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"abstract": "Physicians must acknowledge the potential risk of RSH with enoxaparin. Switching home anticoagulation by enoxaparin upon hospital admission is common, but it may put patients at higher risk for RSH. Management guidelines are needed in this setting.",
"affiliations": "UFC - Coimbra Regional Pharmacovigilance Unit CHAD - Centre for Health Technology Assessment and Drug Research AIBILI - Association for Innovation and Biomedical Research on Light and Image Coimbra Portugal.;UFC - Coimbra Regional Pharmacovigilance Unit CHAD - Centre for Health Technology Assessment and Drug Research AIBILI - Association for Innovation and Biomedical Research on Light and Image Coimbra Portugal.;DruSER.Net - Drug Safety and Effectiveness Research Network Coimbra Portugal.;DruSER.Net - Drug Safety and Effectiveness Research Network Coimbra Portugal.;UFC - Coimbra Regional Pharmacovigilance Unit CHAD - Centre for Health Technology Assessment and Drug Research AIBILI - Association for Innovation and Biomedical Research on Light and Image Coimbra Portugal.;UFC - Coimbra Regional Pharmacovigilance Unit CHAD - Centre for Health Technology Assessment and Drug Research AIBILI - Association for Innovation and Biomedical Research on Light and Image Coimbra Portugal.",
"authors": "Mendes|Diogo|D|https://orcid.org/0000-0003-4923-8717;Penedones|Ana|A|https://orcid.org/0000-0002-2061-4718;Martins|Michele|M|;Cavadas|Susana|S|;Alves|Carlos|C|https://orcid.org/0000-0003-2814-3049;Batel-Marques|Francisco|F|https://orcid.org/0000-0003-4031-7339",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.3427",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904 John Wiley and Sons Inc. Hoboken \n\n10.1002/ccr3.3427\nCCR33427\nCase Report\nCase Reports\nRectus sheath hematoma in patients receiving subcutaneous enoxaparin: A case series of five patients\nMENDES et al.Mendes Diogo https://orcid.org/0000-0003-4923-8717\n1\n\n2\ndiogomendes26@gmail.com Penedones Ana https://orcid.org/0000-0002-2061-4718\n1\n\n2\n Martins Michele \n2\n\n3\n Cavadas Susana \n2\n\n3\n Alves Carlos https://orcid.org/0000-0003-2814-3049\n1\n\n2\n\n4\n Batel‐Marques Francisco https://orcid.org/0000-0003-4031-7339\n1\n\n2\n\n4\n \n1 \nUFC – Coimbra Regional Pharmacovigilance Unit\nCHAD – Centre for Health Technology Assessment and Drug Research\nAIBILI – Association for Innovation and Biomedical Research on Light and Image\nCoimbra\nPortugal\n\n\n2 \nDruSER.Net – Drug Safety and Effectiveness Research Network\nCoimbra\nPortugal\n\n\n3 \nCHBV – Centro Hospitalar do Baixo Vouga\nAveiro\nPortugal\n\n\n4 \nLaboratory of Social Pharmacy and Public Health\nSchool of Pharmacy\nUniversity of Coimbra\nCoimbra\nPortugal\n\n* Correspondence\n\nDiogo Mendes, AIBILI – Association for Innovation and Biomedical Research on Light and Image, Azinhaga de Santa Comba, Celas, 3000‐548 Coimbra, Portugal.\n\nEmail: diogomendes26@gmail.com\n\n27 10 2020 \n12 2020 \n8 12 10.1002/ccr3.v8.123432 3439\n03 7 2020 23 9 2020 03 10 2020 © 2020 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.Abstract\nPhysicians must acknowledge the potential risk of RSH with enoxaparin. Switching home anticoagulation by enoxaparin upon hospital admission is common, but it may put patients at higher risk for RSH. Management guidelines are needed in this setting.\n\nPhysicians must acknowledge the potential risk of RSH with enoxaparin. Switching home anticoagulation by enoxaparin upon hospital admission is common, but it may put patients at higher risk for RSH. Management guidelines are needed in this setting.\n\n\ndrug‐related side effects and adverse reactionsenoxaparinhematomaheparinlow‐molecular‐weightpharmacovigilancerectus abdominis source-schema-version-number2.0cover-dateDecember 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.6 mode:remove_FC converted:21.12.2020\n\n\nMendes \nD \n, \nPenedones \nA \n, \nMartins \nM \n, \nCavadas \nS \n, \nAlves \nC \n, \nBatel‐Marques \nF \n. Rectus sheath hematoma in patients receiving subcutaneous enoxaparin: A case series of five patients\n. Clin Case Rep . 2020 ;8 :3432 –3439\n. 10.1002/ccr3.3427\n==== Body\n1 INTRODUCTION\nRectus sheath hematoma (RSH) is a potentially life‐threatenting bleeding complication which may result from several causes, including anticoagulation therapy. This paper reports five cases of RSH (one fatal) probably induced by subcutaneous enoxaparin that were confirmed by abdominal ultrasounds and/or computerized tomographic (CT) scans in a single hospital within 4 months.\n\nRectus sheath hematoma (RSH) may be caused by the rupture of epigastric arteries or the rectus muscle itself within the rectus sheath.\n1\n It is a relatively rare clinical condition which accounts for less than 2% of patients with acute abdominal pain.\n2\n Risk factors for RSH include anticoagulation therapy (ACT), stage ≥3 chronic kidney disease (CKD), abdominal wall injections, steroid or immunosuppressant therapy, abdominal trauma or surgery, cough, femoral puncture, and antiplatelet therapy (APT).\n3\n Ultrasonography of the abdominal wall is a useful test to identify RSH. However, computerized tomographic (CT) scan should be carried out instead, since it is more sensitive and specific, being the standard diagnostic procedure.\n2\n, \n4\n, \n5\n The diagnosis should be established as earlier as possible because, although its course is usually benign, RSH can also lead to serious adverse clinical outcomes, including death.\n3\n, \n6\n, \n7\n, \n8\n, \n9\n The mortality rate associated with RSH was estimated around 2%‐4% overall,\n6\n, \n10\n though it may be as high as 25% among patients receiving ACT.\n10\n\n\n\nDuring the last years, low‐molecular‐weight heparin (LMWH) has been routinely administered to hospitalized patients as prophylaxis of deep vein thrombosis (DVT).\n11\n Furthermore, therapeutic dosing is a common practice to manage prevalent diagnoses, such as pulmonary embolism (PE), acute DVT, acute coronary syndrome (ACS), and atrial fibrillation (AF).\n9\n Enoxaparin is a LMWH that enhances the activity of anti‐thrombin III (ATIII), which increases the inhibition of factor Xa (and other coagulation factors) and consequently downregulates coagulation.\n12\n LMWH therapy can be associated with hemorrhagic adverse events, such as gastrointestinal bleeding.\n13\n Although rare, cases of RSH have also been observed in patients treated with LMWH.\n3\n, \n6\n, \n7\n, \n14\n, \n15\n\n\n\nThis article presents five cases of RSH probably associated with subcutaneous injections of enoxaparin that were diagnosed in a single hospital within a 4‐month period of time.\n\n2 METHODS\nWe retrospectively analyzed the characteristics of patients receiving subcutaneous injections of enoxaparin who were diagnosed with RSH at “Centro Hospitalar do Baixo Vouga” (Aveiro, Portugal) from November 2017 to February 2018. Medical records were reviewed to identify demographic characteristics (age, gender), clinical history, and cause of hospitalization, as well as home and hospital ACT (dose schedules and therapeutic indications), concomitant medication, symptoms, laboratory tests, and imaging procedures supporting the diagnosis, and treatment, duration, and outcome of RSH. Only RSH diagnoses confirmed by abdominal ultrasound and/or CT scan were considered. The cases were reported to the Regional Unit of Coimbra of the Portuguese Pharmacovigilance System (PPS). The Guidelines for Submitting Adverse Event Reports for Publication were followed to report study results.\n16\n\n\n\n3 RESULTS\n3.1 Case series\nThe five cases are described below. A summary of the main characteristics of each case is presented in Table 1. Three patients were female. The age of patients ranged between 67‐85 years old. Before hospitalization, three patients were on ACT at home (warfarin, n = 2; dabigatran etexilate, n = 1) because of underlying AF. The reasons for hospitalization included respiratory infection (n = 3), DVT (n = 1), and respiratory failure (n = 1). The time interval between initiation of subcutaneous enoxaparin and RSH onset ranged between 2 and 12 days. Two cases of RSH were confirmed with abdominal ultrasound, two with CT scan and one with both imaging procedures. One patient died because of RSH. One patient recovered from the RSH but died later because of hospital‐acquired pneumonia. Three patients recovered in full.\n\nTable 1 Characteristics of the cases of rectus sheath hematoma (RSH) induced by subcutaneous enoxaparin\n\n#\tPatient\tDrugs\tAdverse event\t\nDemography\tMedical history\tHospitalization reason\tSuspect\tConcomitant\tOnset time\na\n\n\tDescription\tTreatment\nb\n\n\tDuration\tOutcome\t\nDose schedule\tIndication\t\t\n1\t85‐y‐old, female (PT‐INFARMED‐B201805‐241)\tAF, CHF, T2DM, arterial hypertension, obesity, hypothyroidism, and CVI\tRespiratory failure\tEnoxaparin, 80 mg, qd, SC, for 8 d, 80 mg, bid, SC, for 6 d, 80 mg, qd, SC, afterward\tReplace/home ACT (oral warfarin) for AF\tMTP (IV)\t12 d\tRenal injury with anuria and hypotension; RSH and hematoma on the right thigh; abdominal CT scan: hemorrhage; hemorrhagic shock\tBlood transfusion, surgery/embolization of bleeding arteries\tFew days (not specified)\tDeath\t\n2\t80‐y‐old, female (PT‐INFARMED‐B201805‐262)\tIdiopathic bronchiectasis\tInfected bronchiectasis\tEnoxaparin, 40 mg, qd, SC, for 5 d\tHospital ACT: VTE prophylaxis\tO2, PRDL (IV), NAC, IB, CAZ, CIP\t5 d\tAbdominal pain and Hb drop; abdominal ultrasound: RSH\tAnalgesics and local ice\t1 d\tRecovered\t\n3\t81‐y‐old, male; (PT‐INFARMED‐B201805‐940)\tAF, CHF, CKD (eGFR < 15 mL/min), respiratory insufficiency, thrombocytopenia\tInfluenza B virus‐associated bronchopneumonia\tEnoxaparin, 60 mg, qd, SC, for 5 d, 20 mg, qd, for 1 d\tReplace/home ACT (oral warfarin) for AF\tMTP (IV), CXM, OTV\t2 d\tAbdominal pain with tumefaction; abdominal ultrasounds and later CT scan: RSH\tBlood and plasma transfusion\t9 d\tRecovered\t\n4\t67‐y‐old, male (PT‐INFARMED‐B201806‐781)\tAF\tPneumonia\tEnoxaparin, 80 mg, bid, SC, for 4 d\tReplace/home ACT (oral dabigatran etexilate, 110 mg, bid) for AF\tO2, AZM, AMC, SXT, IB + SBL\t4 d\tAbdominal pain and nausea; Hb drop; CT scan: RSH; abdominal aortic thrombus; abdominal aortic aneurysm enlargement; hemorrhagic shock\tBlood transfusion; embolization of bleeding arteries\tFew days (not specified)\tRecovered\nc\n\n\t\n5\t72‐y‐old, female (PT‐INFARMED‐B201905‐992)\tUnknown\tDVT\tEnoxaparin, 60 mg, bid, SC, for 8 d\tHospital ACT: DVT\tFluconazole, warfarin\t8 d\tPain in the inguinal region, with further worsening and involvement of iliac fossa, tumefaction; abdominal ultrasound: RSH and peritoneal bleeding\tBlood transfusion; embolization of bleeding arteries\t4 d\tRecovered\t\nAbbreviations: AAS, acetylsalicylic acid; ACE‐i, angiotensin converting enzyme inhibitor; ACT, anticoagulant therapy; AF, atrial fibrillation; AMC, amoxicillin‐clavulanic acid; AZM, azithromycin; bid: twice daily; CAZ, ceftazidime; CHF, Congestive heart failure; CIP, ciprofloxacin; CKD, Chronic kidney disease; CVI, chronic venous insufficiency; CXM, cefuroxime; DVT, deep vein thrombosis; eGFR, estimated glomerular filtration rate; Hb, hemoglobin; IB, ipratropium bromide; IV, intravenous; MTP, methylprednisolone; NAC, N‐acetylcysteine; O2, oxygen; OTV, oseltamivir; PRDL, prednisolone; qd, once daily; RSH, rectus sheath hematoma; SBL, salbutamol; SC, subcutaneous injection; SXT, trimethoprim‐sulfamethoxazole; T2DM, Type 2 diabetes mellitus; VTE, venous thromboembolism.\n\na Onset time: time elapsed between the start of therapy with enoxaparin sodium and the onset of the adverse event.\n\nb Treatment included discontinuation of enoxaparin.\n\nc This patient (case 4) recovered of the RSH but died 13 d later because of hospital‐acquired pneumonia.\n\nJohn Wiley & Sons, Ltd3.1.1 Case 1\nA 85‐year‐old female patient was admitted to hospital due to respiratory failure. Her clinical history included AF, congestive heart failure (CHF), type 2 diabetes mellitus (T2DM), arterial hypertension, obesity, hypothyroidism, and venous insufficiency of the lower limbs. The therapy included the initiation of IV methylprednisolone and the replacement of home ACT (warfarin used to treat AF) by enoxaparin (with dose adjustment for the renal function): 80 mg, SC, qd, during 8 days, followed by a dose increase to 80 mg, bid, for 6 days, and a further dose reduction to 80 mg, SC, qd, until the day of discharge to another hospital. Twelve days after initiation of therapy with enoxaparin, a phlebotomy was performed to extract 200 cc of blood due to high hemoglobin (Hb) count (19.8 g/dL), and the subsequent arterial blood gas (ABG) analysis showed Hb = 16.3 g/dL. On the following day, the patient presented Hb = 12.5 g/dL, hypotension, acute renal failure, and hyperlactacidaemia; she also had large hematomas on both the abdominal wall and the right thigh. An abdominal CT scan showed an active hemorrhage, and RSH was diagnosed (Figure 1). Hypotension was nonresponsive to fluid resuscitation (systolic blood pressure: 60 mm Hg). The patient progressed to hemorrhagic shock. Blood transfusions were performed, and she was further transferred to the department of surgery of another hospital for embolization of bleeding arteries. The patient died a few days later (PT‐INFARMED‐B201805‐241).\n\nFIGURE 1 Case 1: CT scan of the abdomen and pelvis revealing a rectus sheath hematoma. Two relatively communicating high‐density expansive formations, the largest, anterior to the bladder, and the other, slightly lower and lateralized to the right, extending to the meso rectum, compatible with two collected hematomas\n\n3.1.2 Case 2\nA 80‐year‐old female patient was admitted to hospital due to infected bronchiectasis. Treatment with oxygen (O2), acetylcysteine, ipratropium bromide, antibiotics, and corticosteroids (oral prednisolone, 20 mg, qd) was initiated. Enoxaparin, 40 mg, SC, qd, was prescribed to prevent venous thromboembolism (VTE). Five days later, the patient presented abdominal pain and a large palpable mass in the right hypochondrium and flank. There was no hemodynamic rebound, but there was a drop of 1 g/L in the levels of Hb. An abdominal ultrasound showed a right‐sided RSH (Figure 2)—diffuse wall thickening from the upper to the lower insertion of the rectus abdominis muscle, with several internal liquid loci, within which solid material was observed, and with “fresh” and organized areas. The approach was based on conservative measures that included discontinuation of enoxaparin, analgesics, and ice packs. The patient recovered within 1 day (PT‐INFARMED‐B201805‐262).\n\nFIGURE 2 Case 2: Ultrasound of the abdomen revealing a right‐sided rectus sheath hematoma. Diffuse wall thickening from the upper to the lower insertion of the rectus abdominis muscle, with several internal liquid loci, within which solid material is observed, outlining the solid/liquid level, which is compatible with a hematoma (probably spontaneous) in the ultrasound image\n\n3.1.3 Case 3\nA 81‐year‐old male patient was admitted to hospital due to Influenza B virus‐associated bronchopneumonia. The clinical history of the patient included CHF (biological prosthesis for aortic valve), CKD (estimated glomerular filtration rate (eGFR) <15 mL/min), type I respiratory failure, AF, and thrombocytopenia. Treatment with cefuroxime, oseltamivir, and IV methylprednisolone was initiated. Enoxaparin, 60 mg, SC, qd, for 5 days and 20 mg, SC, qd, for 1 day, was given to replace home ACT (oral warfarin) to prevent thromboembolism in AF. Two days later, the patient presented a fixed, nonreducible abdominal wall swelling, without hemodynamic rebound. The ultrasound showed a left‐sided RSH (95 × 48 × 92 mm) (Figure 3). A conservative clinical approach was adopted, including discontinuation of enoxaparin, blood and plasma transfusion and vigilance. A CT scan showed that the hematoma was sustained by the aponeurosis in the lower extremity of the left rectus abdominis. The rate of decrease in the level of Hb was slow, and therefore, conservative treatment was maintained. The patient recovered and was discharged 9 days later (PT‐INFARMED‐B201805‐940).\n\nFIGURE 3 Case 3: CT scan of the abdomen and pelvis revealing a left rectus sheath hematoma. Heterogeneous thickening of the left large rectus abdominis muscle, with dense areas, revealing a hematoma with still relatively recent hemorrhage\n\n3.1.4 Case 4\nA 67‐year‐old male patient was admitted to hospital due to pneumonia. Treatment with O2, antibiotics, and salbutamol + ipratropium bromide was initiated. Enoxaparin, 80 mg, SC, bid, was given to replace home ACT (oral dabigatran etexilate, 110 mg, bid) due to AF. Four days later, the patient presented abdominal pain in the right hypochondrium, nausea without vomiting, and a large palpable mass in the right quadrants. There was a drop in the levels of Hb of 4 g/L. A CT scan showed a large hematoma (19 × 15 × 8 cm) with small foci of active bleeding in the upper portion, aneurysmal dilatation of the abdominal aorta with a maximum caliber of 58 mm over a length of 77 mm, and a parietal thrombus (maximum 25 mm) (Figure 4). Despite treatment, the patient progressed to hemorrhagic shock. Embolization of bleeding arteries and transfusion of 2 units of packed red blood cells were performed, two suction drains were placed in the hematoma cavities, and the patient was transferred to the intensive care unit (ICU). The patient initially recovered, but later developed hospital‐acquired pneumonia associated with invasive intubation/ ventilation and died 13 days later (PT‐INFARMED‐B201806‐781).\n\nFIGURE 4 Case 4: CT scan of the abdomen and pelvis revealing a right rectus sheath hematoma. Massive nodular formation (heterogeneous), with solid and liquid areas, compatible with large hematoma depending on the anterior abdominal wall and right side\n\n3.1.5 Case 5\nA 72‐year‐old female patient was admitted to hospital due to DVT. Treatment with enoxaparin, 60 mg, SC, bid, was initiated. The patient was also on oral fluconazole (100 mg, qd) and 5 days later initiated warfarin (2.5 mg, qd). Eight days after having initiated enoxaparin, the patient had pain in the inguinal region, with further worsening, involving the iliac fossa and swelling. She was hemodynamically stable, but there was a decrease of 2 g/L in the levels of Hb and the international normalized ratio (INR) was estimated at 1.7. The abdominal ultrasound showed RSH (194 × 119 × 102 mm), later confirmed by CT scan (Figure 5). After contrast injection, denser intraluminal foci were observed, indicating active bleeding, but it was not possible to identify the bleeding vessel. There was also a marked densification of the peripheral muscle planes, probably due to hematic infiltration and surrounding effusion, and a small intraperitoneal effusion in the pelvic and sub‐hepatic cavity. Blood transfusion was performed. The patient was transferred to another hospital to perform embolization and recovered within 4 days (PT‐INFARMED‐B201905‐992).\n\nFIGURE 5 Case 5: CT scan of the abdomen and pelvis revealing a right rectus sheath hematoma. Large expansive oval formation depending on the abdominal wall of the right hemi‐abdomen, very markedly heterogeneous, with areas of greater and lesser density, compatible with a hematoma. After contrast injection (arterial phase), denser foci are observed, indicating active bleeding\n\n4 DISCUSSION\nThis study reports a series of five cases of RSH probably induced by subcutaneous injections of enoxaparin, of which one was fatal. All RSH diagnoses were confirmed with either abdominal ultrasound or CT scan. Although a rare complication, these cases occurred in a single hospital over only 4 months. This led to changes in clinical practices, systems review, and training of healthcare personnel to prevent further episodes.\n\nStudies have found that the incidence of RSH is higher in the female and elderly population.\n3\n, \n6\n The anatomic differences in rectus muscles between the two genders, as well as weakening of abdominal wall muscles because of stretching during pregnancy, predispose the female gender to a higher risk of RSH.\n3\n, \n6\n, \n17\n Further, there is a progressive weakening of abdominal wall muscles with age.\n18\n\n\n\nSeveral other risk factors for RSH have been identified in other studies. According to the evaluation of 115 patients hospitalized with RSH (confirmed by CT scan) in the United States, 77% of the individuals were on the ACT, 58% had CKD stage ≥3, 51% were receiving abdominal injections, and 42% were on steroids or immunosuppressant therapy; nearly 29% of the patients receiving subcutaneous abdominal injections were under LMWH therapy.\n3\n In our study, we found that three patients (60%) were on steroids therapy. Whether the use of steroids increases the risk of RSH in patients under treatment with enoxaparin should be further investigated, since this association is frequently used in clinical practice and the evidence on this topic is scarce in both clinical literature and product monographs. As an example, the European Summary of Product Characteristics (SmPC) of the originator enoxaparin only mentions that “systemic glucocorticoids” “may be administered with caution concomitantly with enoxaparin sodium”.\n12\n\n\n\nThe use of a LMWH over a direct oral anticoagulants (DOAC) for VTE prophylaxis in acutely ill hospitalized medical patients is recommended in clinical practice guidelines.