrome; Anticonvulsants; Drug hypersensitivity; Drug reaction with eosinophilia and systemic symptoms; Severe cutaneous adverse reactions; Stevens–Johnson syndrome; Toxic epidermal necrolysis",
"medline_ta": "Clin Mol Allergy",
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"title": "Tolerated drugs in subjects with severe cutaneous adverse reactions (SCARs) induced by anticonvulsants and review of the literature.",
"title_normalized": "tolerated drugs in subjects with severe cutaneous adverse reactions scars induced by anticonvulsants and review of the literature"
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"abstract": "An unusual acute hypotensive syndrome has been observed in association with administration of trimethoprim-sulfamethoxazole (TMP-SMZ) to patients with human immunodeficiency virus (HIV) infection. In the 11 cases that have been reported, the syndrome differs from classic anaphylaxis and resembles septic shock. Mediation by tumor necrosis factor (TNF) has been hypothesized, but the mechanism has not been characterized with cytokine assays, and no invasive hemodynamic measurements have been reported. We describe a case of recurrent hyperdynamic shock--without classic features of anaphylaxis, without detectable IgE antibodies against TMP or SMZ, and without detectable levels of TNF--involving an HIV-infected patient rechallenged with TMP-SMZ.",
"affiliations": "Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.",
"authors": "Nguyen|B Y|BY|;Landucci|D L|DL|;Cunnion|R E|RE|;Yarchoan|R|R|;Walker|R E|RE|",
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"mesh_terms": "D017088:AIDS-Related Opportunistic Infections; D000328:Adult; D000707:Anaphylaxis; D003165:Complement System Proteins; D005334:Fever; D006439:Hemodynamics; D006801:Humans; D007022:Hypotension; D015850:Interleukin-6; D008297:Male; D011020:Pneumonia, Pneumocystis; D012769:Shock; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D014409:Tumor Necrosis Factor-alpha",
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"title": "A case of hyperdynamic shock caused by trimethoprim-sulfamethoxazole in which no tumor necrosis factor or features of anaphylaxis were detected.",
"title_normalized": "a case of hyperdynamic shock caused by trimethoprim sulfamethoxazole in which no tumor necrosis factor or features of anaphylaxis were detected"
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"abstract": "Drug-induced immune hemolytic anemia (DIIHA) and drug-induced immune thrombocytopenia (DIIT) are rare but dangerous complications of pharmacotherapy that may be underrecognized in hematopoietic stem cell transplant (HSCT) patients due to overlap of signs and symptoms with those of more common disease processes.\n\n\n\nA 61-year-old woman with NK-cell deficiency and GATA-2-associated myelodysplastic syndrome, status post-recent allogeneic HSCT (Day +58), presented with 3 days of acute-onset severe back pain, muscle cramps, and increasingly dark urine. She was found to be anemic, thrombocytopenic, and in acute renal failure. On admission, the direct antiglobulin test was positive for complement (C3) only. After careful review of her medication list, the possibility of DIIHA was raised. She had started taking trimethoprim-sulfamethoxazole (TMP-SMX) for Pneumocystis jiroveci pneumonia prophylaxis 24 days prior on a weekend dose schedule. Serologic tests on peripheral blood samples were performed using standard methods. Drug studies were performed at an immunohematology reference laboratory.\n\n\n\nThe patient's serum showed hemolysis of donor red blood cells in the presence of TMP-SMX and also TMP-SMX-induced platelet antibodies. The patient was treated with transfusions, hemodialysis, and immunosuppressive agents. Her clinical condition improved and she was discharged after 8 days in stable condition.\n\n\n\nThis case describes the first reported concurrent DIIHA and DIIT due to TMP-SMX-induced antibodies in an HSCT patient. DIIHA and DIIT can present a diagnostic challenge in the setting of intermittent medication dosing.",
"affiliations": "Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.;Department of Internal Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.;Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.;Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.;Diagnostic Laboratories and Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, Wisconsin.;Diagnostic Laboratories and Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, Wisconsin.;Department of Medicine, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire.;Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.",
"authors": "Linnik|Yevgeniy A|YA|0000-0003-2413-433X;Tsui|Edison W|EW|;Martin|Isabella W|IW|;Szczepiorkowski|Zbigniew M|ZM|;Denomme|Gregory A|GA|0000-0001-8727-1679;Gottschall|Jerome L|JL|;Hill|John M|JM|;Dunbar|Nancy M|NM|",
"chemical_list": "D007166:Immunosuppressive Agents; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
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"issue": "57(12)",
"journal": "Transfusion",
"keywords": null,
"medline_ta": "Transfusion",
"mesh_terms": "D000743:Anemia, Hemolytic; D001803:Blood Transfusion; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008875:Middle Aged; D006435:Renal Dialysis; D013921:Thrombocytopenia; D065227:Transfusion Reaction; D016896:Treatment Outcome; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"nlm_unique_id": "0417360",
"other_id": null,
"pages": "2937-2941",
"pmc": null,
"pmid": "28905389",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The first reported case of concurrent trimethoprim-sulfamethoxazole-induced immune hemolytic anemia and thrombocytopenia.",
"title_normalized": "the first reported case of concurrent trimethoprim sulfamethoxazole induced immune hemolytic anemia and thrombocytopenia"
} | [
{
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{
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"activesubstance": {
"activesubstancename": "TACROLIMUS"
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{
"abstract": "BACKGROUND\nPatients with systemic lupus erythematosus (SLE) have accelerated atherosclerosis that can be assessed by the carotid intima media thickness (CIMT) measurement. A prompt hypolipidemic treatment should be a part of the integral management. The aim of this study is to determine the effect of therapy with pravastatin plus ezetimibe on the CIMT in SLE patients.\n\n\nMETHODS\nLongitudinal, prospective, quasi-experimental trial. Out of 60 SLE patients in whom a carotid ultrasound was performed, we chose 22 with a CIMT>0.7 mm who were administered pravastatin plus ezetimibe during 6 months with determination of CIMT at the end of the study. We performed the following tests: total cholesterol (TC), HDL-cholesterol, LDL-cholesterol, tryglicerides, C-reactive protein (CRP), liver function, muscle enzimes and glucose, basal and at the end of treatment.\n\n\nMETHODS\ndescriptive statistics and Wilcoxon test were used.\n\n\nRESULTS\nThere were 22 women with an age of 42±6.3 years, average disease evolution 7.5±6.6 years, of whom, 18 concluded the study. Right basal CIMT was 0.829±0.1448 vs. final 0.688±0.1453, p<0.003; left CIMT was 0.820±0.1312 vs. 0.724±0.1348, p<0.004. TC 208 mg/dl vs 168 mg/dl, LDL-C 125 mg/dl vs. 72 mg/dl, p=0.0004. CRP 3.12 vs. 2.25 p=0.004. In 2 cases there were gastrointestinal, skin and muscle adverse effects.\n\n\nCONCLUSIONS\nTreatment with pravastatin plus ezetimibe decreases the CIMT with improvement in the concentration of total cholesterol, LDL-C and CRP levels with good toleration.",
"affiliations": "Departamento de Medicina Interna, Hospital de Especialidades, Centro Médico Nacional La Raza, Instituto Mexicano del Seguro Social, Distrito Federal. olgavera62@yahoo.com.mx.",
"authors": "Vera-Lastra|Olga Lidia|OL|;Olvera-Acevedo|Arturo|A|;Hernández|Claudia|C|;Medina|Gabriela|G|;Carrillo-González|Ana Laura|AL|;Ángeles-Garay|Ulises|U|;Peralta-Amaro|Ana Lilia|AL|;Jara|Luis|L|",
"chemical_list": "D000924:Anticholesteremic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000069438:Ezetimibe; D017035:Pravastatin",
"country": "Mexico",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0443-5117",
"issue": "53 Suppl 1()",
"journal": "Revista medica del Instituto Mexicano del Seguro Social",
"keywords": "Atherosclerosis; Ezetimibe; Intima media thickness; Pravastatin; Systemic lupus erythematosus",