\n19\n According to the results of a systematic review of three randomized controlled trials (RCTs) of low risk of bias, the use of DOACs increased the risk of major bleeding (Relative Risk [RR] = 1.99; 95% Confidence Interval [CI], 1.08‐3.65) but did not reduce the risk of symptomatic VTE versus the use of LMWHs in patients hospitalized because of acute diseases.\n20\n However, most patients of the present case series (n = 3/5; 60%) were prescribed with enoxaparin upon the hospitalization to replace the ACT (warfarin or DOAC) they were already using to treat AF. Whether switching therapy from home ACT to subcutaneous LMWH is necessary deserves further research, particularly in the case of patients on ACT for other reasons than VTE prophylaxis. In the BRIDGE Trial, 1884 patients with AF were randomly assigned to receive bridging anticoagulation with LMWH or placebo after perioperative interruption of warfarin therapy.\n21\n There was no difference in the incidence of arterial thromboembolism between the group of patients on LMWH bridging and the no‐bridging group (ie, without anticoagulation); however, the risk of major bleeding was higher in patients receiving LMWH bridging than in those with no‐bridging anticoagulation (RR = 2.44; 95% CI, 1.28‐5.0).\n21\n Furthermore, the PAUSE cohort study reported low rates of major bleeding and arterial thromboembolism in 3007 patients with AF who needed to interrupt long‐term treatment with DOACs (without heparin bridging) before elective surgery or procedure.\n22\n Therefore, perioperative bridging with LMWH may cause more harm than benefit in most anticoagulated patients with AF.\n21\n, \n22\n, \n23\n Nevertheless, evidence is still lacking for patients with AF who are hospitalized because of acute illnesses or other reasons than surgical/invasive procedures. Further research needs to be carried out.\n\nPhysicians should be aware of clinical and imaging features of RSH, aiming at early diagnosis and conservative management approaches to prevent complications. Such awareness is important to preclude misdiagnosis and avoid inappropriate invasive procedures, given that symptoms and signs of RSH (ie, abdominal mass or pain, drop in hematocrit or hypotension, nausea, and vomiting) can mimic other conditions (eg, diverticulitis, appendicitis, and acute pancreatitis).\n3\n, \n9\n, \n14\n Other signs and symptoms of RSH include abdominal distension or ecchymosis, peritoneal irritation, scrotal swelling, and tachycardia.\n3\n, \n6\n Physical examination procedures to differentiate intra‐abdominal from abdominal wall pathology were described elsewhere.\n24\n The maneuver described by Carnett entails palpation of the tender abdomen in the supine and half‐sitting positions. While intra‐abdominal processes are most tender in the supine position and protected by the contracted rectus muscle when the patient is sitting, abdominal wall processes remain tender in both positions.\n24\n Ultrasound and CT scan are the two main imaging procedures to diagnose RSH. Ultrasound can provide results in a faster way, but CT is 100% sensitive and specific and allows to understand whether there is active bleeding.\n2\n, \n9\n, \n25\n Most RSH diagnosis (n = 3/5; 60%) were confirmed by CT in our study. The use of these imaging procedures allows to confirm RSH diagnoses in a heterogeneous population of patients with varying demographic and clinical characteristics. According to Berná et al, RSH is classified into three types based on CT results—type I: intramuscular, unilateral hematoma which does not dissect into the fascial plane; type II: intramuscular (though with blood between the muscle and the transversalis fascia), unilateral or (usually) bilateral hematoma, with no blood occupying the prevesical space; and type III: with or without muscle involvement and blood can be seen within the transversalis fascia, peritoneum, and prevesical space.\n26\n While the treatment of type I and type II RSH is usually conservative, type III RSH often requires blood transfusion.\n26\n If type III RSH leads to hemodynamic instability that is uncontrollable with fresh frozen plasma and fluid resuscitation, invasive treatment may be required; there are two options: angiography with embolization of the bleeding vessel; or surgery with hematoma evacuation, ligation of bleeding vessels, and closed‐suction drainage. The success rate of invasive therapy is usually high in such cases.\n8\n, \n27\n Only one out of the five cases reported was successfully managed with conservative approaches. Angiography with embolization of the bleeding vessel was performed for three patients, of which one died.\n\nThis study presents some limitations, mainly due to the lack of information that was not possible to retrieve in some cases. According to the clinicians who reported the cases, the administration of enoxaparin was initiated on therapeutic doses (with adjustment to the renal function of each patient) and at least 24 hours after the last intake of an anticoagulant for those on ACT at home. Since we are not aware of the full clinical condition of each patient, it is not possible to ascertain whether dose schedules were properly adjusted. It is possible that the clinical history and the concomitant medication were provided in more detail for some patients rather than others, as the information was directly collected from the reporting physicians. Therefore, we were not able to assess the influence of these concomitant factors on the risk of RSH. Furthermore, two patients were transferred to departments of surgery of other hospitals, and therefore, it was not possible to describe in detail the treatment provided for such patients.\n\n5 CONCLUSION\nPhysicians must be aware of the potential risk of RSH induced by subcutaneous injections of enoxaparin, which is commonly prescribed to prevent thromboembolic events in hospitalized patients, even when used under therapeutic adjusted doses. Whether the use of systemic corticosteroids increases the risk of RSH in patients under treatment with subcutaneous enoxaparin deserves further investigation. Home anticoagulation therapies are frequently replaced by subcutaneous enoxaparin when patients are hospitalized, but this practice may put patients at higher risk of RSH. Therefore, updated guidelines on the management of home anticoagulation (ie, switching or maintaining therapy) in hospitalized patients are needed.\n\nCONFLICT OF INTEREST\nNone declared.\n\nAUTHOR CONTRIBUTIONS\nDM and FBM: were involved in the conception and design. MM and SC: collected data. DM, AP, and CA: supervised the collection of data and analyzed the data. DM: wrote the first draft of the paper. DM, AP, SC, CA, and FBM: revised it critically for intellectual content. All authors made substantial contributions, approved the final version of the manuscript, and agreed to be accountable for all aspects of the work.\n\nETHICAL APPROVAL\nEthical approval was not required, since data were retrieved from pseudononymized case reports already submitted to the Portuguese Pharmacovigilance System (PPS).\n\nACKNOWLEDGMENT\nThe authors thank the physicians who reported the cases discussed in this paper.\n==== Refs\nREFERENCES\n1 \n\nHatjipetrou \nA \n, \nAnyfantakis \nD \n, \nKastanakis \nM \n. Rectus sheath hematoma: a review of the literature\n. Int J Surg . 2015 ;13 :267 ‐271\n. 10.1016/j.ijsu.2014.12.015 \n25529279 \n2 \n\nKlingler \nPJ \n, \nWetscher \nG \n, \nGlaser \nK \n, \nTschmelitsch \nJ \n, \nSchmid \nT \n, \nHinder \nRA \n. The use of ultrasound to differentiate rectus sheath hematoma from other acute abdominal disorders\n. 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Medicine (Baltimore) . 2006 ;85 (2 ):105 ‐110\n. 10.1097/01.md.0000216818.13067.5a \n16609349 \n7 \n\nKayrak \nM \n, \nBacaksiz \nA \n, \nYazici \nM \n. Is enoxaparin injection from the abdominal wall safe in elderly people?: a fatal case of rectus sheath hematoma\n. Can Fam Physician . 2008 ;54 (9 ):1246 ‐1248\n.18791099 \n8 \n\nRomic \nI \n, \nPavlek \nG \n, \nMance \nM \n, \nRomic \nM \n, \nMoric \nT \n. Fatal case of spontaneous rectus sheath hematoma caused by anticoagulant and steroid therapy during hospital admission\n. Visc Med . 2018 ;34 (3 ):225 ‐227\n. 10.1159/000485941 \n30140689 \n9 \n\nSullivan \nLEJ \n, \nWortham \nDC \n, \nLitton \nKM \n. Rectus sheath hematoma with low molecular weight heparin administration: a case series\n. BMC Res Notes . 2014 ;7 (1 ):586 \n10.1186/1756-0500-7-586 \n25178308 \n10 \n\nOsinbowale \nO \n, \nBartholomew \nJR \n. Rectus sheath hematoma\n. Vasc Med . 2008 ;13 (4 ):275 ‐279\n. 10.1177/1358863X08094767 \n18940904 \n11 \n\nMazzolai \nL \n, \nAboyans \nV \n, \nAgeno \nW \n, et al. Diagnosis and management of acute deep vein thrombosis: a joint consensus document from the European Society of Cardiology working groups of aorta and peripheral vascular diseases and pulmonary circulation and right ventricular function\n. Eur Heart J . 2018 ;39 (47 ):4208 ‐4218\n. 10.1093/eurheartj/ehx003 \n28329262 \n12 \nCHMP \n. Annex III: Referral under Article 30 of Directive 2001/83/EC, Lovenox and Associated Names INN: Enoxaparin (Procedure Number: EMEA/H/A‐30/1429)\n; 2016 \nhttps://www.ema.europa.eu/en/documents/referral/lovenox‐article‐30‐referral‐annex‐iii_en.pdf. Accessed 23 September, 2020.\n13 \n\nBurr \nN \n, \nLummis \nK \n, \nSood \nR \n, \nKane \nJS \n, \nCorp \nA \n, \nSubramanian \nV \n. Risk of gastrointestinal bleeding with direct oral anticoagulants: a systematic review and network meta‐analysis\n. Lancet Gastroenterol Hepatol . 2017 ;2 (2 ):85 ‐93\n. 10.1016/S2468-1253(16)30162-5 \n28403994 \n14 \n\nAnyfantakis \nD \n, \nKastanakis \nM \n, \nPetrakis \nG \n, \nBobolakis \nE \n. Rectus sheath hematoma in a single secondary care institution: a retrospective study\n. Hernia . 2015 ;19 (3 ):509 ‐512\n.26221649 \n15 \n\nDenard \nPJ \n, \nFetter \nJC \n, \nZacharski \nLR \n. Rectus sheath hematoma complicating low‐molecular weight heparin therapy\n. Int J Lab Hematol . 2007 ;29 (3 ):190 ‐194\n. 10.1111/j.1751-553X.2006.00833.x \n17474896 \n16 \n\nKelly \nWN \n, \nArellano \nFM \n, \nBarnes \nJ \n, et al. Guidelines for submitting adverse event reports for publication\n. Drug Saf . 2007 ;30 (5 ):367 ‐373\n. 10.2165/00002018-200730050-00001 \n17472416 \n17 \n\nHumphrey \nR \n, \nCarlan \nSJ \n, \nGreenbaum \nL \n. Rectus sheath hematoma in pregnancy\n. J Clin Ultrasound . 2001 ;29 (5 ):306 ‐311\n. 10.1002/jcu.1040 \n11486328 \n18 \n\nTahan \nN \n, \nKhademi‐Kalantari \nK \n, \nMohseni‐Bandpei \nMA \n, \nMikaili \nS \n, \nBaghban \nAA \n, \nJaberzadeh \nS \n. Measurement of superficial and deep abdominal muscle thickness: an ultrasonography study\n. J Physiol Anthropol . 2016 ;35 (1 ):17 \n10.1186/s40101-016-0106-6 \n27553830 \n19 \n\nSchünemann \nHJ \n, \nCushman \nM \n, \nBurnett \nAE \n, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients\n. Blood Adv . 2018 ;2 (22 ):3198 ‐3225\n. 10.1182/bloodadvances.2018022954 \n30482763 \n20 \n\nNeumann \nI \n, \nIzcovich \nA \n, \nZhang \nY \n, et al. DOACs vs LMWHs in hospitalized medical patients: a systematic review and meta‐analysis that informed 2018 ASH guidelines\n. Blood Adv . 2020 ;4 (7 ):1512 ‐1517\n. 10.1182/bloodadvances.2019000840 \n32289163 \n21 \n\nDouketis \nJD \n, \nSpyropoulos \nAC \n, \nKaatz \nS \n, et al. Perioperative bridging anticoagulation in patients with atrial fibrillation\n. N Engl J Med . 2015 ;373 (9 ):823 ‐833\n. 10.1056/NEJMoa1501035 \n26095867 \n22 \n\nDouketis \nJD \n, \nSpyropoulos \nAC \n, \nDuncan \nJ \n, et al. Perioperative management of patients with atrial fibrillation receiving a direct oral anticoagulant\n. JAMA Intern Med . 2019 ;179 (11 ):1469 ‐1478\n. 10.1001/jamainternmed.2019.2431 \n\n23 \n\nVan Der Pol \nS \n, \nJacobs \nMS \n, \nMeijer \nK \n, et al. Perioperative bridging of Vitamin K antagonist treatment in patients with atrial fibrillation: only a very small group of patients benefits\n. Europace . 2019 ;21 (5 ):716 ‐723\n. 10.1093/europace/euy308 \n30649301 \n24 \n\nMaharaj \nD \n, \nRamdass \nM \n, \nTeelucksingh \nS \n, \nPerry \nA \n, \nNaraynsingh \nV \n. Rectus sheath haematoma: a new set of diagnostic features\n. Postgrad Med J . 2002 ;78 (926 ):755 ‐756\n. 10.1136/pmj.78.926.755 \n12509696 \n25 \n\nPierro \nA \n, \nCilla \nS \n, \nModugno \nP \n, \nCentritto \nEM \n, \nDe Filippo \nCM \n, \nSallustio \nG \n. Spontaneous rectus sheath hematoma: the utility of CT angiography\n. Radiol Case Reports . 2018 ;13 (2 ):328 ‐332\n. 10.1016/j.radcr.2018.01.016 \n\n26 \n\nBerná \nJD \n, \nGarcia‐Medina \nV \n, \nGuirao \nJ \n, \nGarcia‐Medina \nJ \n. Rectus sheath hematoma: diagnostic classification by CT\n. Abdom Imaging . 1996 ;21 (1 ):62 ‐64\n. 10.1007/s002619900011 \n8672975 \n27 \n\nMendoza Moreno \nF \n, \nDíez Alonso \nM \n, \nVilleta Plaza \nR \n, et al. Spontaneous haematoma of the anterior rectus abdominis muscle\n. Cir Esp . 2016 ;94 (5 ):294 ‐299\n. 10.1016/j.ciresp.2016.02.012 \n27021620\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-0904",
"issue": "8(12)",
"journal": "Clinical case reports",
"keywords": "drug‐related side effects and adverse reactions; enoxaparin; hematoma; heparin; low‐molecular‐weight; pharmacovigilance; rectus abdominis",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "3432-3439",
"pmc": null,
"pmid": "33363947",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports",
"references": "29904466;30649301;26095867;25178308;32289163;18940904;25294636;25529279;27021620;31380891;16609349;10556453;28329262;30482763;12509696;18791099;8672975;15794705;30140689;17472416;9313718;28403994;17474896;27553830;11486328;26221649",
"title": "Rectus sheath hematoma in patients receiving subcutaneous enoxaparin: A case series of five patients.",
"title_normalized": "rectus sheath hematoma in patients receiving subcutaneous enoxaparin a case series of five patients"
} | [
{
"companynumb": "PT-FRESENIUS KABI-FK202109008",
"fulfillexpeditecriteria": "1",
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"patient": {
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{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": null,
... |
{
"abstract": "This case report describes a 65-year-old female with iatrogenic opioid use disorder for chronic lower back pain, who developed Takotsubo cardiomyopathy on multiple occasions following buprenorphine induction. This patient had three opioid transfers to buprenorphine, over 4 years, two of which were complicated by Takotsubo cardiomyopathy. In the transfer where she did not develop Takotsubo cardiomyopathy, she was treated with high doses of the centrally acting agonist, clonidine (three times a day, total of 600 mcg/day), up to and including the day of her transfer. This case highlights the potential consequences of a precipitated withdrawal with buprenorphine in an opioid transfer and its possible prevention with clonidine. To our knowledge, this is the first description of the recurrent Takotsubo cardiomyopathy in an opioid transfer setting. Given that buprenorphine is a partial agonist, in the presence of a full opioid agonist, it can precipitate withdrawal within minutes to hours of its administration. Opioid withdrawal can result in a sympathetic overdrive. Although complications of opioid withdrawal are extensively documented, cardiotoxicity is uncommon. As the use of buprenorphine and its new injectable formulations rise, it is important for prescribers to be aware of this life threatening complication. The prophylactic administration of clonidine can be considered to reduce the risk of cardiotoxicity, as well as manage opioid withdrawal symptoms.",
"affiliations": "Department of Clinical Pharmacology and Toxicology and Drug health services, Royal Prince Alfred Hospital, Level 6, King George Building, Missenden Rd, Camperdown, NSW, Australia. Nazila.jamshidi@health.nsw.gov.au.;Emergency Department, Royal North Shore Hospital, St Leonards, NSW, Australia.;School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia.",
"authors": "Jamshidi|Nazila|N|0000-0002-6049-9654;Clark|Danielle|D|;Murnion|Bridin|B|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s12012-020-09624-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1530-7905",
"issue": "21(5)",
"journal": "Cardiovascular toxicology",
"keywords": "Buprenorphine; Opioid withdrawal; Takotsubo cardiomyopathy",
"medline_ta": "Cardiovasc Toxicol",
"mesh_terms": null,
"nlm_unique_id": "101135818",
"other_id": null,
"pages": "349-353",
"pmc": null,
"pmid": "33481183",
"pubdate": "2021-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Recurrent Takotsubo Cardiomyopathy Associated with Opioid Withdrawal During Buprenorphine Induction.",
"title_normalized": "recurrent takotsubo cardiomyopathy associated with opioid withdrawal during buprenorphine induction"
} | [
{
"companynumb": "AU-ALVOGEN-2021-ALVOGEN-116771",
"fulfillexpeditecriteria": "1",
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{
"actiondrug": "5",
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"activesubstancename": "KETAMINE"
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... |
{
"abstract": "To describe the characteristic clinical features and management of keratitis in the patients receiving miltefosine for post-kala-azar dermal leishmaniasis (PKDL).\n\n\n\nThe medical records of five patients with PKDL who presented with keratitis were reviewed retrospectively from April 2018 to December 2019. The evaluation included a thorough medical history including details on drugs used, particularly miltefosine. The drug causality assessment was also performed. The clinical and microbiological characteristics of keratitis were noted.\n\n\n\nThe ocular symptoms included pain, redness, watering, photophobia and diminution of vision. Slit-lamp biomicroscopy revealed peripheral, paralimbal, ring-shaped, full-thickness stromal infiltration resulting in ulcerative keratitis in all cases. Two patients had unilateral keratitis, while three had bilateral keratitis. All five patients received miltefosine for an average period of 48 days before the onset of keratitis. The corrected distance visual acuity at presentation ranged from hand movement to 20/125. The causality assessment revealed a 'probable' association between the adverse drug reaction and miltefosine in all patients. Discontinuation of miltefosine and initiation of corticosteroid therapy resulted in resolution of keratitis in all cases. The unilateral keratitis treated with topical corticosteroids had improved outcomes, but poor outcomes were found in the bilateral keratitis.\n\n\n\nThese observations indicate that prolonged use of miltefosine might cause keratitis that resembles infectious keratitis. Early diagnosis with discontinuation of the drug and initiation of corticosteroid therapy are the key to successful management.",
"affiliations": "Regional Institute of Ophthalmology, Indira Gandhi Institute of Medical Sciences, Patna, Bihar, India drkrakhi@yahoo.com.;Regional Institute of Ophthalmology, Indira Gandhi Institute of Medical Sciences, Patna, Bihar, India.;Regional Institute of Ophthalmology, Indira Gandhi Institute of Medical Sciences, Patna, Bihar, India.;Regional Institute of Ophthalmology, Indira Gandhi Institute of Medical Sciences, Patna, Bihar, India.;Regional Institute of Ophthalmology, Indira Gandhi Institute of Medical Sciences, Patna, Bihar, India.;Rajendra Memorial Research Institute of Medical Sciences, Patna, Bihar, India.",
"authors": "Kusumesh|Rakhi|R|0000-0001-9253-5755;Ambasta|Anita|A|;Arya|Lalan Kumar|LK|;Mohan|Nilesh|N|;Sinha|Bibhuti Prassan|BP|;Ravidas|Vidyanand|V|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bjophthalmol-2020-317325",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1161",
"issue": "105(11)",
"journal": "The British journal of ophthalmology",
"keywords": "Acanthamoeba keratitis; Annular ulcer; Miltefosine; Post-kala-azar dermal leishmaniasis; Ring ulcer",
"medline_ta": "Br J Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "0421041",
"other_id": null,
"pages": "1497-1503",
"pmc": null,
"pmid": "32962993",
"pubdate": "2021-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Keratitis occurring in patients treated with miltefosine for post-kala-azar dermal leishmaniasis.",
"title_normalized": "keratitis occurring in patients treated with miltefosine for post kala azar dermal leishmaniasis"
} | [
{
"companynumb": "IN-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-324868",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN"
},
"d... |
{
"abstract": "Uterine leiomyosarcoma (ULMS) is an aggressive tumor associated with high rates of progression, recurrence, and mortality. Pazopanib is the only approved molecular targeted drug for advanced soft tissue sarcoma, and it has been proven to prolong progression-free survival relative to placebo. We herein report a case of ULMS with multiple lung metastases treated with pazopanib, which led to sustained disease control for 44 weeks. A 53-year-old woman was referred to our hospital due to massive uterine bleeding from a uterine corpus tumor mass. Total abdominal hysterectomy with bilateral salpingo-oophorectomy was performed as emergency surgery. The final histopathological diagnosis was uterine leiomyosarcoma, and computed tomography revealed multiple lung metastases. After chemotherapy with 17 cycles of gemcitabine and docetaxel and two cycles of doxorubicin, the lung metastases had increased in size and new lesions had appeared. Pazopanib administration at 800 mg/day was started as third-line therapy. Ten weeks later, the dose of pazopanib was reduced to 600 mg/day because of hepatic impairment and hypertension. However, lung metastases of ULMS were stabilized by pazopanib administration for about 44 weeks without a decline in the patient's quality of life. After 44 weeks of therapy, pazopanib administration was discontinued because of progressive disease and worsening of the patient's respiratory status. Pazopanib is an oral multityrosine kinase inhibitor of vascular endothelial growth factor receptor-1, -2, and -3; platelet-derived growth factor-α and -β; and c-Kit receptor. The role of pazopanib may be clinically significant in the treatment of advanced ULMS.",