"medline_ta": "Rev Med Inst Mex Seguro Soc",
"mesh_terms": "D000328:Adult; D000924:Anticholesteremic Agents; D050197:Atherosclerosis; D059168:Carotid Intima-Media Thickness; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D000069438:Ezetimibe; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008137:Longitudinal Studies; D008180:Lupus Erythematosus, Systemic; D008875:Middle Aged; D017035:Pravastatin; D011446:Prospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "101243727",
"other_id": null,
"pages": "S74-9",
"pmc": null,
"pmid": "26020669",
"pubdate": "2015",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Effect of pravastatine plus ezetimibe on carotid intima media thickness in patients with lupus erythematosus.",
"title_normalized": "effect of pravastatine plus ezetimibe on carotid intima media thickness in patients with lupus erythematosus"
} | [
{
"companynumb": "MX-LUPIN PHARMACEUTICALS INC.-2016-00537",
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "EZETIMIBE"
},
"drugadditional... |
{
"abstract": "Transfemoral catheterization continues to be a safe and popular approach for the evaluation of cardiac and limb ischemia. In spite of the use of vascular closing devices, complications can still arise, and rarely, scrotal hematoma with groin swelling in males, which could cause significant morbidity and possibly mortality in those patients at risk. Understanding the different presentations and different ways of management of scrotal hematoma could potentially prevent significant urological complications and exsanguination. This is a case report of a patient who suffered this rare complication that can be used as a comparison with the other few reported cases.",
"affiliations": "General Surgery, Brandon Regional Hospital, Brandon FL, USA.;General Surgery, Brandon Regional Hospital, Brandon FL, USA.;General Surgery, Brandon Regional Hospital, Brandon FL, USA.;General Surgery, Brandon Regional Hospital, Brandon FL, USA.",
"authors": "Hung Fong|Suy Sen|SS|0000-0002-8285-9980;Jaafar|Sahned|S|;Misra|Subhasis|S|;Narasimha|Vijay|V|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/jscr/rjy310",
"fulltext": "\n==== Front\nJ Surg Case RepJ Surg Case RepjscrJournal of Surgical Case Reports2042-8812Oxford University Press 10.1093/jscr/rjy310rjy310Case ReportScrotal hematoma with pseudo-aneurysm after transfemoral catheterization http://orcid.org/0000-0002-8285-9980Hung Fong Suy sen Jaafar Sahned Misra Subhasis Narasimha Vijay General Surgery, Brandon Regional Hospital, Brandon FL, USACorrespondence address. General Surgery, Brandon Regional Hospital, Brandon FL 33511, USA. Tel: +(813) 541-3057; E-mail: suysen.hungfong@hcahealthcare.com2 2019 13 2 2019 13 2 2019 2019 2 rjy31007 10 2018 26 10 2018 Published by Oxford University Press and JSCR Publishing Ltd. All rights reserved. © The Author(s) 2019.2019This 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\nTransfemoral catheterization continues to be a safe and popular approach for the evaluation of cardiac and limb ischemia. In spite of the use of vascular closing devices, complications can still arise, and rarely, scrotal hematoma with groin swelling in males, which could cause significant morbidity and possibly mortality in those patients at risk. Understanding the different presentations and different ways of management of scrotal hematoma could potentially prevent significant urological complications and exsanguination. This is a case report of a patient who suffered this rare complication that can be used as a comparison with the other few reported cases.\n==== Body\nINTRODUCTION\nTransfemoral catheterization is a relative safe, minimally invasive procedure to assess coronary arteries and limb ischemia and subsequently revascularization with the placement of a stent or balloon angioplasty. However, complications can still manifest as bleeding, infection, hematoma, pseudo-aneurysm, arteriovenous (AV) fistula formation and femoral artery thrombosis [1]. In spite of appropriate use of vascular closing devices (VCD) and its lower rate of vascular complications as compared to manual compression [2, 3], there have also been reported rare cases of scrotal hematoma following post-transfemoral catheterization for coronary intervention [4–7]. We report a similar case of scrotal and right groin hematoma post-transfemoral vascular access, but for evaluation of limb ischemia.