"affiliations": "Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan.;Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan.;Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan.;Department of Obstetrics and Gynecology, Hyogo Prefectural Awaji Medical Center, 1-1-137 Shioya, Sumoto, Hyogo 656-0021, Japan.;Department of Obstetrics and Gynecology, Hyogo Prefectural Awaji Medical Center, 1-1-137 Shioya, Sumoto, Hyogo 656-0021, Japan.;Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan.",
"authors": "Nagamata|Satoshi|S|;Ebina|Yasuhiko|Y|;Yamano|Yumika|Y|;Miyamoto|Takeo|T|;Nishijima|Mitsuhiro|M|;Yamada|Hideto|H|",
"chemical_list": "D000970:Antineoplastic Agents; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0023-2513",
"issue": "62(2)",
"journal": "The Kobe journal of medical sciences",
"keywords": "Lung metastases; Multityrosine kinase inhibitor; Pazopanib; Soft tissue sarcoma; Uterine leiomyosarcoma",
"medline_ta": "Kobe J Med Sci",
"mesh_terms": "D000970:Antineoplastic Agents; D005260:Female; D006801:Humans; D007191:Indazoles; D007890:Leiomyosarcoma; D008175:Lung Neoplasms; D008875:Middle Aged; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D016879:Salvage Therapy; D013449:Sulfonamides; D014057:Tomography, X-Ray Computed; D014594:Uterine Neoplasms",
"nlm_unique_id": "0413531",
"other_id": null,
"pages": "E45-8",
"pmc": null,
"pmid": "27578036",
"pubdate": "2016-07-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20456972;24504442;25302110;22595799;26033286;18394689;18534250;15459493;19853898",
"title": "A Case of Uterine Leiomyosarcoma with Long-Term Disease Control by Pazopanib.",
"title_normalized": "a case of uterine leiomyosarcoma with long term disease control by pazopanib"
} | [
{
"companynumb": "JP-CIPLA LTD.-2018JP08691",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional... |
{
"abstract": "Othello syndrome (OS) is a type of delusional jealousy, characterized by the false absolute certainty of the infidelity of a partner. This syndrome is not uncommon in Parkinson's Disease (PD), appearing as side effect of Dopaminergic Agonists (DA) therapy. We analyze the observations of five patients with OS, diagnosed in a series of 250 consecutive PD patients during two years. All patients are men, with a particularly young age at onset of PD. The mean duration of DA therapy at OS onset was 3 years. One patient had hypersexuality and another had punding. Significant cognitive impairment was present in two patients. All patients were treated with DA: two with Pramipexol and three with Piribedil. At the time of the management of the OS, three patients had already divorced their spouse. It is imperative for clinicians to know this underestimated syndrome in order to identify it early and approach it adequately to avoid irreversible negative prejudice.",
"affiliations": "Neurology Department, Ibn Rochd Hospital, Casablanca, Morocco; Genetics and Molecular Biology Laboratory, Faculty of Medicine, Hassan II University, 67, rue AbouAllaa Zahr, No. 20, Casablanca, Morocco. Electronic address: hichamotmani@hotmail.com.;Neurology Department, Ibn Rochd Hospital, Casablanca, Morocco.;Neurology Department, Ibn Rochd Hospital, Casablanca, Morocco.;Neurology Department, Ibn Rochd Hospital, Casablanca, Morocco; Genetics and Molecular Biology Laboratory, Faculty of Medicine, Hassan II University, 67, rue AbouAllaa Zahr, No. 20, Casablanca, Morocco.;Neurology Department, Ibn Rochd Hospital, Casablanca, Morocco.",
"authors": "El Otmani|H|H|;Sabiry|S|S|;Bellakhdar|S|S|;El Moutawakil|B|B|;Abdoh Rafai|M|M|",
"chemical_list": "D018491:Dopamine Agonists",
"country": "France",
"delete": false,
"doi": "10.1016/j.neurol.2020.08.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0035-3787",
"issue": "177(6)",
"journal": "Revue neurologique",
"keywords": "Delusional Jealousy; Othello syndrome; Parkinson's disease",
"medline_ta": "Rev Neurol (Paris)",
"mesh_terms": "D003702:Delusions; D018491:Dopamine Agonists; D006801:Humans; D007578:Jealousy; D008297:Male; D010300:Parkinson Disease",
"nlm_unique_id": "2984779R",
"other_id": null,
"pages": "690-693",
"pmc": null,
"pmid": "33276961",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Othello syndrome in Parkinson's disease: A diagnostic emergency of an underestimated condition.",
"title_normalized": "othello syndrome in parkinson s disease a diagnostic emergency of an underestimated condition"
} | [
{
"companynumb": "MA-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-311637",
"fulfillexpeditecriteria": "1",
"occurcountry": "MA",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PRAMIPEXOLE"
},
"dru... |
{
"abstract": "Transcatheter aortic valve implantation (TAVI) was introduced as an alternative treatment for patients with severe symptomatic aortic stenosis for whom surgery would be high-risk. Prosthetic aortic valve endocarditis is a serious complication of surgical AVR (SAVR) with high morbidity and mortality. According to recent cases, post-TAVI prosthetic valve endocarditis (PVE) seems to occur very rarely. We present the case of a 75-year-old woman who underwent TAVI (Edwards Saphien XT) with an uneventful postoperative stay. She was diagnosed with endocarditis using three dimensional (3D) echocardiography on the TAVI device 7 months later and she subsequently underwent surgical aortic valve replacement. Little experience of the interpretation of transoesophageal echocardiography (TEE) and the clinical course and effectiveness of treatment strategies in post-TAVI endocarditis exists. We report a case of PVE in a TAVI patient which was diagnosed with three-dimensional transoesophageal echocardiography (3DTEE).",
"affiliations": "Department of Cardiology, Ataturk Research and Training Hospital, Ankara, Turkey. Electronic address: cengaver61@yahoo.com.;Yıldırım Beyazıt University, Cardiology Department, Ankara, Turkey.;Department of Cardiology, Ataturk Research and Training Hospital, Ankara, Turkey.;Yıldırım Beyazıt University, Cardiology Department, Ankara, Turkey.;Department of Cardiovascular Surgery, Ataturk Research and Training Hospital, Ankara, Turkey.;Department of Cardiology, Ataturk Research and Training Hospital, Ankara, Turkey.;Department of Cardiology, Ataturk Research and Training Hospital, Ankara, Turkey.;Yıldırım Beyazıt University, Cardiology Department, Ankara, Turkey.;Department of Cardiology, Ataturk Research and Training Hospital, Ankara, Turkey.;Yıldırım Beyazıt University, Cardiology Department, Ankara, Turkey.;Yıldırım Beyazıt University, Cardiology Department, Ankara, Turkey.;Yıldırım Beyazıt University, Cardiology Department, Ankara, Turkey.",
"authors": "Sarı|Cenk|C|;Durmaz|Tahir|T|;Karaduman|Bilge Duran|BD|;Keleş|Telat|T|;Bayram|Hüseyin|H|;Baştuğ|Serdal|S|;Özen|Mehmet Burak|MB|;Bayram|Nihal Akar|NA|;Bilen|Emine|E|;Ayhan|Hüseyin|H|;Kasapkara|Hacı Ahmet|HA|;Bozkurt|Engin|E|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1109-9666",
"issue": "57(2)",
"journal": "Hellenic journal of cardiology : HJC = Hellenike kardiologike epitheorese",
"keywords": "3D echocardiography; Infective endocarditis; Transcatheter aortic valve implantation",
"medline_ta": "Hellenic J Cardiol",
"mesh_terms": "D000368:Aged; D019560:Echocardiography, Three-Dimensional; D017548:Echocardiography, Transesophageal; D004696:Endocarditis; D005260:Female; D006801:Humans; D011475:Prosthesis Failure; D012214:Rheumatic Heart Disease; D065467:Transcatheter Aortic Valve Replacement",
"nlm_unique_id": "101257381",
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"title": "Prosthetic valve endocarditis 7 months after transcatheter aortic valve implantation diagnosed with 3D TEE.",
"title_normalized": "prosthetic valve endocarditis 7 months after transcatheter aortic valve implantation diagnosed with 3d tee"
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"abstract": "A 62-year-old woman complained of diarrhea and vomiting after receiving chemotherapy for cervical cancer in association with high doses of corticosteroids. Two months later, the patient developed acute respiratory distress syndrome, and numerous Strongyloides stercoralis parasites were found in the intrabronchial discharge. Ivermectin was administered daily until nematodes were no longer detected in the sputum, and the patient's condition was successfully rescued. Antibodies for human T-cell lymphotropic virus-1 (HTLV-1) were positive. HTLV-1 infection and the administration of corticosteroids are known risk factors for strongyloides hyperinfection syndrome. Therefore, physicians should consider this disease in the differential diagnosis of patients from endemic areas who present with gastrointestinal symptoms under these risk factors.",
"affiliations": "Department of Infectious Diseases, Respiratory and Digestive Medicine, Faculty of Medicine, University of the Ryukyus, Japan.",
"authors": "Kinjo|Takeshi|T|;Nabeya|Daijiro|D|;Nakamura|Hideta|H|;Haranaga|Shusaku|S|;Hirata|Tetsuo|T|;Nakamoto|Tomoko|T|;Atsumi|Eriko|E|;Fuchigami|Tatsuya|T|;Aoki|Yoichi|Y|;Fujita|Jiro|J|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D007559:Ivermectin",
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"mesh_terms": "D000305:Adrenal Cortex Hormones; D000818:Animals; D005260:Female; D006801:Humans; D007559:Ivermectin; D008875:Middle Aged; D012128:Respiratory Distress Syndrome; D012307:Risk Factors; D013183:Sputum; D017171:Strongyloides stercoralis; D013322:Strongyloidiasis; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms",
"nlm_unique_id": "9204241",
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"references": null,
"title": "Acute respiratory distress syndrome due to Strongyloides stercoralis infection in a patient with cervical cancer.",
"title_normalized": "acute respiratory distress syndrome due to strongyloides stercoralis infection in a patient with cervical cancer"
} | [
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"abstract": "Aim: This study evaluated use of liposomal bupivacaine (LB) versus standard bupivacaine (SB) alone in quadratus lumborum (QL) blocks for laparoscopic colorectal surgery. Materials & methods: In this prospective, randomized controlled trial, patients received QL1 blocks with either LB (40 ml 0.125% SB plus 20 ml of LB) or SB (60 ml of 0.25% SB) with 30 ml per side. Opioid usage, pain scores, side effects and other medications were recorded. Results: For 78 patients (38 LB; 40 SB), all parameters were similar between groups, except that the LB group had a higher 48 h need for metoclopramide. Conclusion: LB provided no analgesic benefit over SB alone for QL blocks. Clinical Trials registration number: NCT03702621.",
"affiliations": "Department of Anesthesia, Indiana University School of Medicine, 1130 W Michigan Street, Fesler Hall 204, Indianapolis, IN 46202, USA.;Department of Anesthesia, Indiana University School of Medicine, 1130 W Michigan Street, Fesler Hall 204, Indianapolis, IN 46202, USA.;Department of Anesthesia, Indiana University School of Medicine, 1130 W Michigan Street, Fesler Hall 204, Indianapolis, IN 46202, USA.;Department of Anesthesia, Indiana University School of Medicine, 1130 W Michigan Street, Fesler Hall 204, Indianapolis, IN 46202, USA.;Department of Anesthesia, Indiana University School of Medicine, 1130 W Michigan Street, Fesler Hall 204, Indianapolis, IN 46202, USA.;Department of Surgery, Indiana University School of Medicine, 545 Barnhill Drive, Indianapolis, IN 46202, USA.;Department of Surgery, Indiana University School of Medicine, 545 Barnhill Drive, Indianapolis, IN 46202, USA.;Indiana University School of Medicine, 340 W 10th Street, Fairbanks Hall 6200, Indianapolis, IN 46202, USA.",
"authors": "Yeap|Yar L|YL|0000-0003-3168-9405;Wolfe|John|J|;Stewart|Jennifer|J|;McCutchan|Amy|A|;Chawla|Gulraj|G|;Robb|Bruce|B|;Holcomb|Bryan|B|;Vickery|Ben|B|",
"chemical_list": "D000701:Analgesics, Opioid; D000779:Anesthetics, Local; D002045:Bupivacaine",
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"fulltext": null,
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"issn_linking": "1758-1869",
"issue": "12(1)",
"journal": "Pain management",
"keywords": "block; bupivacaine; colorectal; liposomal; opioid usage; pain scores; quadratus lumborum; regional analgesia",
"medline_ta": "Pain Manag",
"mesh_terms": "D000701:Analgesics, Opioid; D000779:Anesthetics, Local; D002045:Bupivacaine; D003107:Colorectal Surgery; D006801:Humans; D010149:Pain, Postoperative; D011446:Prospective Studies",
"nlm_unique_id": "101555934",
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"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Liposomal bupivacaine addition versus standard bupivacaine alone for colorectal surgery: a randomized controlled trial.",
"title_normalized": "liposomal bupivacaine addition versus standard bupivacaine alone for colorectal surgery a randomized controlled trial"
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"abstract": "► Fever ► Generalized rash ► Recent history of calcaneal osteomyelitis.",
"affiliations": "Family Medicine Residency Program, JPS Health Network, Fort Worth, TX, USA. Email: w.jacob.cobb@gmail.com.",
"authors": "Cobb|W Jacob|WJ|",
"chemical_list": "D047090:beta-Lactams; D000077723:Cefepime",
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"issn_linking": "0094-3509",
"issue": "69(7)",
"journal": "The Journal of family practice",
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"medline_ta": "J Fam Pract",
"mesh_terms": "D000077723:Cefepime; D063926:Drug Hypersensitivity Syndrome; D005076:Exanthema; D005334:Fever; D006801:Humans; D008297:Male; D008875:Middle Aged; D010019:Osteomyelitis; D016896:Treatment Outcome; D047090:beta-Lactams",
"nlm_unique_id": "7502590",
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"pages": "353-356",
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"pubdate": "2020-09",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "45-year-old man • fever • generalized rash • recent history of calcaneal osteomyelitis • Dx?",
"title_normalized": "45 year old man fever generalized rash recent history of calcaneal osteomyelitis dx"
} | [
{
"companynumb": "US-QILU PHARMACEUTICAL CO.LTD.-QLU-000320-2020",
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"abstract": "Disseminated histoplasmosis can occur in immunocompromised patients such as in HIV disease and patients with medication-induced immunosuppression. Most of these patients present with fever, weight loss, hepatosplenomegaly, lymphadenopathy, and pancytopenia. There are increasing reports of coronavirus disease 2019 (COVID-19) pneumonia associated with fungal infections including aspergillus and mucormycosis. It is not typical for immunocompetent patients to present with disseminated fungal disease. We herein report a case of a 50-year-old immunocompetent male with a recent recovery from COVID-19 pneumonia who presented with fever and pancytopenia. Chest computed tomography (CT) demonstrated new-onset right upper lobe lung mass, subcarinal lymphadenopathy, and splenomegaly. Mediastinal lymph nodes and bone marrow biopsies were performed, and the patient was diagnosed with disseminated histoplasmosis. The association between COVID-19 pneumonia and fungal infections is increasingly reported. Diagnosis requires a high index of suspicion, especially in immunocompetent patients.",
"affiliations": "Pulmonary and Critical Care, University of Louisville, Louisville, USA.;Pulmonary and Critical Care, University of Louisville, Louisville, USA.;Pathology and Laboratory Medicine, University of Louisville, Louisville, USA.;Interventional Pulmonary, University of Louisville, Louisville, USA.;Pulmonary and Critical Care, University of Nebraska Medical Center, Omaha, USA.",
"authors": "Taylor|Matthew|M|;Ghodasara|Arjun|A|;Ismail|Ali|A|;Gauhar|Umair|U|;El-Kersh|Karim|K|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.17269",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.17269\nPathology\nInfectious Disease\nPulmonology\nDisseminated Histoplasmosis in an Immunocompetent Patient After COVID-19 Pneumonia\nMuacevic Alexander\nAdler John R\nTaylor Matthew 1\nGhodasara Arjun 1\nIsmail Ali 2\nGauhar Umair 3\nEl-Kersh Karim 4\n1 Pulmonary and Critical Care, University of Louisville, Louisville, USA\n2 Pathology and Laboratory Medicine, University of Louisville, Louisville, USA\n3 Interventional Pulmonary, University of Louisville, Louisville, USA\n4 Pulmonary and Critical Care, University of Nebraska Medical Center, Omaha, USA\nMatthew Taylor matt.j.taylor14@gmail.com\n18 8 2021\n8 2021\n13 8 e1726917 8 2021\nCopyright © 2021, Taylor et al.\n2021\nTaylor et al.\nhttps://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/64569-disseminated-histoplasmosis-in-an-immunocompetent-patient-after-covid-19-pneumonia\nDisseminated histoplasmosis can occur in immunocompromised patients such as in HIV disease and patients with medication-induced immunosuppression. Most of these patients present with fever, weight loss, hepatosplenomegaly, lymphadenopathy, and pancytopenia. There are increasing reports of coronavirus disease 2019 (COVID-19) pneumonia associated with fungal infections including aspergillus and mucormycosis. It is not typical for immunocompetent patients to present with disseminated fungal disease. We herein report a case of a 50-year-old immunocompetent male with a recent recovery from COVID-19 pneumonia who presented with fever and pancytopenia. Chest computed tomography (CT) demonstrated new-onset right upper lobe lung mass, subcarinal lymphadenopathy, and splenomegaly. Mediastinal lymph nodes and bone marrow biopsies were performed, and the patient was diagnosed with disseminated histoplasmosis. The association between COVID-19 pneumonia and fungal infections is increasingly reported. Diagnosis requires a high index of suspicion, especially in immunocompetent patients. \n\ncovid-19\ndisseminated histoplasmosis\nfungal\nimmunocompetent\ndexamethasone\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\npmcIntroduction\n\nCoronavirus disease 2019 (COVID-19) pneumonia-associated fungal infections are well documented with risk factors including ICU prolonged length of stay, neutropenia, hematological malignancies treated with chemotherapy, transplantation, and other immunocompromised states like HIV [1,2]. Disseminated histoplasmosis is often seen in immunosuppressed patients, and can present with multisystem involvement including the lungs, skin, gastrointestinal tract, and bone marrow [3-5]. Disseminated histoplasmosis in patients with post-COVID-19 pneumonia is rare and is difficult to diagnose [6]. A disseminated disease requires treatment and with amphotericin B for one to two weeks followed by azole antifungal therapy [7].\n\nCase presentation\n\nA 50-year-old male that lived in the Ohio River Valley with a history of mild intermittent asthma well controlled on albuterol and fluticasone-salmeterol and no recent requirement of oral corticosteroids was admitted for daily cyclical fevers after COVID-19 pneumonia. One month before admission, the patient was treated on the medical-surgical floor for COVID-19 pneumonia with a five-day course of remdesivir and a 10-day course of dexamethasone. The patient recovered and he was discharged home without oxygen. Two weeks after discharge, he developed fever and myalgias. The patient had two polymerase chain reaction (PCR) COVID-19 testing that both were negative. On hospital admission, COVID-19 PCR testing was also negative. His blood work on admission revealed WBC 7.9 x 103 uL, hemoglobin 11.8 g/dL, and platelets 146 x 103 uL. A non-contrast chest computed tomography (CT) revealed interval improvement of ground-glass opacities, a new 3.9 cm mass-like density in the right upper lobe (RUL), mildly enlarged mediastinal lymphadenopathy, and moderate-severe hepatosplenomegaly (Figures 1, 2). The patient was started on vancomycin and cefepime and transitioned to linezolid, levofloxacin, voriconazole, and piperacillin-tazobactam after no improvement in his fevers as high as 39.9°C. The patient continued to be febrile daily until hospital day 14 despite antipyretics. He was first noted to have pancytopenia on hospital day 7 with a possible cause due to Linezolid which was stopped on hospital day six. His repeat blood work revealed WBC 2.8 x 103 uL, hemoglobin 8.8 g/dL, platelets 50 x 103 uL, and ferritin 2,934 ng/mL. The patient underwent bronchoscopy with endobronchial ultrasound and transbronchial needle aspiration of subcarinal lymph node and biopsy of the RUL mass. Fine needle aspiration of the subcarinal lymph node showed budding yeast suggestive of histoplasmosis on the Grocott methenamine silver (GMS) stain (Figure 3). The Histoplasma galactomannan urine antigen was positive at 1.6 ng/mL (reference range < 0.2 ng/mL). The patient’s serum cryptococcal antigen and antibody and blastomyces antibody were negative. The bronchial alveolar lavage and tissue biopsy of the right upper lobe mass isolated Histoplasma capsulatum. Bone marrow biopsy revealed extensive granulomatous inflammation consistent with disseminated histoplasmosis. His cyclic fevers ceased, and pancytopenia improved with amphotericin-B. He was discharged from the hospital one week after starting treatment with a plan of two weeks of therapy and transition to oral fluconazole.\n\nFigure 1 CT of the chest with right upper lobe (RUL) mass.\n\nFigure 2 CT of the chest with subcarinal lymph node enlargement.\n\nFigure 3 Grocott methenamine silver (GMS) stain with budding yeast.\n\nDiscussion\n\nRisk factors for most of the reported cases of disseminated histoplasmosis in immunocompetent patients include living in a rural setting due to the likely exposure to histoplasma in the soil [8]. Most of these patients experienced fever, weight loss, hepatosplenomegaly, lymphadenopathy, pancytopenia, elevated ESR, elevated hepatic transaminases, and had bone marrow involvement [8,9]. An immunocompromised state, including HIV/AIDS and chemotherapy-induced immunosuppression, is a known risk factor for disseminated histoplasmosis. There is a reported case of disseminated histoplasmosis in a patient with HIV/AIDS after COVID-19. This patient presented with an initial CD4 count of 113 cells/mm3 and a viral load of 38,503 RNA copies/ml. One week after the initial presentation, the patient was diagnosed with COVID-19 and with suspected disseminated histoplasmosis based on a positive histoplasmosis antigen and CT scan with lymphadenopathy and hepatosplenomegaly [6]. Another patient with underlying asthma and diabetes mellitus presented with COVID-19 pneumonia complicated by pulmonary embolism and prolonged hospitalization was diagnosed with pulmonary histoplasmosis based on positive Histoplasma capsulatum complement fixation titers [10]. \n\nCo-infecting pathogens with COVID-19 are well documented, and patients are more likely to die than those without a co-infection [2]. Initial reports included both viral and bacterial causes [2,11]. Fungal co-infections are increasingly reported after COVID-19 and are also known to increase mortality as well [12]. Most reported cases include aspergillus with a prevalence as high as 8.5% in retrospective studies and 9% in a meta-analysis [2]. Risk factors not mentioned previously for aspergillosis include antibiotics, particularly azithromycin (cumulative dose >/= 1500 mg) [13]. Many of these patients may be treated with Voriconazole to avoid the potentially nephrotoxic liposomal amphotericin B [12]. Candida, which is often isolated in the respiratory tract, is usually not thought to be pathogenic [1,2] and the reported cases of candida bacteremia were thought to be related to central line infections [14]. Other reported non-disseminated fungal co-infections include coccidioidomycosis, mucormycosis, and cryptococcosis [1,11].\n\nAcute pulmonary histoplasmosis presents with either asymptomatic disease, flu-like symptoms, caseating or noncaseating granulomatous disease, or mediastinal adenopathy. Chronic pulmonary histoplasmosis presents with an either cavitary or noncavitary disease with associated nodules, infiltrates, and mediastinal lymphadenopathy. Disseminated disease is often seen in immunosuppressed patients. Manifestations can include skin involvement with polymorphic plaques, nodules, and erosions, gastrointestinal involvement with hepatosplenomegaly and colonic ulcerations, and bone marrow suppression [3,4].\n\nDiagnosis of disseminated disease is complex as many tests take weeks. Cultures often take two to four but up to eight weeks with the greatest yield occurring in those with disseminated disease. Complement fixing antibodies may appear two to six weeks following acute infection and may persist for years following infection. Immunodiffusion antibody assay tests for the presence of M and H precipitin bands. M bands develop with acute infections and persist for months to years. H bands appear after an M band and may disappear earlier than M bands. These may indicate active histoplasmosis [3]. Antigen testing may be more effective in acute disease and immunocompromised patients who cannot amount an antibody response with improved sensitivity utilizing both serum and urine testing. A polymerase chain reaction is available but still needs further standardization [3,15].\n\nTreatment for the mild asymptomatic acute pulmonary disease is often unnecessary. Moderate to severe acute pulmonary disease requires treatment with amphotericin B followed by azole antifungal therapy for weeks. Chronic pulmonary disease is treated with azole antifungal therapy for 12-24 months. The disseminated disease requires treatment with amphotericin B for one to two weeks followed by azole antifungal therapy for at least 12 months [7]. \n\nConclusions\n\nWe presented a case of disseminated histoplasmosis after COVID-19 pneumonia effectively treated with amphotericin-B and fluconazole. The patient was eventually discharged home with resolution of his cyclic fevers and pancytopenia. Fungal infections are increasingly reported in association with COVID-19 pneumonia. Although not able to prove, prolonged courses of dexamethasone may be a risk factor for disseminated fungal infections. Clinicians need to be aware of the possibility of disseminated fungal diseases even in immunocompetent patients.\n\nHuman Ethics\n\nFigure 2 provided by Dr. Ali Ismail MBBS, Department of Pathology and Laboratory Medicine, University of Louisville School of Medicine 2021.\n\nThe authors have declared financial relationships, which are detailed in the next section.\n\nKarim El-Kersh declare(s) personal fees from United Therapeutics, Actelion, Acceleron Pharma. Speaker, Consultant (advisory board) for United Therapeutics. Consultant (advisory board) for Actelion. Consultant for Acceleron Pharma.\n\nConsent was obtained or waived by all participants in this study. The University of Louisville Institutional Review Board issued approval 727224. The IRB Chair/Vice-Chair (or An IRB member) has reviewed your submission. The project described does not meet the “Common Rule” definition of human subjects’ research. The IRB has classified this project as Non-Human Subjects Research (NHSR). The project can proceed.\n==== Refs\nReferences\n\n1 Fungal co-infections associated with global COVID-19 pandemic: a clinical and diagnostic perspective from China Mycopathologia Song G Liang G Liu W 599 606 185 2020 32737747\n2 Co-infections in people with COVID-19: a systematic review and meta-analysis J Infect Lansbury L Lim B Baskaran V Lim WS 266 275 81 2020 32473235\n3 Histoplasmosis Infect Dis Clin North Am Araúz AB Papineni P 471 491 35 2021 34016287\n4 Disseminated histoplasmosis diagnosed in a bone marrow sample [Epub ahead of print] Hematol Transfus Cell Ther Mussá NY Ismail S Carvalho D 2020\n5 Diagnosis by molecular pathology of an early and atypical histoplasmosis lesion in the duodenum of an immunocompromised patient: a case report Biomed Rep Sumiyoshi S Tanaka S Kato H 6 14 2021 33235721\n6 COVID-19-associated histoplasmosis in an AIDS patient Mycopathologia Basso RP Poester VR Benelli JL 109 112 186 2021 33156463\n7 Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America Clin Infect Dis Wheat LJ Freifeld AG Kleiman MB Baddley JW McKinsey DS Loyd JE Kauffman CA 807 825 45 2007 17806045\n8 Disseminated Histoplasmosis in Immunocompetent Individuals- not a so Rare Entity, in India Mediterr J Hematol Infect Dis De D Nath UK 0 7 2015\n9 Disseminated histoplasmosis in an immunocompetent individual diagnosed with gastrointestinal endoscopy: a case report BMC Infect Dis Dang Y Jiang L Zhang J 992 19 2019 31752711\n10 Opportunistic fungal infection associated with COVID-19 Open Forum Infect Dis Cafardi J Haas D Lamarre T Feinberg J 0 2021 https://doi.org/10.1093/ofid/ofab016.\n11 The coincidence of 2 epidemics, coccidioidomycosis and SARS-CoV-2: a case report J Investig Med High Impact Case Rep Shah AS Heidari A Civelli VF 8 2020\n12 Invasive fungal disease complicating COVID-19: when it rains it pours [Epub ahead of print] Clin Infect Dis Hoenigl M 2020\n13 Risk factors associated with COVID-19-associated pulmonary aspergillosis in ICU patients: a French multicentric retrospective cohort Clin Microbiol Infect Dellière S Dudoignon E Fodil S 2020\n14 Bacterial and fungal coinfection among hospitalized patients with COVID-19: a retrospective cohort study in a UK secondary-care setting Clin Microbiol Infect Hughes S Troise O Donaldson H Mughal N Moore LS 1395 1399 26 2020 32603803\n15 Combining urine antigen and blood polymerase chain reaction for the diagnosis of disseminated histoplasmosis in hospitalized patients with advanced HIV disease [Epub ahead of print] Med Mycol Vidal JE Werlang PC Muniz BM 2021\n\n",
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"issue": "13(8)",
"journal": "Cureus",
"keywords": "covid-19; dexamethasone; disseminated histoplasmosis; fungal; immunocompetent",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e17269",
"pmc": null,
"pmid": "34540490",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports",
"references": "33962466;32887998;31752711;32737747;33339776;33156463;17806045;32603803;32493147;33235721;32473235;25960856;34016287;33316401",
"title": "Disseminated Histoplasmosis in an Immunocompetent Patient After COVID-19 Pneumonia.",
"title_normalized": "disseminated histoplasmosis in an immunocompetent patient after covid 19 pneumonia"
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"abstract": "A 41-year-old woman who had been taking paroxetine began taking tramadol for bilateral ankle pain. A few days later, the patient presented acutely with both feet tremors. During a mental arithmetic task, index-finger pointing posture briefly appeared on the left side. Co-administration of paroxetine and tramadol increases the risk of serotonin toxicity. This is the first reported case of index-finger pointing posture which was associated with serotonin toxicity.",
"affiliations": "Department of Neurology, Nagoya City University West Medical Center, Aichi, Japan.;Department of Neurology, Nagoya City University West Medical Center, Aichi, Japan.;Department of Neurology, Nagoya City University West Medical Center, Aichi, Japan.;Department of Neurology, Nagoya City University Graduate School of Medical Sciences, Aichi, Japan.",
"authors": "Yamada|Gohei|G|;Toyoda|Takanari|T|;Katada|Eiichi|E|;Matsukawa|Noriyuki|N|",
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"fulltext": "\n==== Front\nClin Park Relat Disord\nClin Park Relat Disord\nClinical Parkinsonism & Related Disorders\n2590-1125\nElsevier\n\nS2590-1125(21)00023-2\n10.1016/j.prdoa.2021.100111\n100111\nCase Report\nIndex finger pointing posture in a patient with drug-induced foot tremor\nYamada Gohei gohyamada@yahoo.co.jp\na⁎\nToyoda Takanari a\nKatada Eiichi a\nMatsukawa Noriyuki b\na Department of Neurology, Nagoya City University West Medical Center, Aichi, Japan\nb Department of Neurology, Nagoya City University Graduate School of Medical Sciences, Aichi, Japan\n⁎ Corresponding author at: 1-1, Hirate-cho, Kita-ku Nagoya, Aichi 462-8508, Japan. gohyamada@yahoo.co.jp\n07 10 2021\n2021\n07 10 2021\n5 1001119 8 2021\n28 9 2021\n1 10 2021\n© 2021 The Author(s)\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).\nHighlights\n\n• Drug-induced index finger pointing posture has not been reported.\n\n• A 41-year-old patient began taking tramadol in addition to paroxetine.\n\n• The patient presented with acute foot tremor and brief index-finger pointing posture.\n\n• Serotonin toxicity related movement disorder has a broad clinical spectrum.\n\nA 41-year-old woman who had been taking paroxetine began taking tramadol for bilateral ankle pain. A few days later, the patient presented acutely with both feet tremors. During a mental arithmetic task, index-finger pointing posture briefly appeared on the left side. Co-administration of paroxetine and tramadol increases the risk of serotonin toxicity. This is the first reported case of index-finger pointing posture which was associated with serotonin toxicity.\n\nKeywords\n\nDrug-induced movement disorder\nIndex finger pointing posture\nSerotonin toxicity\nParoxetine\nTramadol\n==== Body\npmc1 Introduction\n\nIndex-finger pointing posture is an unusual neurological manifestation commonly observed in patients with craniocervical dystonia, Parkinson’s disease, essential tremor, and epilepsy [1], [2]. The prevalence of index-finger pointing posture in diverse neurological disorders remains unclear. Herein, we report a case of foot tremor with index-finger pointing posture. The cause of foot tremor and index-finger pointing posture was presumed to be the combined use of paroxetine and tramadol. To the best of our knowledge, this is the first reported case of drug-induced index-finger pointing posture.\n\n2 Case report\n\nA 41-year-old woman with a history of depression developed intermittent shaking of both feet. She had been taking paroxetine (50 mg/day) for more than ten years. A few days before the onset of the tremor, the patient began taking tramadol (150 mg/day) for bilateral ankle pain. The pain was well controlled. The patient had no complaints of fatigue, agitation, or anxiety. Her vital signs were as follows: blood pressure, 136/92 mmHg; heart rate, 103 bpm; and body temperature, 36.9 °C. Neurological examination was remarkable for foot tremor (Supplementary Video) and generalized hyperreflexia. When the patient attempted to maintain her foot in plantar flexion, the tremor was exacerbated. Quick holding of her arms outstretched did not disrupt the foot tremor. When the patient was holding her unilateral foot off the ground, grounding with her whole sole, or lying in the supine position, tremor did not appear. Ankle clonus was absent. Muscle weakness, hypertonicity, ataxia, and sensory impairment in the upper and lower extremities were not observed. Since the onset of tremor depended on the posture of the foot, essential or enhanced physiological tremor was considered. When the patient was performing a mental arithmetic task, the left index-finger suddenly extended, and a tremulous movement immediately appeared (Video). During the task, the foot tremor persisted. In laboratory tests, hepatic function, renal function, thyroid function, blood glucose, and serum concentrations of sodium, calcium, and magnesium were within the normal range. Magnetic resonance imaging (MRI) of the brain revealed no causative lesion. Paroxetine is a selective serotonin reuptake inhibitor. Although tramadol is an opioid, it blocks serotonin uptake by inhibiting the serotonin transporter and acts as a direct serotonin-releasing hormone. Paroxetine is a selective serotonin reuptake inhibitor. Hence, the co-administration of paroxetine and tramadol increased the risk of serotonin toxicity. The patient fulfilled the Hunter Serotonin Toxicity Criteria with tremor and hyperreflexia [3]. Enhanced physiological tremor represents a phenotype of drug-induced movement disorders. Because depressive symptoms were absent for several years, paroxetine was discontinued. One week after discontinuation of paroxetine, foot tremor, index-finger pointing posture under a mental arithmetic task, and generalized hyperreflexia had disappeared (Video). Her mental status remained unchanged. Based on these clinical findings, the patient was diagnosed with a serotonin toxicity-related movement disorder. The tremor has not relapsed for over three years.\n\n3 Discussion\n\nDrug-induced index-finger pointing posture is a unique finding in the present case. A “pointing gun” dystonic posture, which is observed in patients with progressive supranuclear palsy, represents a neurological sign similar to the index finger pointing posture; however, it is characterized by an extended thumb and index finger with the other fingers flexed [4]. In a previous study, index-finger pointing posture was observed during walking in non-psychogenic movement disorders, including craniocervical dystonia, Parkinson’s disease, and essential tremor [2]. This symptom is likely to be a mild form of hand dystonia. The distinctive feature in the present case was that index-finger pointing posture appeared not during walking, but when the patient performed a mental arithmetic task. However, it is well known that dystonia is induced by various tasks, including mental arithmetic tasks. Index-finger pointing posture in the present case could be a dystonic posture.\n\nMRI of the brain did not show any lesion, and electroencephalography was not performed. However, the origin of the index-finger pointing posture seemed to be the central nervous system, because abnormal finger movement was induced by a mental arithmetic task and strictly localized in the left index finger. The central nervous origin is also supported by the high prevalence of index-finger pointing posture in patients with localization-related epilepsy during generalized convulsions [5]. In a positron emission tomographic scan study, communicative pointing posture was associated with the activation of a small area in the medial prefrontal cortex and the temporoparietal junction [6]. As both paroxetine and tramadol inhibit serotonin uptake, a serotonergic mechanism is likely involved in the present case. The increased concentration of serotonin in the synaptic junction might induce hyperexcitability in the medial prefrontal cortex and the temporoparietal junction, triggering this unique finger movement. Index-finger pointing posture is a mild and brief neurological sign that may be overlooked in patients with outstanding foot tremor, such as in the present case. Although tremor, myoclonus, and dystonia are induced by serotonergic drugs, abnormal single finger movements have not been reported. The present case highlights the broad clinical spectrum of serotonin toxicity-related movement disorders.\n\n4 Funding disclosure\n\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\n5 Patient consent form\n\nWe retained patient consent form to use case details and video tape of movement disorder.\n\nCRediT authorship contribution statement\n\nGohei Yamada: Conceptualization, Writing - original draft. Takanari Toyoda: Writing - review & editing. Eiichi Katada: Writing - review & editing. Noriyuki Matsukawa: Writing - review & editing.\n\nDeclaration of Competing Interest\n\nThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\n\nAppendix A Supplementary data\n\nThe following are the Supplementary data to this article:Supplementary video 1\n\nAppendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.prdoa.2021.100111.\n==== Refs\nReferences\n\n1 Ferando I. Soss J.R. Elder C. Shah V. Lo Russo G. Tassi L. Tassinari C.A. Engel J. Hand posture as localizing sign in adult focal epileptic seizures Ann. Neurol. 86 5 2019 793 800 31498917\n2 Vives-Rodriguez A. Louis E.D. Index finger pointing (likely a subtle form of hand dystonia): prevalence across movement disorders Front. Neurol. 9 542 2018\n3 Dunkley E.J.C. Isbister G.K. Sibbritt D. Dawson A.H. Whyte I.M. The hunter serotonin toxicity criteria: simple and accurate diagnostic decision rules for serotonin toxicity QJM: An International Journal of Medicine 96 9 2003 635 642 12925718\n4 Marsili L. Bologna M. Kojovic M. Berardelli A. Espay A.J. Colosimo C. Dystonia in atypical parkinsonian disorders Parkinsonism Relat Disord 66 2019 25 33 31443953\n5 Siegel J. Tatum W.O. Hand postures in primary and secondary generalized tonic-clonic seizures Neurology 87 17 2016 1802 1805 27664987\n6 Cleret de Langavant L. Remy P. Trinkler I. McIntyre J. Dupoux E. Berthoz A. Bachoud-Lévi A.-C. Sirigu A. Behavioral and neural correlates of communication via pointing PLoS ONE 6 3 2011 e17719 21423659\n\n",
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"keywords": "Drug-induced movement disorder; Index finger pointing posture; Paroxetine; Serotonin toxicity; Tramadol",
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"title": "Index finger pointing posture in a patient with drug-induced foot tremor.",
"title_normalized": "index finger pointing posture in a patient with drug induced foot tremor"
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"abstract": "BACKGROUND\nNewly developed antineoplastic drugs have resulted in improvements in morbidity and mortality from many forms of cancers. However, some of these new chemotherapeutic agents have potentially lethal side effects, which are now being exposed with their widespread use. Gemcitabine is a nucleoside analog, which is a commonly used agent for various solid organ malignancies. Phase 1 and 2 trials with gemcitabine did not show significant risk for cardiotoxicity; however, with its widespread clinical use over the last decade, a few cases of cardiotoxicity related to gemcitabine use have been reported. Cardiomyopathy after the use of gemcitabine monotherapy is extremely rare; and only one such case has been reported in detail previously.\n\n\nMETHODS\nWe report a case of a 56-year-old African American man with pancreatic cancer who presented with signs and symptoms of congestive heart failure after being treated with gemcitabine for two cycles (six doses). A two-dimensional echocardiography showed left ventricular ejection fraction of 15 to 20 percent with global hypokinesia. With the absence of significant risk factors for coronary artery disease and a strong temporal relationship with the initiation of chemotherapy, it was concluded that our patient's cardiomyopathy was related to the use of gemcitabine. Gemcitabine was discontinued and our patient responded well to standard heart failure therapy. Two months later, a repeat echocardiogram showed significant improvements in left ventricular systolic function.\n\n\nCONCLUSIONS\nGemcitabine should be considered as a potential cause of cardiomyopathy in patients receiving chemotherapy with this drug. We need further studies to look into potential mechanisms and treatments of gemcitabine-induced cardiac dysfunction.",