\n\nCASE PRESENTATION\nA 72-year-old male with history of penile implant, hypertension, hyperlipidemia, severe peripheral vascular disease with extensive smoking history presented in clinic for severe bilateral lower extremities claudication. Doppler exam showed weak monophasic flow bilaterally. Patient also had a history of left popliteal stent placement and has been taking aspirin and Plavix since then. CT angiography of the lower extremities showed critical stenosis of superficial femoral artery of both lower extremities and a patent stent on the left popliteal artery. Decision was made to perform bilateral lower extremities angiograms via a transfemoral approach with possible revascularization of the right lower extremity (LE) first and then the left side on two different procedures one week apart. Both procedures were accessed through a transfemoral approach that involved balloon angioplasty of the left (L) and right (R) superficial femoral artery (SFA) and left proximal popliteal artery. No immediate post procedure complications were noted, VCDs were deployed and hemostasis was achieved on both occasions. Patient was discharged same day and aspirin and Plavix were resumed.\n\nOn the following day after the right transfemoral access approach, patient presents to ED with R groin and scrotal pain. On evaluation, severe tenderness on the R groin and scrotum was noted associated with worsening swelling and ecchymosis (Fig. 1). Vitals were within normal limits and initial hemoglobin of 12 g/dl. Ultrasound of the right groin showed a 6.3 × 4.0 × 4.9 cm hematoma (Fig. 2), his duplex ultrasound of bilateral testicle showed diminished blood flow on the right compared to the left (Fig. 3). CT of the pelvis revealed a pseudo-aneurysm on the R groin originating from the common femoral artery (CFA) measuring 2.5 × 1.4 cm and extending into the R inguinal canal, filled with hemorrhage and extension into the R scrotum that measures 13.7 × 6.4 × 6.6 cm (Fig. 4). During his clinical course, he has been hemodynamically stable in spite of drops in daily hemoglobin from 12, 8.9, 6.9, 5.9 g/dl, respectively, requiring two units of blood transfusions on hospital Day 3, and achieving a rise in hemoglobin to 8.6 g/dl. Patient then underwent an ultrasound-guided thrombin injection of the pseudo-aneurysm by the interventional radiologist without any complications and without any evidence of recurrence on ultrasound on the following day. Urology was consulted and offered no urologic interventions as his symptoms were improving. The scrotal and groin hematoma subsequently decreased in size. Patient was discharged on hospital Day 6 with aspirin and Plavix. Patient was followed up in clinic with no complains. On exam, there was a decreasing scrotal and R groin swelling/ecchymosis and improvement of penile swelling.\n\nFigure 1: Initial ED appearance of scrotal hematoma and right groin swelling.\n\nFigure 2: Ultrasound of the right groin showing 6.3 × 4.0 × 4.9 cm hematoma.\n\nFigure 3: Right testicle is heterogeneous in texture and demonstrates relatively attenuated vascular flow compared to the left.\n\nFigure 4: Pseudo-aneurysm from right CFA that extends obliquely measuring up to 2.5 × 1.4 cm. The pseudo-aneurysm appears to extend into the right inguinal canal, filled with hemorrhage extending into the inferior aspect of the right scrotum as well.\n\nDISCUSSION\nTransfemoral approach continues to be the standard technique for vascular access due to its optimal catheter control and immediate access to large diameter devices as compared to trans-radial approach in coronary interventions [8]. In spite the use of VCD, which reduces the vascular complication rate as compared to manual compression and providing earlier ambulation post catheterization [2, 3], associated complications can still arise following vascular access including bleeding, hematoma, infection, pseudo-aneurysm, AV malformation [1]; however, due to the increase popularity of the transfemoral approach involving the groin, it is anticipated to have an increase in urologic complication involving groin hematoma and scrotal edema [4]. Bleeding above the inguinal ligament such as retroperitoneal hemorrhage and bleeding from the inferior epigastric vessel through the pre-peritoneal space both have the potential to dissect down into the spermatic cord and into the inguinal canal, causing groin and scrotal hematoma [4, 9].