"affiliations": "Department of Medicine, Southern Arizona VA Health Care System, 3601 South 6th Avenue (SAVAHCS, 1-11C), Tucson, AZ 85723, USA. docfahadkhan@yahoo.com.",
"authors": "Khan|Muhammad F|MF|;Gottesman|Silvija|S|;Boyella|Ravichandra|R|;Juneman|Elizabeth|E|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; C056507:gemcitabine",
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"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central 1752-1947-8-2202495790510.1186/1752-1947-8-220Case ReportGemcitabine-induced cardiomyopathy: a case report and review of the literature Khan Muhammad F 1docfahadkhan@yahoo.comGottesman Silvija 1silvija@email.arizona.eduBoyella Ravichandra 2boyella@yahoo.comJuneman Elizabeth 2Elizabeth.Juneman@va.gov1 Department of Medicine, Southern Arizona VA Health Care System, 3601 South 6th Avenue (SAVAHCS, 1-11C), Tucson, AZ 85723, USA2 Department of Medicine, Division of Cardiology, Southern Arizona VA Health Care System, 3601 South 6th Avenue (SAVAHCS, 1-11C), Tucson, AZ 85723, USA2014 23 6 2014 8 220 220 10 1 2014 5 5 2014 Copyright © 2014 Khan et al.; licensee BioMed Central Ltd.2014Khan et al.; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Introduction\nNewly developed antineoplastic drugs have resulted in improvements in morbidity and mortality from many forms of cancers. However, some of these new chemotherapeutic agents have potentially lethal side effects, which are now being exposed with their widespread use. Gemcitabine is a nucleoside analog, which is a commonly used agent for various solid organ malignancies. Phase 1 and 2 trials with gemcitabine did not show significant risk for cardiotoxicity; however, with its widespread clinical use over the last decade, a few cases of cardiotoxicity related to gemcitabine use have been reported. Cardiomyopathy after the use of gemcitabine monotherapy is extremely rare; and only one such case has been reported in detail previously.\n\nCase presentation\nWe report a case of a 56-year-old African American man with pancreatic cancer who presented with signs and symptoms of congestive heart failure after being treated with gemcitabine for two cycles (six doses). A two-dimensional echocardiography showed left ventricular ejection fraction of 15 to 20 percent with global hypokinesia. With the absence of significant risk factors for coronary artery disease and a strong temporal relationship with the initiation of chemotherapy, it was concluded that our patient’s cardiomyopathy was related to the use of gemcitabine. Gemcitabine was discontinued and our patient responded well to standard heart failure therapy. Two months later, a repeat echocardiogram showed significant improvements in left ventricular systolic function.\n\nConclusions\nGemcitabine should be considered as a potential cause of cardiomyopathy in patients receiving chemotherapy with this drug. We need further studies to look into potential mechanisms and treatments of gemcitabine-induced cardiac dysfunction.\n\nGemcitabineCardiomyopathyCardiotoxicity\n==== Body\nIntroduction\nAnticancer therapy has emerged tremendously over the last few years. Newly available drugs and protocols have resulted in improvements in morbidity and mortality from many forms of cancers. However, these new antineoplastic drugs and protocols are not without potentially lethal side effects. It is therefore very important to recognize serious toxicities associated with some of these medications, so appropriate measures can be taken to avoid and manage such problems.\n\nGemcitabine is a nucleoside analog and a pyrimidine antimetabolite that inhibits deoxyribonucleic acid (DNA) synthesis by inhibition of DNA polymerase and ribonucleotide reductase [1]. It is a commonly used antineoplastic for various solid organ malignancies including advanced pancreatic, ovarian, breast, bladder and non-small cell lung cancers [2-7]. The Gastrointestinal Tumor Study Group Phase III trial has shown promising results and has led to the adoption of adjuvant chemoradiotherapy with gemcitabine as the standard of care for advanced pancreatic cancer [6].\n\nGemcitabine is generally well tolerated and is considered relatively safe as compared to many other chemotherapeutic agents. Its most common toxicities include myelosuppression, changes in gastrointestinal function (nausea, vomiting and diarrhea) and abnormalities in liver and renal function tests [8].\n\nPhase 1 and 2 studies with gemcitabine did not show significant risk for cardiotoxicity, however, with its widespread clinical use over the last decade, a few cases of acute myocardial infarction (AMI) and arrhythmias associated with gemcitabine use have been reported. Here, we report a case of a 56-year-old man with pancreatic cancer who developed dilated cardiomyopathy after being treated with gemcitabine.\n\nCase presentation\nA 56-year-old African American man who initially presented with diarrhea, weight loss and painless jaundice, was subsequently found to have adenocarcinoma of the head of pancreas. An initial workup revealed localized cancer with no evidence of distant metastases. He then underwent pancreaticoduodenectomy with complete surgical resection of a 5cm moderately differentiated pancreatic adenocarcinoma. Although our patient underwent complete surgical resection, a pathological examination revealed a neoplastic invasion of the resected adjacent organs, and one out of the seven resected lymph nodes contained cancer (T3N1M0). At that point, the oncology department recommended to proceed with adjuvant chemotherapy with gemcitabine (1000mg/m2 IV on days 1, 8, 15 on a 28-day cycle for six cycles) to try to reduce the likelihood of recurrence.\n\nHowever, after completing two cycles (a total of six doses) of chemotherapy, he presented to the emergency department with worsening exertional dyspnea, three-pillow orthopnea, paroxysmal nocturnal dyspnea and fatigue. His physical examination revealed an elevated jugular venous pressure (JVP) (10cm above the sternal angle), bibasilar rales and +2 pitting edema of both lower extremities. Cardiac auscultation revealed a gallop rhythm with an S3 and a grade 3 holosystolic murmur over precordium. A chest X-ray showed cardiomegaly with mild to moderate-sized right-sided pleural effusion. It was thought that his presentation was consistent with fluid overload secondary to congestive heart failure (CHF) and he was started on intravenous (IV) furosemide with partial improvement in his symptoms.\n\nThe next day, a two-dimensional echocardiography (2D Echo) was performed, which showed left ventricular ejection fraction (LVEF) of 15 to 20 percent with global hypokinesia along with moderate mitral regurgitation. Given the findings of 2D Echo and the absence of significant risk factors for coronary artery disease (CAD) and ischemic cardiomyopathy (CMP), it was concluded that our patient’s CMP was related to the recent use of gemcitabine. Our patient was then started on carvedilol and an angiotensin-converting enzyme inhibitor in addition to diuretics and he was discharged from the hospital two days later in a euvolemic state.\n\nAt that point, the cardiology department recommended stopping further chemotherapy with gemcitabine. The oncology department advised further testing to rule out ischemia as a cause of CMP as, in their opinion, chemotherapy with gemcitabine was the only option to reduce the risk of recurrence in this patient. Two weeks later, our patient underwent myocardial perfusion imaging (MPI), which showed a fixed small- to moderate-sized inferior wall defect without any evidence of active ischemia. The ejection fraction (EF) on MPI was calculated to be around 17 to 20 percent with severe global hypokinesia. Our patient was continued on standard heart failure therapy with one more admission to the hospital for CHF exacerbation about two months later. He responded well to IV furosemide and adjustment of heart failure therapy. A 2D Echo was repeated a few months later and it showed improvement in systolic function with an LVEF of 40 percent.\n\nDue to his poor functional status and underlying CMP, further gemcitabine chemotherapy was stopped. Later, our patient developed a recurrence of his pancreatic cancer; he refused further chemotherapy and decided to proceed with palliative care.\n\nAlthough the exact etiology of our patient’s dilated cardiomyopathy remains unclear, gemcitabine remains the most likely culprit. The temporal relationship of his symptoms to the initiation of gemcitabine chemotherapy; the lack of risk factors for ischemic CMP and prior history of CAD, finding of global hypokinesia on 2D Echo, absence of ischemia on MPI; and improvement in his systolic function after discontinuation of gemcitabine were all consistent with gemcitabine-induced cardiomyopathy.\n\nDiscussion\nGemcitabine is generally not considered as one of the cardiotoxic agents, and its cardiotoxicity has been very rarely reported in the literature. An overview of phase 1 trials of gemcitabine therapy revealed cardiac arrhythmias in 0.7 to 1.4 percent of the patients, significant reduction in LVEF in 0.2 percent of the patients and the development of exudative pericarditis in 0.2 percent of the patients [9].\n\nSimilarly, phase 2 trials of gemcitabine monotherapy did not show evidence of significant cardiotoxicity. To evaluate overall safety of gemcitabine, Aapro et al. reviewed 22 phase 2 clinical trials (a total of 979 patients) and found very low incidence of AMI (0.5 percent), CMP (0.4 percent), arrhythmias (0.2 percent) and only one case of mild pericarditis [8]. Among the cardiomyopathy cases, one patient had World Health Organization (WHO) grade 4 toxicity indicating symptomatic cardiac dysfunction not responding to conventional therapy. The other three cases of CHF had WHO grade 3 toxicity, manifesting as symptomatic systolic dysfunction, which responded to therapy [8]. Since the publication of the above mentioned review, we could find two additional cases of heart failure [10,11], four cases of AMI [10,12-14] and one case of supraventricular tachycardia (SVT) [15] in phase 2 gemcitabine trials [Table 1]. In a recent review of the French PharmacoVigilance Database (FPVD), Montastruc et al. also found a potential association between dilated cardiomyopathy and chemotherapy with gemcitabine [16].\n\nTable 1 Case reports of cardiotoxicity with gemcitabine monotherapy\n\nAuthor\tDemography\tDose of gemcitabine\tDuration of treatment\tSide effect\tHistory of CAD\tTiming\tOutcome\tProbability\t\nOzturk \net al. [17]\t59F with metastatic leiomyosarcoma\t900mg/m2\t8 days\tCoronary vasospasm\tYes\t30 minutes after infusion\tSurvived. Gemcitabine therapy stopped\tStrong\t\nBdair \net al\n. [18]\t43F with metastatic NSCLC\t1000mg/m2\t7 weeks\tNSTEMI VT\tYes\t3 days after infusion\tSurvived. Gemcitabine therapy stopped\tWeak\t\nKalapura \net al\n. [19]\t54M with metastatic pancreatic cancer\t1900mg\t5th cycle\tNSTEMI\tNo CAD, no risk factors\t6 hours after infusion\tSurvived. Recurrent symptoms with 7th cycle\tStrong\t\nTayer-Shifman et al. [20]\t67F with metastatic ductal carcinoma of breast\t1000-1400mg/m2\t3rd cycle\tSVT/AVNRT\tNo CAD, no risk factors\tHours after infusion\tSurvived. Gemcitabine therapy stopped\tStrong\t\nSantini et al. [21]\t78M with pancreatic adenocarcinoma\tNK\t1st cycle\tAF\tHistory of AF in the past\t18-22 hours after the infusion\tSurvived 6 total episodes of AF 18-22 hours after the infusion\tStrong\t\nFerrari et al. [22]\t72F with metastatic lung adenocarcinoma\t1200mg/m2\t1st cycle\tAF\tNo history of AF\t18 hours after the infusion\tSurvived 3 total episodes of AF each after 18 hours of infusion\tStrong\t\nFerrari et al. [22]\t73F with NSCLC\t1200mg/m2\t3rd cycle\tAF\tNo history of AF\t12 hours after the infusion\tSurvived. Gemcitabine stopped\tStrong\t\nTavil et al. [23]\t65M with NSCLC\t1200mg/m2\t2nd cycle\tAF\tNo history of AF\t7 hours after the infusion\tGemcitabine stopped\tStrong\t\nCiotti et al. [24]\t70M with metastatic pancreatic adenocarcinoma\tNK\t1st cycle\tAF\tNo history of AF\t6 days after the infusion\tAF recurred with further therapy\tStrong\t\nYajima et al. [25]\t82F with advanced pancreatic carcinoma\t16, 800mg-total dose\tTwo years of treatment\tHF\tNK\t2 years\tGemcitabine stopped\tWeak\t\nKhan et al. [present case]\t56M with pancreatic adenocarcinoma\t1000mg/m2\tTwo cycles (2 months)\tCMP/HF\tNo prior history of CHF/CAD\t2 months\tGemcitabine stopped, partial recovery\tStrong\t\nCAD, coronary artery disease; F, female; NSCLC, non-small cell lung cancer; NSTEMI, non-ST elevation myocardial infarction; VT, ventricular tachycardia; M, male; SVT, supraventricular tachycardia; AVNRT, AV nodal re-entrant tachycardia; NK, not known; AF, atrial fibrillation; HF, heart failure; CMP, cardiomyopathy; CHF, congestive heart failure.\n\nBased on the review of medical literature, cardiotoxicity of gemcitabine can be divided into acute toxicities and chronic toxicities.\n\nAcute toxicities include arrhythmias and myocardial ischemia or infarction. In almost all the cases, AMI developed within few hours to a couple of days after gemcitabine infusion. The longest time interval between gemcitabine infusion and the development of AMI was reported to be six days, however in that case, the association of the AMI to gemcitabine therapy was weak. The exact reasons of gemcitabine-induced acute coronary syndrome are not clear, however, authors have speculated a direct endothelial injury resulting in coronary thrombosis or gemcitabine-induced vascular spasm as possible underlying mechanisms. The evidence for prothrombotic and procoagulant effects of gemcitabine comes from several reports of occurrence of vascular events (like thrombotic microangiopathies, strokes, visceral infractions and vasculitides) in association with gemcitabine infusion [26]. Furthermore, in one other study of gemcitabine monotherapy for cutaneous T-cell lymphoma, authors noticed higher incidence of thrombosis and vascular events in patients treated with gemcitabine [10]. Vasospasm was proposed as a cause of chest pain and new-onset left bundle branch block in a patient who developed these symptoms during gemcitabine infusion. Vasospasm then resolved within 10 minutes of antianginal therapy and serological markers for myocardial damage remained negative [17]. Interestingly, all the patients who developed AMI related to gemcitabine therapy had pre-existing CAD. Two of these patients were already on appropriate antianginal medications before they experienced gemcitabine-related myocardial ischemia [17,18]. In another patient with a previous episode of gemcitabine-induced myocardial ischemia, the next gemcitabine infusion was started concomitantly with IV nitroglycerine and beta blockers [19]. However, despite these measures he continued to have recurrent ischemic symptoms with further gemcitabine treatments.\n\nSVTs including atrial fibrillation (AF) have been rarely reported as a manifestation of gemcitabine cardiotoxicity. In contrast to AMI, where most of the patients had underlying CAD, only one of the patients who developed AF related to gemcitabine infusion had previous history of AF [21]. Almost all the SVT episodes developed six to 18 hours after the administration of gemcitabine infusion. Based on this observation, some authors have argued that direct myocardial toxicity from an active metabolite of 2′,2′-difluorodeoxyuridine (which has a half-life of 18 to 24 hours) is likely responsible for these electrical disturbances [21,22]. With the exception of one patient who remained in AF at the time of discharge [22], sinus rhythm could be restored in all of the other patients. Patients who underwent chemical cardioversion (amiodarone or propafenone) converted to sinus rhythm within two hours of onset of AF. Those who were treated conservatively with rate control strategy converted spontaneously to sinus rhythm on the average two days after the presentation. Three patients suffered recurrent AF episodes with further gemcitabine infusions [21,22,24], and two of them had recurrence of AF despite being on prophylactic antiarrhythmics [21,24].\n\nCMP is among the frequently reported cardiotoxicity for many chemotherapeutic agents like anthracyclines, but it has been rarely encountered with gemcitabine monotherapy. The cardiomyopathy seems to develop after a few months to years of treatments with gemcitabine. The exact mechanisms of myocardial damage, and the total dose of gemcitabine required to induce myocardial toxicity are unknown. Most of the patients in phase 1 and 2 clinical trials who developed gemcitabine-induced CMP had underlying CAD. Although our patient did not have known CAD or CAD risk factors, it is still possible that he had a prior silent event (a fixed inferior wall defect on MPI). However, a fixed inferior wall defect did not explain severely depressed left ventricular (LV) systolic function and global hypokinesia seen on 2D Echo. Given the fact that his heart failure symptoms started after the initiation of gemcitabine, we strongly suspected gemcitabine cardiotoxicity as a cause of his CMP. This argument is further affirmed by the fact that his LV systolic function improved significantly after the discontinuation of gemcitabine and the initiation of appropriate treatment.\n\nGemcitabine has also been implicated in the development of exudative pericardial effusions. Four cases of symptomatic and hemodynamically significant pericardial effusions requiring drainage were reported by Vogl et al. [27]. All of these patients were exposed to unblocked cardiac radiations in the past, and all these patients had pericardial abnormalities seen on echocardiography before the initiation of gemcitabine chemotherapy. The authors concluded that gemcitabine therapy in these patients resulted in radiation recall reaction, that is, gemcitabine recalled previous radiation-related inflammation in the pericardium.\n\nConclusions\nIn our opinion, gemcitabine-induced cardiotoxicity should be considered as a potential cause of arrhythmias, ischemia or cardiomyopathy in patients receiving chemotherapy with this drug. We need further studies to look into the potential mechanisms of gemcitabine-induced cardiac dysfunction. In the case of toxicity, discontinuation of further therapy with gemcitabine appears to be the next appropriate step in the management.\n\nConsent\nWritten informed consent for publication could not be obtained from the patient as he has died and the next-of-kin could not be contacted despite all reasonable attempts. However, every effort has been made to protect patient anonymity and there is no reason to think that the patient or family would object to publication.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\nMK contributed to the concept/design of the study, data collection, data analysis/interpretation, drafting the manuscript, critical revision of the manuscript, preparation and approval of the manuscript. SG contributed to the concept/design of the study, data collection, drafting the manuscript, approval and preparation of the manuscript. RB contributed to the data analysis/interpretation, critical revision of the manuscript, approval and preparation of the manuscript. EJ contributed to the data analysis/interpretation, critical revision of the manuscript, approval and preparation of the manuscript.\n==== Refs\nPlunkett W Huang P Xu YZ Heinemann V Grunewald R Gandhi V Gemcitabine: metabolism, mechanisms of action, and self-potentiation Semin Oncol 1995 22 Suppl 11 3 10 7481842 \nCarmichael J Fink U Russell RC Spittle MF Harris AL Spiessi G Blatter J Phase II study of gemcitabine in patients with advanced pancreatic cancer Br J Cancer 1996 73 101 105 8554969 \nAbratt RP Bezwoda WR Falkson G Goedhals L Hacking D Rugg TA Efficacy and safety profile of gemcitabine in non-small-cell lung cancer: a phase II study J Clin Oncol 1994 12 1535 1540 8040664 \nGatzemeier U Groth G Butts C Van Zandwijk N Shepherd F Ardizzoni A Barton C Ghahramani P Hirsh V Randomized phase II trial of gemcitabine-cisplatin with or without trastuzumab in HER2-positive non-small-cell lung cancer Ann Oncol 2004 15 19 27 14679114 \nLorusso V Crucitta E Silvestris N Catino A Caporusso L Mazzei A Guida M Latorre A Sambiasi D D’Amico C Schittulli F Calabrese P De Lena M Phase I/II study of gemcitabine plus mitoxantrone as salvage chemotherapy in metastatic breast cancer Br J Cancer 2003 88 491 495 12592360 \nMattiucci GC Ippolito E D’Agostino GR Alfieri S Antinori A Crucitti A Balducci M Deodato F Luzi S Macchia G Smaniotto D Morganti AG Valentini V Long-term analysis of gemcitabine-based chemoradiation after surgical resection for pancreatic adenocarcinoma Ann Surg Oncol 2013 20 423 429 23208130 \nvon der Maase H Hansen SW Roberts JT Dogliotti L Oliver T Moore MJ Bodrogi I Albers P Knuth A Lippert CM Kerbrat P Sanchez Rovira P Wersall P Cleall SP Roychowdhury DF Tomlin I Visseren-Grul CM Conte PF Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study J Clin Oncol 2000 18 3068 3077 11001674 \nAapro MS Martin C Hatty S Gemcitabine-a safety review Anticancer Drugs 1998 9 191 201 9625429 \nStorniolo AM Allerheiligen SR Pearce HL Preclinical, pharmacologic, and phase I studies of gemcitabine Semin Oncol 1997 24 Suppl 7 2 7 \nDuvic M Talpur R Wen S Kurzrock R David CL Apisarnthanarax N Phase II evaluation of gemcitabine monotherapy for cutaneous T-cell lymphoma Clin Lymphoma Myeloma 2006 7 51 58 16879770 \nJidar K Ingen-Housz-Oro S Beylot-Barry M Paul C Chaoui D Sigal-Grinberg M Morel P Dubertret L Bachelez H Gemcitabine treatment in cutaneous T-cell lymphoma: a multicentre study of 23 cases Br J Dermatol 2009 161 660 663 19438862 \nDumontet C Morschhauser F Solal-Celigny P Bouafia F Bourgeois E Thieblemont C Leleu X Hequet O Salles G Coiffier B Gemcitabine as a single agent in the treatment of relapsed or refractory low-grade non-Hodgkin’s lymphoma Br J Haematol 2001 113 772 778 11380469 \nGridelli C Perrone F Gallo C Rossi A Barletta E Barzelloni ML Creazzola S Gatani T Fiore F Guida C Scognamiglio F Single-agent gemcitabine as second-line treatment in patients with advanced non small cell lung cancer (NSCLC): a phase II trial Anticancer Res 1999 19 4535 4538 10650806 \nNeubauer MA Reynolds CH Joppert MG Whitaker T Ghaddar H Marsland TA Asmar L Results of a phase II trial of gemcitabine in patients with non-small-cell lung cancer and a performance status of 2 Clin Lung Cancer 2005 6 245 249 15694017 \nPoon D Foo KF Chew L Leong SS Wee J Tan EH Phase II trial of gemcitabine and cisplatin sequentially administered in Asian patients with unresectable or metastatic non-small cell lung cancer Ann Acad Med Singapore 2006 35 33 37 16470272 \nMontastruc G Favreliere S Sommet A Pathak A Lapeyre-Mestre M Perault-Pochat MC Montastruc JL Drugs and dilated cardiomyopathies: a case/noncase study in the French PharmacoVigilance database Br J Clin Pharmacol 2010 69 287 294 20233200 \nOzturk B Tacoy G Coskun U Yaman E Sahin G Buyukberber S Yildiz R Kaya AO Topal S Ozdemir M Benekli M Gemcitabine-induced acute coronary syndrome: a case report Med Princ Pract 2009 18 76 80 19060498 \nBdair FM Graham SP Smith PF Javle MM Gemcitabine and acute myocardial infarction–a case report Angiology 2006 57 367 371 16703198 \nKalapura T Krishnamurthy M Reddy CV Acute myocardial infarction following gemcitabine therapy-a case report Angiology 1999 50 1021 1025 10609769 \nTayer-Shifman OE Rottenberg Y Shuvy M Gemcitabine-induced supraventricular tachycardia Tumori 2009 95 547 549 19856675 \nSantini D Tonini G Abbate A Di Cosimo S Gravante G Vincenzi B Gemcitabine-induced atrial fibrillation: a hitherto unreported manifestation of drug toxicity Ann Oncol 2000 11 479 481 10847470 \nFerrari D Carbone C Codeca C Fumagalli L Gilardi L Marussi D Tartaro T Oldani S Zannier F Foa P Gemcitabine and atrial fibrillation: a rare manifestation of chemotherapy toxicity Anticancer Drugs 2006 17 359 361 16520666 \nTavil Y Arslan U Okyay K Sen N Boyaci B Atrial fibrillation induced by gemcitabine treatment in a 65-year-old man Onkologie 2007 30 253 255 17460420 \nCiotti R Belotti G Facchi E Cantu A D’Amico A Gatti C Sudden cardio-pulmonary toxicity following a single infusion of gemcitabine Ann Oncol 1999 10 997 10509166 \nYajima T Furukawa Y Ishii Y Hattori Y Matsumoto N Yamamoto M Yamaoka Y Fujihara M Fujita M Kuniki H Two cases of advanced pancreatic cancer responding to gemcitabine with long survival of 2 years Gan To Kagaku Ryoho 2004 31 953 957 15222120 \nDasanu CA Gemcitabine: vascular toxicity and prothrombotic potential Expert Opin Drug Saf 2008 7 703 716 18983217 \nVogl DT Glatstein E Carver JR Schuster SJ Stadtmauer EA Luger S Nasta SD Porter DL Elstrom R Tsai DE Gemcitabine-induced pericardial effusion and tamponade after unblocked cardiac irradiation Leuk Lymphoma 2005 46 1313 1320 16109609\n\n",
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"mesh_terms": "D000964:Antimetabolites, Antineoplastic; D009202:Cardiomyopathies; D066126:Cardiotoxicity; D003841:Deoxycytidine; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms; D014463:Ultrasonography; D018487:Ventricular Dysfunction, Left",
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"title": "Gemcitabine-induced cardiomyopathy: a case report and review of the literature.",
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"abstract": "Post-transplant lymphoproliferative disorder (PTLD) is a fatal complication of transplantation. There is no clear consensus on the treatment of PTLD. In most cases, the pathogenetic mechanism of PTLD involves the Epstein-Barr virus (EBV). We report the case of an elderly kidney transplant recipient who developed EBV-positive monomorphic T-cell PTLD 14 years after transplantation. Conversion from conventional immunosuppressants to everolimus induced complete remission of PTLD accompanied by a decrease in blood EBV-DNA level without chemotherapy.",
"affiliations": "Surgical Branch, Institute of Kidney Diseases, Jichi Medical University Hospital, Shimotsuke, Japan.;Surgical Branch, Institute of Kidney Diseases, Jichi Medical University Hospital, Shimotsuke, Japan.;Surgical Branch, Institute of Kidney Diseases, Jichi Medical University Hospital, Shimotsuke, Japan.;Surgical Branch, Institute of Kidney Diseases, Jichi Medical University Hospital, Shimotsuke, Japan.;Surgical Branch, Institute of Kidney Diseases, Jichi Medical University Hospital, Shimotsuke, Japan.",
"authors": "Nanmoku|Koji|K|https://orcid.org/0000-0003-3987-4832;Shinzato|Takahiro|T|;Kubo|Taro|T|;Shimizu|Toshihiro|T|;Yagisawa|Takashi|T|",
"chemical_list": "D007166:Immunosuppressive Agents; D000068338:Everolimus",
"country": "Denmark",
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"doi": "10.1111/tid.13116",
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"issue": "21(4)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "Epstein-Barr virus-DNA; kidney transplantation; mammalian target of rapamycin inhibitor",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000368:Aged; D020031:Epstein-Barr Virus Infections; D000068338:Everolimus; D004854:Herpesvirus 4, Human; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008232:Lymphoproliferative Disorders; D008297:Male; D011183:Postoperative Complications; D012074:Remission Induction; D066027:Transplant Recipients",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13116",
"pmc": null,
"pmid": "31102475",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Remission of Epstein-Barr virus-positive post-transplant lymphoproliferative disorder by conversion to everolimus in a kidney transplant recipient.",
"title_normalized": "remission of epstein barr virus positive post transplant lymphoproliferative disorder by conversion to everolimus in a kidney transplant recipient"
} | [
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"companynumb": "JP-PFIZER INC-2019389694",
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"abstract": "Background: Neovascular glaucoma (NVG) is a severe, potentially blinding disease and a therapeutic challenge. The purpose of this study was to evaluate the safety and efficacy of an integrative surgical approach to neovascular glaucoma. Methods: Retrospective analysis of a one-year follow-up of a consecutive interventional case series of NVG. Eyes underwent transscleral cyclophotocoagulation, pars plana vitrectomy, near-confluent panretinal photocoagulation, and intravitreal bevacizumab. Phakic eyes underwent concomitant cataract surgery. Best-corrected visual acuity (BCVA, logMAR), intraocular pressure (IOP, mmHg), number of glaucoma medication, visual analog pain scale (VAPS, 0-10) were recorded at baseline, and 1, 3, 6, and 12 months. Blind eyes were excluded. Results: Seventy-seven eyes of 77 patients (45 male, 32 female, mean age 73.6±12.2 years) were included. NVG underlying conditions included retinal vein occlusion (41.6%), proliferative diabetic retinopathy (35.1%), central retinal artery occlusion (19.5%), and ocular ischemic syndrome (3.9%). Mean IOP decreased postoperatively from 46.3±10.1 mmHg to 14.5±7.9 mmHg (p<0.001), glaucoma medication from 4.7±1.3 to 1.8±1.8 (p<0.001), and VAPS from 6.0±1.8 to 0. BCVA remained unchanged. Postoperative intraocular inflammation had resolved in all eyes at the one-month follow-up. 71.4% (55/77) eyes did not require additional major interventions during follow-up. Conclusions: A single, comprehensive surgery session lowered IOP significantly, reduced GMS, and controlled pain.",
"affiliations": "Department of Ophthalmology, School of Medicine, University Hospital Wuerzburg, 97080, Germany.;Department of Ophthalmology, School of Medicine, University Hospital Wuerzburg, 97080, Germany.;Department of Ophthalmology, School of Medicine, University Hospital Wuerzburg, 97080, Germany.;Department of Ophthalmology, School of Medicine, University Hospital Wuerzburg, 97080, Germany.;Department of Ophthalmology, School of Medicine, University Hospital Wuerzburg, 97080, Germany.",
"authors": "Strzalkowski|Piotr|P|;Strzalkowska|Alicja|A|;Göbel|Winfried|W|;Loewen|Nils A|NA|0000-0001-7167-1213;Hillenkamp|Jost|J|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab",
"country": "England",
"delete": false,
"doi": "10.12688/f1000research.26879.2",
"fulltext": "\n==== Front\nF1000Res\nF1000Res\nF1000Research\nF1000Research\n2046-1402\nF1000 Research Limited London, UK\n\n10.12688/f1000research.26879.2\nResearch Article\nArticles\nCombined vitrectomy, near-confluent panretinal endolaser, bevacizumab and cyclophotocoagulation for neovascular glaucoma — a retrospective interventional case series\n[version 2; peer review: 2 approved]\n\nStrzalkowski Piotr Conceptualization Data Curation Investigation Methodology Writing – Original Draft Preparation a1\nStrzalkowska Alicja Data Curation Investigation Methodology Writing – Original Draft Preparation 1\nGöbel Winfried Writing – Review & Editing 1\nLoewen Nils A. Supervision Validation Writing – Original Draft Preparation Writing – Review & Editing https://orcid.org/0000-0001-7167-1213\n1\nHillenkamp Jost Methodology Supervision Validation Writing – Original Draft Preparation Writing – Review & Editing 1\n1 Department of Ophthalmology, School of Medicine, University Hospital Wuerzburg, 97080, Germany\na strzalkows_p@ukw.de\nNo competing interests were disclosed.\n\n2 3 2021\n2020\n9 123626 2 2021\nCopyright: © 2021 Strzalkowski P et al.\n2021\nThis is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\n\nBackground: Neovascular glaucoma (NVG) is a severe, potentially blinding disease and a therapeutic challenge. The purpose of this study was to evaluate the safety and efficacy of an integrative surgical approach to neovascular glaucoma.\n\nMethods: Retrospective analysis of a one-year follow-up of a consecutive interventional case series of NVG. Eyes underwent transscleral cyclophotocoagulation, pars plana vitrectomy, near-confluent panretinal photocoagulation, and intravitreal bevacizumab. Phakic eyes underwent concomitant cataract surgery. Best-corrected visual acuity (BCVA, logMAR), intraocular pressure (IOP, mmHg), number of glaucoma medication, visual analog pain scale (VAPS, 0-10) were recorded at baseline, and 1, 3, 6, and 12 months. Blind eyes were excluded.\n\nResults: Seventy-seven eyes of 77 patients (45 male, 32 female, mean age 73.6±12.2 years) were included. NVG underlying conditions included retinal vein occlusion (41.6%), proliferative diabetic retinopathy (35.1%), central retinal artery occlusion (19.5%), and ocular ischemic syndrome (3.9%). Mean IOP decreased postoperatively from 46.3±10.1 mmHg to 14.5±7.9 mmHg (p<0.001), glaucoma medication from 4.7±1.3 to 1.8±1.8 (p<0.001), and VAPS from 6.0±1.8 to 0. BCVA remained unchanged. Postoperative intraocular inflammation had resolved in all eyes at the one-month follow-up. 71.4% (55/77) eyes did not require additional major interventions during follow-up.\n\nConclusions: A single, comprehensive surgery session lowered IOP significantly, reduced GMS, and controlled pain.\n\nNeovascular glaucoma\nintegrative surgical approach\niris neovascularization\nThe author(s) declared that no grants were involved in supporting this work.Revised Amendments from Version 1\n\nWe are grateful for the opportunity to improve our manuscript. We appreciate the helpful comments and have provided our replies below. We trust that we were able to address the concerns that were raised. In the Introduction, second paragraph, we changed the phrasing. “In 1994, Miller et al. showed that laser occlusion of all branch retinal veins in a primate could lead to CRVO and subsequent retinal ischemia.” In the Results “arterial hypertension” was changed to hypertension as this is the currently accepted terminology. In Table 1 and in the manuscript– we changed “R stadium” to “NVI stage” We clarified in the results, that all 3 patients with a retinal detachment consecutively developed a painless phthisis bulbi. To provide comparison to our study we added a literature overview (Table 3) of different surgical approaches. In the Discussion regarding NVI stage and interventions, we added, that “there was no difference between stage 2 and stage 3”. Further we added more details on trabeculectomy in NVG.\n==== Body\nIntroduction\n\nNeovascular glaucoma (NVG) is a serious complication of a variety of ocular and systemic conditions. Neovascularization is the formation of abnormal blood vessels in an abnormal location triggered by an imbalance of anti-angiogenic and proangiogenic factors caused by retinal ischemia 1. NVG accounts for 3.9 to 9.2% of all new glaucoma diagnoses 2– 4. According to the Federal Statistical Office of Germany, NVG’s age-specific incidence in Germany in the age group from 45 to 64 years is 8 per 100,000. It increases to 24 per 100,000 in subjects older than 64 years 5. The incidence of NVG varies depending on the etiology of retinal ischemia. For central retinal vein occlusion (CRVO) the reported incidence is 16% 6, for proliferative diabetic retinopathy (PDR) 21.3% 7, for central retinal artery occlusion (CRAO) 14.5% 8, and ocular ischemic syndrome (OIS) 12.9% 9, respectively. Carotid artery obstructive disease and fistulas are additional, extraocular vascular causes of retinal ischemia 10. Early recognition and treatment of NVG are imperative to prevent aggressive evolution with severe vision loss and intractable pain that can require enucleation within a few months 11. NVG also carries a poor prognosis for general health: remarkably, the expected lifespan of patients with NVG decreased by 52% compared to an age-correlated normal population, which corresponds to 6.5 years. In diabetics with NVG, the expected lifespan was reduced even more significantly by 72% (5.1 years in this subgroup) 12.\n\nIn 1994, Miller et al. showed that retinal laser coagulation of primates could lead to CRVO and subsequent retinal ischemia with iris neovascularization 13. In this model, neovascularization was mediated by vascular endothelial growth factor (VEGF) and correlated to its concentration. Several members of the VEGF family have since been identified, including VEGFA, VEGFB, VEGFC, VEGFD, and the placental growth factor (PLGF) with specific receptor-binding patterns. VEGFA primarily binds to VEGFR2, the activation of which stimulates neovascularization, relevant to NVG, and angiogenesis, the formation of normal blood vessels in normal development. In the eye, VEGF-A is produced by the retinal pigment epithelium, retinal ganglion cells, astrocytes, the endothelium, photoreceptors, and Müller cells 14– 17. Retinal hypoxia upregulates VEGF primarily via the hypoxia-inducible factor (HIF-1α and HIF-2α). The concentration of HIF increases when hydroxylases are inhibited during hypoxia so that HIF is not degraded by the proteasome 18. HIF binds to the hypoxia-responsive element (HRE) of the VEGF gene in the nucleus leading to its upregulation 19.\n\nAlthough the mechanism by which NVG emerges is hence relatively well understood, there is no consensus on how to best initiate treatment to address the different aspects. Treatment steps include lowering of IOP (topical and systemic glaucoma medications, glaucoma drainage implants, cyclodestruction) 20– 24, anti-inflammatory treatment (topical or intraocular steroids), reduction of retinal ischemia (panretinal photocoagulation (PRP)) 25, 26, and inhibition of VEGF 27– 29. Vitrectomy with PRP and silicone oil tamponade may also reduce IOP in eyes with NVG 30, 31.\n\nHere, we evaluated the safety and efficacy of an integrative combined surgical approach for evolving NVG that combined pars plana vitrectomy, near-confluent full-scatter panretinal photocoagulation, off-label use of intravitreal bevacizumab, and transscleral cyclophotocoagulation in a single surgical session. We hypothesized that such a combined surgical approach for NVG would reduce IOP, medication, pain, reduce the number of necessary outpatient visits, and prevent the necessity of further surgeries.\n\nMethods\n\nEthical statement\n\nOur retrospective study was reviewed and approved by the Ethics Committee of the University of Würzburg (reference: 9/17-sc, dated February 3, 2017) and a clearance certificate for retrospective data evaluation was issued (reference: 20180108 02, dated January 30, 2018). For retrospective anonymized data analysis, patient’s consent was not necessary. The Declaration of Helsinki, the Good Clinical Practice (GCP) guidelines and applicable data protection regulations were complied with.\n\nStudy design\n\nWe included all patients between October 2014 and August 2019 with NVG who met the inclusion criteria in this consecutive interventional case series.\n\nInclusion criteria were: 1) neovascularization of iris (NVI) or neovascularization of the angle (NVA), 2) IOP > 21 mmHg, 3) best-corrected visual acuity (BCVA, logMAR) ≧ light perception, and 4) 18 years or older.\n\nAll patients were treated at the University Eye Hospital in Würzburg, Germany. The combined intervention was part of routine patient care at our clinic and all patients with decompensated neovascular glaucoma and preserved visual function received this intervention. BCVA, intraocular pressure (IOP, mmHg), the number of glaucoma medication, visual analog pain scale (VAPS, 0-10) was recorded at baseline and at follow-up visits at one, three, six, and 12 months as part of routine care. Iris and anterior chamber neovascularization were graded using the Weiss and Gold rubeosis grading system 32. Hypotony was defined as IOP ≤ 5 mmHg with hypotonous maculopathy, choroidal folds, or optic neuropathy 33. Phthisis bulbi 34 was defined as IOP ≤ 5 mmHg in a shrunken eye with worse than hand motion vision with or without pain containing atrophic and disorganized intraocular structures. Success was defined as lOP ≤ 21 mmHg or IOP reduction ≥ 30% from baseline, with or without glaucoma medication and without vision loss 35.\n\nAll patients underwent decimal visual acuity testing, which was converted to a logMAR scale. Counting fingers (CF), hand movements (HM), light perception (LP), and no light perception (NLP) were converted into logMAR units 1.9, 2.3, 2.7, and 3.0, respectively 36.\n\nWe retrospectively analyzed all patients treated with neovascular glaucoma at our clinic via the electronic hospital information system SAP®. The medical records of the treated patients were analyzed individually. The initial diagnosis of neovascular glaucoma and hospitalization served as the starting point. The cardiovascular risks were taken from the anesthesia premedication form.\n\nPatient treatment and follow-up\n\nSurgical technique. All eyes underwent transscleral cyclophotocoagulation (810 nm diode laser, 360 degrees treatment to pop threshold with 20 spots and leaving out 3 and 9 o’clock), standard 3-port 23 gauge pars plana vitrectomy with a detachment of the posterior vitreous if not already present, near-confluent full-scatter panretinal photocoagulation (PRP) applied under indentation in all four quadrants from the vascular arcades to the ora serrata, intravitreal application of 0,1 mL of bevacizumab (Avastin®️ 25 mg/1 mL, Roche Pharma, Switzerland), and air tamponade. Phakic eyes underwent concomitant cataract surgery. The operation was carried out either with a retrobulbar block or general anesthesia.\n\nRetreatment. At follow-up, all eyes with elevated IOP were treated following an escalation scheme. First, glaucoma medications were increased to what was maximally tolerated. Eyes were then treated with transscleral cyclophotocoagulation (810 nm diode laser, 360 degrees treatment to pop threshold with 20 spots). Eyes that failed to respond to cyclophotocoagulation with a significant IOP reduction and had retained ambulatory visual acuity underwent tube shunt surgery. Repeated vitrectomy, including fill-in PRP, transscleral cyclophotocoagulation, and off-label use of intravitreal bevacizumab was applied to eyes with elevated IOP and dense vitreous hemorrhage. Fill-in PRP was applied when PRP could not be completed during surgery in eyes with extensive intraretinal hemorrhage. Further intravitreal injections of VEGF inhibitors were only applied for clinically significant non-ischemic macular edema and BCVA ≥1.1 logMAR.\n\nPatients lost to follow-up. All patients who failed to attend follow-up visits completed a standardized telephone survey that contained the following questions: What was the main reason for not following up? What is your current vision function? How many glaucoma drops are you using? Do you have any eye pain? Are you overall satisfied with the outcome of the treatment?\n\nStatistical methods\n\nData analysis was performed using Statistica 13.1 (Tulsa, Oklahoma, United States). The frequency of observations described categorical variables. Continuous variables were described as mean with standard deviation (SD) or median with range (minimum-maximum). Friedman test and Wilcoxon signed-rank test were used to compare data measured on an ordinal scale and continuous variables with non-normal distribution. Evaluation of data normality was performed using the Shapiro-Wilk test. Welch’s t-test for unequal variances was used for IOP between pain versus no-pain group comparison. Categorical variables of the relationship between neovascularization stage and type of intervention were compared using the χ2 test with odds ratio (OR) measurement. Kaplan–Meier curve and log-rank test were used for success analysis. P-values <0.05 were considered significant.