\n\nFew other case reports have been published with similar complications and symptoms of groin and scrotal pain along with drastic drop of hemoglobin [4–7]. On these four case reports, the clinical presentations and managements associated with scrotal hematoma had some similarities and differences (Table 1). The most common manifestation was inguino-scrotal swelling and pain associated with ecchymosis. All fours cases reported were from patients who underwent cardiac catheterization and only two cases reported used of anticoagulants due to a history of drug eluting stent placement [5, 7]. Despite that majority of the reported cases used VCD, groin and scrotal hematoma was inevitable, most commonly from a CFA injury with some cases presenting with sign and symptoms of hemorrhagic shock with a drop of hemoglobin of approximately 2 g/dl. Scrotal hematoma can lead to signs and symptoms of hemorrhagic shock [4, 5, 7], whereas some may be hemodynamically stable regardless of the significant low level of hemoglobin [6]. Interestingly, one of the reported cases with hemorrhagic shock was successfully managed conservatively with blood transfusions [5].\nTable 1 Differences and similarities across reported cases\n\nCase reports\tPolavarapu et al.\tKumar et al.\tThomas et al.\tAskari et al.\t\nPresentation with hemorrhagic shock\tNot present\tPresent\tPresent\tPresent\t\nAnticoagulation\tN/A\tTigagrelor and aspirin\tN/A\tPlavix and aspirin\t\nUse of vascular closing device\tUsed\tUsed\tNot used\tUsed\t\nMechanical compression\tNot used\tNot used\tD-stat hemostatic bandage with manual compression\tNot used\t\nInjured vessel\tRight common femoral artery (CFA)\tR CFA\tRight inferior epigastric artery\tR CFA\t\nDrop in hemoglobin (g/dl) or hematocrit (%)\t5.7 g/dl\t11.3 g/dl and 33.4%\t21%\t7.5 g/dl and 23.3%\t\nInterventions or conservative management\tGroin exploration and repair of CFA\tConservative management\tGroin exploration with vessel ligation\tRight femoral angiography with left femoral approach\t\n\n\nThe level of hemodynamic instability will depend on the degree and acuity of the hemoglobin drop and whether there is evidence of any active bleeding. The differences in clinical and surgical management would depend on the surgeon’s judgment based on the patient’s clinical presentation; their response to blood transfusions and whether any further drop in hemoglobin is seen. Given that scrotal hematoma is a urological complication, an urology consult is warranted for the possibility of scrotal exploration and salvage of testicles from ischemia [4]. In summary, there has not been any mortality cases associated with this rare complication after a transfemoral vascular access, but predicting those who may be at risk would definitely help prevent significant morbidity and mortality in these patients.\n\nCONFLICT OF INTEREST STATEMENT\nNone declared.\n==== Refs\nREFERENCES\n1 \nNikolsky E , Mehran R , Halkin A , Aymong ED , Mintz GS , Lasic Z , et al \nVascular complications associated with arteriotomy closure devices in patients undergoing percutaneous coronary procedures . J Am Coll Cardiol 2004 ;44 :1200 –9 .15364320 \n2 \nBontrager M , Abraham S , Ando G \nComparison of complications after transfemoral coronary angiography between mechanical and manual closure techniques . Cogent Med 2017 ;4 :1 .\n3 \nSchulz-Schüpke S , Helde S , Gewalt S , Ibrahim T , Linhardt M , Hass K , et al \nComparison of vascular closure devices vs manual compression after femoral artery puncture: the ISAR-CLOSURE randomized clinical trial . JAMA 2014 ;312 :1981 –7 .25399273 \n4 \nThomas AA , Hedgepeth R , Sarac PT , Vasavada PS \nMassive scrotal hematoma following transfemoral cardiac catheterization . Can J Urol 2008 ;15 :4020 –3 .18405454 \n5 \nKumar V , Soni P , Chadha S , Malik B \nPenoscrotal haematoma after cardiac catheterization . BMJ Case Rep 2017 \n10.1136/bcr-2016-218934 . \n6 \nPolavarapu HV , Reyes JM , Anoia EJ , Jubelirer RA \nMassive penoscrotal hematoma and testicular ischemia from failed vascular closing device . Eur J Vasc Endovasc Surg 2011 ;41 :864 .\n7 \nAskari R , Khouzam RN , Dishmon DA \nImage diagnosis: rapidly enlarging scrotal hematoma: a complication of femoral access? Perm J 2017 ;21 :16 –111 .\n8 \nAgostoni P , Biondi-Zoccai GGL , De Benedictis ML , Rigattieri S , Turri M , Anselmi M , et al \nRadial versus femoral approach for percutaneous coronary diagnostic and interventional procedures . J Am Coll Cardiol 2004 ;44 :349 –56 .15261930 \n9 \nKawamura A , Piemonte TC , Nesto RW , Gossman DE \nRetroperitoneal hemorrhage from inferior epigastric artery: value of femoral angiography for detection and management . Catheter Cardiovasc Interv 2006 ;68 :267 –70 .16819773\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2042-8812",
"issue": "2019(2)",
"journal": "Journal of surgical case reports",
"keywords": null,
"medline_ta": "J Surg Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101560169",
"other_id": null,
"pages": "rjy310",
"pmc": null,
"pmid": "30792838",
"pubdate": "2019-02",
"publication_types": "D002363:Case Reports",
"references": "15261930;15364320;16819773;18405454;25399273;28476905;28609265",
"title": "Scrotal hematoma with pseudo-aneurysm after transfemoral catheterization.",
"title_normalized": "scrotal hematoma with pseudo aneurysm after transfemoral catheterization"
} | [
{
"companynumb": "US-BAYER-2020-214628",
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"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
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{
"abstract": "We report a case of Epstein-Barr virus (EBV)-driven haemophagocytic lymphohistiocytosis (HLH) in a man with Crohn's disease treated with 6-mercaptopurine and adalimumab therapy who was successfully treated with rituximab therapy alone. This is the first published case in an adult patient with EBV-driven HLH in the setting of thiopurine use and inflammatory bowel disease to be successfully treated with rituximab therapy alone. Here, we will discuss putative immunological mechanisms which may contribute to this potentially life-threatening complication.",
"affiliations": "Department of Immunology, Fiona Stanley Hospital, Murdoch, Western Australia, Australia.;Department of Haematology, Fiona Stanley Hospital, Murdoch, Western Australia, Australia.;Harry Perkins Institute of Medical Research Perkins South, Perth, Bahrain.;Department of Immunology, Fiona Stanley Hospital, Murdoch, Western Australia, Australia.",
"authors": "Thompson|Grace|G|;Pepperell|Dominic|D|;Lawrence|Ian|I|;McGettigan|Benjamin David|BD|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D000069283:Rituximab; D015122:Mercaptopurine; D000068879:Adalimumab",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2016-218578",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000068879:Adalimumab; D000893:Anti-Inflammatory Agents; D003424:Crohn Disease; D020031:Epstein-Barr Virus Infections; D006801:Humans; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D051359:Lymphohistiocytosis, Hemophagocytic; D008297:Male; D015122:Mercaptopurine; D000069283:Rituximab; D055815:Young Adult",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28228435",
"pubdate": "2017-02-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11385576;15342983;15958083;16374252;16926601;16937360;18045564;18506437;19177429;19667203;21119115;21710533;21722918;22640698;23565820;24509696;24520429;25737788;26461149;26461151;26557937;26728022;38175",
"title": "Crohn's disease complicated by Epstein-Barr virus-driven haemophagocytic lymphohistiocytosis successfully treated with rituximab.",
"title_normalized": "crohn s disease complicated by epstein barr virus driven haemophagocytic lymphohistiocytosis successfully treated with rituximab"
} | [
{
"companynumb": "AU-MYLANLABS-2017M1027015",
"fulfillexpeditecriteria": "1",
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"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MESALAMINE"
},
"drugadditional": null,
... |
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