\n\nAn earlier version of this article can be found on medRxiv (doi: https://doi.org/10.1101/2020.01.19.20017889)\n\nResults\n\nAll 77 patients (45 male, 32 female, mean 73.6±12.2 years, range 29–91 years) completed a one-year follow-up and were included in the retrospective analysis ( Figure 1). Conditions that lead to NVG included CRVO 41.6% (32/77), PDR 35.1% (27/77), CRAO 19.5% (15/77), and ocular ischemic syndrome 3.9% (3/77) 37 ( Table 1).\n\nFigure 1. Flow chart.\n\nEyes with no light perception and patients with a history of glaucoma other than neovascular glaucoma were excluded. *Telephone survey with all patients lost to follow-up.\n\nTable 1. Demographic characteristics of neovascular glaucoma patients.\n\nVariables\tn = 77\t\nAge (years)\t73.6±12.2 (range 29–91)\t\nGender\tn (%)\t\n Female\t32 (41.6)\t\n Male\t45 (58.4)\t\nLaterality\tn (%)\t\n Right\t34 (44.2)\t\n Left\t43 (55.8)\t\nDiagnosis\tn (%)\t\n CRAO\t15 (19.5)\t\n CRVO\t32 (41.6)\t\n PDR\t27 (35.1)\t\n OIS\t3 (3.9)\t\nBMI (kg/m 2)\tn (%)\t\n <18.5\t1 (1.3)\t\n 18.5-24.9\t19 (24.7)\t\n 25-29.9\t31 (40.3)\t\n 30-34.9\t19 (24.7)\t\n >35\t7 (9.1)\t\nNVI stage\tn (%)\t\n Stage 1\t0 (0)\t\n Stage 2\t9 (11.7)\t\n Stage 3\t26 (33.8)\t\n Stage 4\t42 (54.5)\t\nBMI, body mass index; CRAO, central retinal artery occlusion; CRVO, central retinal vein occlusion; PDR, proliferative diabetic retinopathy; OIS, ocular ischemic syndrome.\n\nThe most common cardiovascular risk factor was hypertension 87.0% (67/77), followed by hyperlipidemia 67.5% (52/77), diabetes mellitus 59.7% (46/77), and smoking 11.7% (9/77). While one patient did not have any cardiovascular risk factors, 24.7% (19/77) had at least one risk factor, and 74.0% (57/77) had multiple risk factors.\n\nThe mean body mass index (BMI kg/m²) for the study group was 28.7±5.0 (underweight ≤ 18.5, normal weight = 18.5–24.9, overweight = 25–29.9, obesity ≥ 30 38). 1.3% (1/77) were underweight, 24.7% (19/77) had a normal weight, 40.3% were overweight (31/77) and 33,8% (26/77) obese.\n\nMean logMAR BCVA was 1.9±0.7 at baseline,1.7±0.8 at one month, 1.8±0.8 at three months, 1.8±0.8 at six months, and 1.8±0.8 at 12 months (p=0.47, Figure 2). At baseline, 35.1% (27/77) of patients and at 12 months, 45.5% (35/77) of patients had an ambulatory visual acuity (≥ logMAR 1.7), respectively, but was not statistically significant (p=0.0931). One eye worsened from LP to NLP at one week, three eyes at six months, and three eyes at 12 months.\n\nFigure 2. Visual acuity during follow-up (mean ± SD) (p=0.47).\n\nIOP decreased significantly from 46.3±10.1 mmHg at baseline to 21.4±10.9 mmHg at one month, 18.6±10,7 mmHg at three months, 15.1±7.6 mmHg at six months, and 14.5±7.9 mmHg at 12 months (p<0.001; Figure 3). At one-year follow-up, 89.6% (n=69) of patients had an IOP ≤ 21 mmHg. IOP ≤ 5 mmHg was found in 7.8% (n=6) and tolerated without complications. 96.1% (n=74) presented at baseline with IOP≥30 mmHg. The number of glaucoma medication decreased from 4.7±1.3 at baseline to 1.9±1.9 at one month, 1.8±1.7 at three months, 1.8±1.5 at six months, and 1.8±1.8 (p<0.001; Figure 4) at 12 months.\n\nFigure 3. Intraocular pressure (IOP) during follow-up (mean ± SD) (p<0.001).\n\nFigure 4. Number of glaucoma medication during follow-up (mean ± SD) (p<0.001).\n\nWhile 32.5% (n=29) of patients complained of ocular pain at baseline (VAPS: 6.0±1.8), all patients were without pain at all follow-up visits. Patients with pain had a significantly higher baseline IOP of 49.9±9.0 mmHg than patients without pain 44.1±10.3 mmHg (p<0.01).\n\nEarly postoperative complications (day 1 to four weeks) included intraocular fibrin 67.5% (52/77), hyphema 20.8% (16/77), choroidal detachment 16.9 (13/77), and corneal erosion 14.3% (11/77). Late postoperative complications (> 1 months) included retinal detachment in 3.9% (3/77) and consecutively a painless phthisis in these 3 cases ( Table 2).\n\nTable 2. Early postoperative inflammation and postoperative complications.\n\nComplications\tn (%)\t\nEarly inflammation/complications\t\t\n Extensive fibrin\t52 (67.5)\t\n Hyphema\t16 (20.8)\t\n Choroidal swelling\t13 (16.9)\t\n Corneal erosion\t11 (14.3)\t\nLate complications\tn (%)\t\n Retinal detachment\nand Phthisis bulbi\t3 (3.9)\t\n\nAt the one-year follow-up, surgical intervention was required in 16.9% (22/77) eyes. Of these eyes, 63.6% (14/22) received vitrectomy, 22.7% (5/22) a Baerveldt glaucoma drainage implant, 4.5% (1/22) a trabeculectomy with mitomycin C and 4.5% (1/22) a keratoplasty. One painful and blind eye needed enucleation.\n\nRepeat transscleral cyclophotocoagulation was performed in 11.6% (15/77). 3.9% (5/77) of patients with a mean BCVA 1.1±0.3 logMAR received an additional 4.0±0.8 anti-VEGF injections.\n\nAt baseline, 11.7% (9/77) had neovascularization of the iris (NVI) stage of 2, 33.8% (26/77) stage 3 and 54.5% (42/77) stage 4. The combined average stage was 3.4±0.7 (range 2–4). Patients with stage 4 needed significantly more major interventions compared with stage 3 (OR 25.0, 95% CI 3.09-201.7, p=0.003) and stage 2 (OR 19.0, 95% CI 1.03-347.3, p=0.047). There was no statistically significant difference between the number of interventions required at stage 2 and stage 3 (OR 0.89, 95% CI 0.03-23.9, p=0.9471). Kaplan-Meier analysis showed a probability of success of 65% at one-year follow-up ( Figure 5).\n\nFigure 5. Kaplan-Meier univariate estimates of the probability of success: intraocular pressure (lOP) ≤ 21 mmHg or IOP reduction ≥ 30% from baseline, with or without glaucoma medication, without vision loss.\n\nLost to follow-up\n\n21 patients were lost to follow-up. 10 patients died during the one-year follow-up period. All 21 patients lost to follow-up completed a telephone survey. The main reasons for missed visits were general health issues in 52.4% (11/21), long-distance to our clinic 38.1% (8/21), and family-related reasons in 9.5% (2/21). 57.1% (12/21) of patients had retained at least ambulatory vision. 71.4% (15/21) used 1.7±1.2 glaucoma eye drops. 95.2% (21/22) reported overall satisfaction with the treatment. All patients were pain-free.\n\nDiscussion\n\nBy 1871, NVG was known as “glaucoma haemorrhagicum et apoplecticum” and feared as a consequence of ischemia that quickly led to enucleation due to “hefty ciliary neuralgia” 39. In 1963, using improved equipment, Weiss et al. found that emerging neovascularization and fibrovascular membranes of the iris and the angle could be observed well before the onset of advanced NVG 40, hinting at a window to initiate treatment. Today, the ability to detect neovascularization early is complemented by improved interventions that address both the underlying pathology and elevated IOP. However, these interventions need to be implemented during the early stages of the disease because NVG continues to have a rapid evolution and a poor prognosis for both the eye and the patient 12. One study showed that the expected lifespan of patients with NVG decreased by 52% compared to an age-correlated normal population, corresponding to a loss of 6.5 years. In diabetics with NVG, the lifespan was reduced even more by 72% 12. In our study, 74% (57/77) of patients had multiple cardiovascular risk factors and were overweight or obese. During follow-up, ten patients died. The high mortality rate is a reminder that any treatment strategy of NVG should aim at keeping the number of necessary follow-up visits and additional interventions at a minimum. We tried to address this need by combining several interventions in a single surgical session.\n\nRetinal ischemia is the primary cause of NVG 10, 41. Accordingly, PRP is the standard of care to reduce posterior pole oxygen demand and angiogenic drive while vitrectomy is performed to increase the partial pressure of vitreous oxygen 42, 43. We performed lens extraction, pars plana vitrectomy, and endoscopic PRP because of significant media opacities and because endoscopic laser through the pars plana approach facilitates the delivery of 360° near-confluent peripheral retinal laser treatment out to the ora serrata. In our clinical experience, even relatively small areas of retinal ischemia may cause further NVG progression. Therefore, we took care to apply 360° PRP to near-confluence up to the ora serrata. Such extensive treatment would be challenging or impossible using standard PRP with an indirect ophthalmoscope or at the slit lamp.\n\nIn the healthy eye, the vitreous body and the iris-lens diaphragm form a relative diffusion barrier that maintains a higher oxygen partial pressure in the posterior chamber than the vitreous overlying the posterior pole. Concurrently, it reduces the diffusion of angiogenic mediators. Recreating a relative diffusion barrier after vitrectomy 44 is beneficial and reduces NVI occurrence 45. A relative barrier can be achieved with silicone oil 46 that reduces the incidence of NVG 46, 47. Following this concept, Bartz-Schmidt et al. treated 32 NVG patients with pars plana vitrectomy, retinal, and ciliary body photocoagulation, and silicone oil tamponade as eyes were left aphakic. This approach controlled IOP (defined as an IOP between 8 and 21 mmHg) in 72% of patients for at least one year 30. In our study we achieved an IOP control in 77.9% and all eyes were pseudophakic and without silicone oil at the conclusion of the surgery, thereby suggesting that silicone oil as a diffusion barrier may not be necessary 30.\n\nOur success rate of 65%, defined as an IOP <22 mmHg, with or without glaucoma medication and without vision loss after a one-year follow-up, is similar to success rates reported for glaucoma drainage devices, which range from 62% to 66.7% 24, 48– 50. One study reported a 73% success rate in 38 eyes that received a glaucoma drainage device and had relatively few postoperative complications 51. However, this report is the exception as others have found 24, 48– 50. ( Table 3).\n\nTable 3. Literature overview.\n\nAuthors\tYear\tDesign\tIntervention\tn\tIOP preOP\n(mmHg)\tSuccess\n(%)\tVision\nloss (%)\tPhthisis\nbulbi (%)\t\nMermoud et al. 60\t1993\tretrospective\tMolteno-Valve\t60\t42.3 ± 13.2\t62\t48\t18\t\nEvery et al. 49\t2006\tprospective\tMolteno-Valve\t145\t40.1 ± 13.0\t72\t32\tN/A\t\nYalvac et al. 8, 48\t2007\tretrospective\tAhmed-Valve vs Molteno-\nValve\t38/27\t39.5 ± 4.5 vs\n39.3 ± 3.9\t63 vs 37\t23-33\t7.9-14.8\t\nTakihara et al. 56\t2009\tretrospective\tTrabeculectomy + MMC\t101\t35.9 ± 11.3\t62.6\t12.9\t5.0\t\nNetland et al. 51\t2010\tretrospective\tAhmed-Valve ± NVG\t38/38\t39.1 ± 11.2 vs\n43.8 ± 11.0\t89.2 vs\n73.1\t23,7\t13,2\t\nShen et al. 61\t2011\tretrospective\tTrabeculectomy versus\nAhmed-Valve\t20/20\t47.7 ± 10.2 vs\n47.8 ± 11.3\t70 vs 65\t15 vs 30\t5.0\t\nXie et al. 50\t2019\tretrospective\tAhmed-Valve\t66\t48.23±8.17\t66.7\tN/A\tN/A\t\nStrzalkowski et al. 37\t2021\tretrospective\tPPV+EL+Avastin+ CPC\t77\t46.0 ± 10.3\t64.6\t3.9\t5.7\t\n\nTrabeculectomy has been one of the most important intraocular pressure lowering operations in glaucoma since the 1960s 89,90, so this surgical technique was also used in NVG. Different studies have shown a failure rate of up to 80% 52, 53. The use of mitomycin C (MMC) and 5-fluorouracil (5-FU) led to a higher success rate and was 54% after 18 months for MMC used intraoperatively and 55% after 35 months for 5-FU 54. A combined trabeculectomy and retinal cryotherapy did not seem to improve the surgical success outcome for NVG in diabetic patients 55. However, in this study patients had received panretinal photocoagulation prior to the surgery and in contrast to our study IOP ≤ 21 mmHg was the only success criteria.\n\nNeovascular glaucoma is a major risk factor for failure of trabeculectomy 56, 57. Chronic blood-retinal barrier insufficiency, for example in advanced diabetic retinopathy, in which endothelial damage and the subsequent release of serum proteins occurs, plays an important role 58. Retinal ischemia also leads to the production of inflammatory mediators 59, which can lead to filtering bleb scarring and postoperative failure of the trabeculectomy 58.\n\nOur integrative surgical approach avoided tube-specific complications (e.g., tube exposure, retraction, corneal touch, obstruction), ranging from 13% to 26% in NVG over five years 24, 48– 51. It delivers both retina and glaucoma treatment in a single surgical session and reduces the patient and health care system burden by simplifying postoperative care and follow-up. Our telephone survey with all patients lost to follow-up revealed that the main reasons for missed visits were other (general) health issues in 52.4% and long distance to the clinic in 38.1% but a high subjective satisfaction rate.\n\nPatients with NVI stage 4 needed significantly more major interventions than stage 3 or stage 2, but there was no difference between stage 2 and stage 3. This finding suggests that early and comprehensive treatment may be more beneficial than a stepwise treatment strategy.\n\nIt is worth noting that IOP reduction can also be achieved without cyclodestruction applying only pars plana vitrectomy, lensectomy with a preserved anterior capsule, and panretinal endophotocoagulation as reported by Kinoshita et al. 31. However, this study included only 13 eyes with a lower mean preoperative IOP of 29 mmHg as in our study. By contrast, other studies that only used anti-VEGF agents as primary treatment 28, 62 reported failure rates up to 88% 62. Anti-VEGF agents may be best used as an adjuvant treatment 29. Consistent with our findings, a study that used pars plana vitrectomy, endoscopic peripheral panretinal photocoagulation, and endocyclophotocoagulation (ECP) also achieved an IOP reduction which was more effective than panretinal photocoagulation, intravitreal bevacizumab, pars plana vitrectomy, and trabeculectomy with mitomycin C or Ahmed valve placement. However, the authors reported a higher phthisis rate of 7.4% 63.\n\nBecause of the underlying ocular disease, visual function remained low in most eyes in our study.\n\nThere are limitations to our study. Because the integrative surgical approach described here was the primary practice pattern, there was no control group. This limited us to an intragroup comparison of before versus after treatment data. As a retrospective study, it can only inform on future prospective studies’ parameters and design and help formulate, but not answer, hypotheses about associations between treatment and outcomes.\n\nIn conclusion, this study shows that NVG can be controlled in most cases by an integrative surgical approach delivered in a single surgical session that combines transscleral cyclophotocoagulation, cataract removal, pars plana vitrectomy, near-confluent full-scatter panretinal photocoagulation, and intravitreal bevacizumab. Patients with advanced iris neovascularization required significantly more additional interventions. The described approach lowered IOP significantly, reduced the number of glaucoma medications, and controlled pain.\n\nData availability\n\nUnderlying data\n\nOpen Science Framework: Combined vitrectomy, near-confluent panretinal endolaser, bevacizumab and cyclophotocoagulation for neovascular glaucoma — a retrospective interventional case series. https://doi.org/10.17605/OSF.IO/QTCGV 37.\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n10.5256/f1000research.54199.r80498\nReviewer response for version 2\nEller Andrew W. 1Referee\nKapoor Saloni 2Co-referee https://orcid.org/0000-0003-2238-1177\n\n1 Retina Service, Department of Ophthalmology, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, USA\n2 University of Pittsburgh Medical Center, Pittsburgh, USA\n17 3 2021 Copyright: © 2021 Eller AW and Kapoor S\n2021\nThis is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nVersion 2recommendationapprove\nThe authors have satisfactorily addressed the comments we provided and made all the changes we suggested. They have not provided a regression analysis as they would like to put this forward in another manuscript which we look forward to reading.\n\nIs the work clearly and accurately presented and does it cite the current literature?\n\nYes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\n\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility?\n\nYes\n\nIs the study design appropriate and is the work technically sound?\n\nYes\n\nAre the conclusions drawn adequately supported by the results?\n\nYes\n\nAre sufficient details of methods and analysis provided to allow replication by others?\n\nYes\n\nReviewer Expertise:\n\nNA\n\nWe confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.\n\n10.5256/f1000research.29684.r75197\nReviewer response for version 1\nDithmar Stefan 1Referee\n1 Department of Ophthalmology, HELIOS Dr. Horst Schmidt Kliniken, Wiesbaden, Germany\n1 12 2020 Copyright: © 2020 Dithmar S\n2020\nThis is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nVersion 1recommendationapprove\nThe authors present a very interesting observational study on the therapy of neovascularization glaucoma. The treatment of this clinical entity is difficult and often unsatisfactory. The authors report on a convincing surgical approach and present retrospective results in a relatively large patient group. The presentation of the results is good and the manuscript is well written.\n\nTaking into account the reviewer report by Andrew W. Eller, I have no further comments to make.\n\nIs the work clearly and accurately presented and does it cite the current literature?\n\nYes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\n\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility?\n\nYes\n\nIs the study design appropriate and is the work technically sound?\n\nYes\n\nAre the conclusions drawn adequately supported by the results?\n\nYes\n\nAre sufficient details of methods and analysis provided to allow replication by others?\n\nYes\n\nReviewer Expertise:\n\nRetina research\n\nI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.\n\n10.5256/f1000research.29684.r73906\nReviewer response for version 1\nEller Andrew W. 1Referee\nKapoor Saloni 2Co-referee https://orcid.org/0000-0003-2238-1177\n\n1 Retina Service, Department of Ophthalmology, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, USA\n2 University of Pittsburgh Medical Center, Pittsburgh, USA\n20 11 2020 Copyright: © 2020 Eller AW and Kapoor S\n2020\nThis is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nVersion 1recommendationapprove-with-reservations\nIn this study Dr Strzalkowski et al. provide a retrospective observational analysis of a single center’s experience with aggressive upfront treatment of neovascular glaucoma (NVG) with combined vitrectomy, near confluent pan retinal endolaser, bevacizumab and transscleral cyclophotocoagulation.\n\nThe authors hypothesize that upfront combined treatment would improve outcomes in terms of IOP, antiglaucoma medications, pain, necessity of further surgeries and help reduce follow-up visits. They report baseline characteristics and one-year outcomes for 77 patients with neovascular glaucoma that underwent the combined procedure. We congratulate them on implementing a success strategy in treating these complex cases. Often patients with NVG have disastrous outcomes with poorly controlled IOP and significant loss of vision. In this series, a number of patients were able to maintain reasonable vision. It can often be difficult to “titrate” treatment of IOP, often resulting in hypotony. There were three patients with phthisis bulbi and another six with hypotony for a total of nine or 11.7%. Three patients developed retinal detachment. Perhaps these were the same three patients who developed phthisis bulbi. \n\nThe major drawback of this study is the lack of alternate treatments for randomization. This limits our ability to draw any conclusions about optimal management strategies and only hypotheses can be generated. This is appropriately acknowledged by the authors who are careful not to overstate their conclusions.\n\nThe authors seemed to have corelated surgical success with the stage of iris neovascularization. In other words, there were more surgical interventions with stage 4, then stages 2 or 3. It is the experience of this reviewer that one can corelate treatment success of NVG with presenting IOP and the immediate response of IOP to medical therapy. In clinic, if the initial IOP is less than 40 mmHg and medical treatment can reduce the IOP into the low 20’s, these patients can often be treated with an initial injection of an anti-VEGF medication, followed by PRP laser. In the long term, any residual glaucoma can usually be treated with medical therapy alone. Those patients presenting with an IOP greater than 40 mmHg, and not responding to medical therapy will require more aggressive treatment. If the visual potential is reasonable, this treatment may include anti-VEGF, PRP laser (with vitrectomy if visualization of the retina is poor), and glaucoma surgery. If the visual potential is very poor, then not invasive glaucoma treatment such as transscleral CPC) is advised. Using their data, are the authors able to confirm our observations regarding treatment of NVG.\n\nAs the authors have stated, there are a number of different underlying causes of neovascular glaucoma and they have been combined in this series. This is a fairly large series and we question whether the severity of the NVG and response to treatment may have differed according to the underlying pathology. For example, the iris neovascularization and glaucoma in central retinal vein occlusions (CRVO) tends to progress more rapidly then seen with diabetic retinopathy. Once the retinal ischemia has been addressed in CRVO, it seems these eyes are more likely to develop hypotony. What was the experience of the authors in this study?\n\nThe authors cite two studies from the mid-1980’s when the use of silicone oil was very much in its early stages of clinical usage. At that time, it was felt that silicone oil reduced or perhaps prevented the flow of VEGF into the anterior chamber and therefore decreased the risk of iris neovascularization and glaucoma. We believe this theory has been discounted as we know that there is a flow of aqueous humor from the posterior segment into the anterior chamber. Retinal detachment alone increases VEGF production and it occurs in cases of proliferative diabetic retinopathy there can be an even more profound angiogenic effect. An alternative explanation for this observation is that silicone oil improves the outcome in these eyes by simply improving the chances for retinal re-attachment.\n\nIn the Introduction, the authors hypothesize that the combined approach would help decrease outpatient visits. This is again emphasized in the Discussion where authors report that patients with neovascular glaucoma have significant comorbidities and lower life expectancy and would therefore benefit from decreased outpatient visits. The counter-argument to be made is that combined aggressive surgical intervention would increase risk of complications and require closer monitoring. No data is provided on the number of follow up visits. Consider adding to results if available. The authors could consider performing a regression analysis to determine which baseline characteristics predicted success with this combined technique. This analysis will help identify patients in whom this technique would be most helpful. It could also show when this technique may be more aggressive than necessary in some cases, and could be more aggressive in others when the addition of a glaucoma drainage device may be beneficial.\n\nSpecific comments for revision: In the Introduction , second paragraph, suggest following change. “In 1994, Miller et al. showed that laser occlusion of all branch retinal veins in a primate could lead to CRVO and subsequent retinal ischemia.”\n\nIn the Results, consider rephrasing “arterial hypertension” to hypertension as this is the currently accepted terminology.\n\nIn Table 1 – consider rephrasing “R stadium” to read “NVI Stage” or Weiss and Gold Rubeosis grading to ensure clarity.\n\nIn the Discussion, it would be beneficial to see outcomes with staged surgical approach (Incisional surgical management with trabeculectomy/tubes, followed by cryotherapy if poor response) from existing literature to enable some comparison with the combined approach reported in this manuscript.\n\nIn the Discussion, the authors state “Patients with stage 4 anterior chamber neovascularization needed significantly more major interventions than stage 3 or stage 2, but there was a difference between stage 2 and stage 3”. The data reports NO significant difference between stage 2 and 3. Please clarify.\n\nOverall, a well-organized manuscript with a practical approach to the treatment of neovascular glaucoma with novel data.\n\nIs the work clearly and accurately presented and does it cite the current literature?\n\nYes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\n\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility?\n\nYes\n\nIs the study design appropriate and is the work technically sound?\n\nYes\n\nAre the conclusions drawn adequately supported by the results?\n\nYes\n\nAre sufficient details of methods and analysis provided to allow replication by others?\n\nYes\n\nReviewer Expertise:\n\nOphthalmology, Vitreo-Retinal Diseases and Surgery\n\nWe confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however we have significant reservations, as outlined above.\n\nStrzalkowski Piotr University Hospital Würzburg, Germany\n\n23 1 2021 Dear Reviewers,\n\nWe are grateful for the opportunity to improve our manuscript. We appreciate the helpful comments and have provided our replies below. We trust that we were able to address the concerns that were raised.\n\nThank you,\n\nPiotr Strzalkowski\n\nReviewers' comments:\n\nReviewer #1 (“R1” in the following): There were three patients with phthisis bulbi and another six with hypotony for a total of nine or 11.7%. Three patients developed retinal detachment. Perhaps these were the same three patients who developed phthisis bulbi.\n\n Authors: That is exactly correct. We appreciate the thoughtful analysis. All three patients with retinal detachment also developed phthisis bulbi. We added this important information to our manuscript.\n\nR1, 1: As the authors have stated, there are a number of different underlying causes of neovascular glaucoma and they have been combined in this series. This is a fairly large series and we question whether the severity of the NVG and response to treatment may have differed according to the underlying pathology. For example, the iris neovascularization and glaucoma in central retinal vein occlusions (CRVO) tends to progress more rapidly than seen with diabetic retinopathy. Once the retinal ischemia has been addressed in CRVO, it seems these eyes are more likely to develop hypotony. What was the experience of the authors in this study?\n\n Authors: Thank you for sharing your clinical experience. Based on our data we could not find a statistical significant difference in postoperative IOP or hypotony between CRVO and PDR patients.\n\nR1, 2: No data is provided on the number of follow up visits. Consider adding to results if available.\n\nAuthors: Information about the number of follow up visits is provided in section “study design”: All patients were treated at the University Eye Hospital in Würzburg, Germany. The combined intervention was part of routine patient care at our clinic and all patients with decompensated neovascular glaucoma and preserved visual function received this intervention. BCVA, intraocular pressure (IOP, mmHg), the number of glaucoma medication, visual analog pain scale (VAPS, 0-10) was recorded at baseline and at follow-up visits at one, three, six, and 12 months as part of routine care.\n\nR1, 3: The authors could consider performing a regression analysis to determine which baseline characteristics predicted success with this combined technique. This analysis will help identify patients in whom this technique would be most helpful.\n\n Authors: Regression analysis was not included in this study on purpose because this analysis is part of our ongoing study.\n\nR1, Specific Comments: In the Introduction, second paragraph, suggest following change. “In 1994, Miller et al. showed that laser occlusion of all branch retinal veins in a primate could lead to CRVO and subsequent retinal ischemia.”\n\nIn the Results, consider rephrasing “arterial hypertension” to hypertension as this is the currently accepted terminology.\n\nIn Table 1 – consider rephrasing “R stadium” to read “NVI Stage” or Weiss and Gold Rubeosis grading to ensure clarity.\n\nIn the Discussion, it would be beneficial to see outcomes with staged surgical approach (Incisional surgical management with trabeculectomy/tubes, followed by cryotherapy if poor response) from existing literature to enable some comparison with the combined approach reported in this manuscript.\n\nIn the Discussion, the authors state “Patients with stage 4 anterior chamber neovascularization needed significantly more major interventions than stage 3 or stage 2, but there was a difference between stage 2 and stage 3”. The data reports NO significant difference between stage 2 and 3. Please clarify.\n\nAuthors: We have changed the manuscript to include these suggestions.\n\nCompeting interests: No competing interests were disclosed.\n\nCompeting interests: No competing interests were disclosed.\n\nCompeting interests: No competing interests were disclosed.\n\nCompeting interests: No competing interests were disclosed.\n==== Refs\n1 Karaman S Leppänen VM Alitalo K : Vascular endothelial growth factor signaling in development and disease. Development. 2018;145 (14 ):dev151019. 10.1242/dev.151019 30030240\n2 Liao N Li C Jiang H : Neovascular glaucoma: a retrospective review from a tertiary center in China. BMC Ophthalmol. 2016;16 (1 ):14. 10.1186/s12886-016-0190-8 26818828\n3 Drobec P : Das hämorrhagische Sekundärglaukom. Klinische Monatsblätter für Augenheilkunde. 1982;180 (02 ):138–40.7087341\n4 Mocanu C Barăscu D Marinescu F : [Neovascular glaucoma--retrospective study]. 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"title": "Combined vitrectomy, near-confluent panretinal endolaser, bevacizumab and cyclophotocoagulation for neovascular glaucoma - a retrospective interventional case series.",
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"abstract": "Systemic sclerosis, or scleroderma, is a complex medical disorder characterized by limited or diffuse skin thickening with frequent involvement of internal organs such as lungs, gastrointestinal tract, or kidneys. Docetaxel is a chemotherapeutic agent which has been associated with cutaneous side effects. An uncommon cutaneous side effect of docetaxel is scleroderma-like skin changes that extend from limited to diffuse cutaneous systemic sclerosis. Several case reports have been published regarding the association of docetaxel and systemic sclerosis. However, those reports demonstrated the association between docetaxel and scleroderma-like skin changes without internal organ involvement. Here, we report a case of systemic sclerosis with pulmonary arterial hypertension and a microangiopathic kidney involvement induced by docetaxel chemotherapy. After an exhaustive literature review, this could be the first case of docetaxel-induced systemic sclerosis involving internal organs.",
"affiliations": "Department of Family Medicine, Henry Ford Hospital, Wayne State University School of Medicine, Detroit, MI 48202, USA.;Department of Family Medicine, Henry Ford Hospital, Wayne State University School of Medicine, Detroit, MI 48202, USA.;Department of Family Medicine, Henry Ford Hospital, Wayne State University School of Medicine, Detroit, MI 48202, USA.;Department of Family Medicine, Henry Ford Hospital, Wayne State University School of Medicine, Detroit, MI 48202, USA.;Department of Family Medicine, Henry Ford Hospital, Wayne State University School of Medicine, Detroit, MI 48202, USA.",
"authors": "Park|Bumsoo|B|0000-0003-4505-2368;Vemulapalli|Raghavendra C|RC|;Gupta|Amit|A|;Shreve|Maria E|ME|;Rees|Della A|DA|",
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"fulltext": "\n==== Front\nCase Reports ImmunolCase Reports ImmunolCRIICase Reports in Immunology2090-66092090-6617Hindawi 2826547410.1155/2017/4249157Case ReportDocetaxel-Induced Systemic Sclerosis with Internal Organ Involvement Masquerading as Congestive Heart Failure http://orcid.org/0000-0003-4505-2368Park Bumsoo \n*\nVemulapalli Raghavendra C. Gupta Amit Shreve Maria E. Rees Della A. Department of Family Medicine, Henry Ford Hospital, Wayne State University School of Medicine, Detroit, MI 48202, USA*Bumsoo Park: bpark1@hfhs.orgAcademic Editor: Necil Kütükçüler\n\n2017 6 2 2017 2017 42491572 11 2016 9 1 2017 22 1 2017 Copyright © 2017 Bumsoo Park et al.2017This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Systemic sclerosis, or scleroderma, is a complex medical disorder characterized by limited or diffuse skin thickening with frequent involvement of internal organs such as lungs, gastrointestinal tract, or kidneys. Docetaxel is a chemotherapeutic agent which has been associated with cutaneous side effects. An uncommon cutaneous side effect of docetaxel is scleroderma-like skin changes that extend from limited to diffuse cutaneous systemic sclerosis. Several case reports have been published regarding the association of docetaxel and systemic sclerosis. However, those reports demonstrated the association between docetaxel and scleroderma-like skin changes without internal organ involvement. Here, we report a case of systemic sclerosis with pulmonary arterial hypertension and a microangiopathic kidney involvement induced by docetaxel chemotherapy. After an exhaustive literature review, this could be the first case of docetaxel-induced systemic sclerosis involving internal organs.\n==== Body\n1. Introduction\nSystemic sclerosis, or scleroderma, is a heterogeneous disorder characterized by skin sclerosis as the baseline pathology. Systemic sclerosis is classified into three subsets: limited cutaneous systemic sclerosis, diffuse cutaneous systemic sclerosis, and systemic sclerosis without skin involvement [1]. The limited subset typically involves skin sclerosis that is restricted to hands or, to a lesser extent, to the face and neck, whereas the diffuse subset involves skin thickening extending to either proximal extremities or trunk and has demonstrated a higher frequency of internal organ involvement (lungs, gastrointestinal tract, or kidneys).\n\nDocetaxel is a chemotherapeutic agent as a member of taxane drug class. Well-known side effects of docetaxel include peripheral neuropathy, myelosuppression, arthralgia, myalgia, fluid retention, and cutaneous reactions. One uncommon cutaneous side effect of docetaxel is a scleroderma-like skin change for which there have been more than 10 case reports in the literature. However, the side effects that all of the case reports have shown were scleroderma-like skin change, or limited/diffuse cutaneous systemic sclerosis, without providing evidence of internal organ involvement.\n\nHerein we report a case with docetaxel-induced systemic sclerosis with internal organ involvement masquerading as a congestive heart failure (CHF). After an exhaustive literature review, this could be the first case of docetaxel-induced systemic sclerosis involving systemic organs.\n\n2. Case Report\nA 49-year-old African American woman presented with shortness of breath, who was discharged from the other hospital one week earlier with the diagnosis of acute exacerbation of CHF. Patient was given oral furosemide and carvedilol at discharge, however, she admitted to losing her prescription for carvedilol resulting in her not taking it since discharge. She exhibited bilateral leg edema on examination without crackles or jugular venous distention. Brain natriuretic peptide was elevated to 1330 pg/mL. Chest radiograph demonstrated cardiomegaly with minimal interstitial edema. Echocardiography from the other hospital showed an ejection fraction (EF) of 50%, pulmonary arterial pressure (PAP) of 56 mmHg, and normal left ventricular diastolic filling. Recurrent exacerbation of CHF secondary to idiopathic pulmonary arterial hypertension (PAH) triggered by medication noncompliance was initially diagnosed, and the patient was started on intravenous furosemide. However, no clinical improvement was noted with no reasonable urine output. The medical team doubted the diagnosis of CHF exacerbation and started to do more thorough history taking and a comprehensive physical examination.\n\nThe patient had a history of breast cancer and underwent left lumpectomy followed by 4 cycles of chemotherapy using docetaxel/cyclophosphamide and radiation therapy about a year ago. She was given 134 mg of docetaxel and 1,074 mg of cyclophosphamide on a monthly basis. On repeat examination, she demonstrated diffuse thickening/sclerosis of bilateral hands that crossed metacarpophalangeal joints extending up to bilateral proximal upper extremities (Figure 1). Extensive sclerosis of skin and subcutaneous tissue of anterior chest wall and the left breast were also noted. Patient endorsed that she started to have pain and stiffness of both hands right after she finished the last cycle of chemotherapy. Echocardiography before the chemotherapy showed EF of 55%, PAP of 26 mmHg, and normal left ventricular (LV) diastolic filling. LV size has been normal without change before and after the chemotherapy. Therefore, her estimated systolic PAP has increased by more than 2-fold after the chemotherapy with newly developing skin sclerosis. Docetaxel-related systemic sclerosis was suspected. Serologic test showed positive antinuclear antibody, but negative anticentromere and anti-Scl-70 antibodies. Pulmonary function test was normal with slightly decreased diffusing capacity. High-resolution computed tomography of the chest did not show interstitial lung disease. Finally, it was noted that she met the 2013 American College of Rheumatology Classification Criteria of Systemic Sclerosis as she demonstrated skin thickening of the fingers of both hands extending proximal to the metacarpophalangeal joints (score 9) and PAH (score 2). Per the criteria, patients with a total score of ≥9 are classified as having definite systemic sclerosis [2].\n\nWe discontinued diuretic treatment and continued on beta-blocker with calcium-channel blocker. Patient's clinical condition improved and was discharged with follow-up appointment with Rheumatology and Pulmonary Hypertension (PH) clinic.\n\nUpon follow-up chart review, the patient is currently following Rheumatology, Pulmonology, and Dermatology but is also on hemodialysis given worsening renal function with following Nephrology. Renal biopsy was performed and it showed thrombotic microangiopathy pattern (classic “onion-peeling” appearance) which is suggestive of scleroderma per pathologic documentation. She was diagnosed with scleroderma renal crisis by Nephrology and was started on captopril. Patient is currently stable with normal blood pressure and stable serum creatinine levels.\n\n3. Discussion\nOur case showed newly developed PAH, thrombotic microangiopathy of the kidney with scleroderma renal crisis, and skin sclerosis of bilateral hands definitive of systemic sclerosis, status post docetaxel treatment.\n\nAmong side effects of docetaxel, it has been reported that docetaxel can induce a variety of skin toxicities [3]. One of the rare cutaneous side effects of docetaxel is a scleroderma-like change, and there have been more than 10 case reports. Since three cases of limited systemic sclerosis induced by docetaxel were reported at first [4], there have been reports regarding both limited cutaneous systemic sclerosis [5, 6] and diffuse cutaneous systemic sclerosis [7, 8] induced by docetaxel. The exact mechanism by which docetaxel induces skin sclerosis is unclear. Versican is a large chondroitin sulfate proteoglycan expressed by human fibroblasts. It interacts with cells and enables them to proliferate, migrate, adhere, and assemble an extracellular matrix [9]. Hesselstrand et al. suggested that versican may contribute to skin thickening with excess collagen deposits in systemic sclerosis [10]. Okada et al. reported that intense versican deposits were found in the skin after docetaxel administration [11]. Therefore, versican may play a role in pathogenesis of docetaxel-induced systemic sclerosis.\n\nOne of the interesting findings in our report is that our patient developed PAH after docetaxel treatment. So far, no cases have been reported associating docetaxel with PAH. It has been hypothesized that PAH in systemic sclerosis occurs as a consequence of progressive remodeling of pulmonary vasculature with inflammation and endothelial injury as common precursors. A recent study revealed that docetaxel facilitates endothelial injury through oxidative stress mechanism [12]. Thus, docetaxel may induce PAH either by oxidative injury to the endothelial cells or by stimulating fibroblast cells as mentioned earlier.\n\nPH can also be developed by LV dysfunction (Group 2 PH), and it is possible that the patient might have had Group 2 PH given decreased EF from 60% to 50%. However, based on the fact that estimated systolic PAP increased by more than 2-fold compared to decrease in EF by 17% and the LV diastolic function remained normal before and after chemotherapy, it is more likely that the patient might have developed primary PAH (Group 1 PH). Another possible consideration is that cyclophosphamide which the patient was given can cause dilated cardiomyopathy, and this condition might have caused Group 2 PH. However, given the fact that LV size remained constantly normal before and after chemotherapy, it is less likely that the patient developed dilated cardiomyopathy after cyclophosphamide treatment.\n\nIt should also be considered that systemic sclerosis might have developed as a manifestation of breast cancer. Joseph et al. have suggested that a tumor antigen can trigger autoimmune response which can develop systemic sclerosis after they found that a certain genetic mutation triggered cellular immunity and cross-reactive humoral immune responses [13]. However, based on the fact that the patient started to have skin thickening after she finished the chemotherapy and she was diagnosed with breast cancer 2 years ago, it is more likely that the patient developed systemic sclerosis secondary to chemotherapy.\n\nOur study has a limitation that the PAH was diagnosed only based on echocardiography, but not confirmed by right heart catheterization (RHC). RHC should be performed to diagnose PAH in systemic sclerosis per 2013 American College of Rheumatology Classification Criteria of Systemic Sclerosis. We deferred RHC while the patient was hospitalized since the patient was too weak and fatigued to tolerate invasive procedures. However, as the patient also demonstrated biopsy-proven microangiopathic kidney involvement which was pertinent to systemic sclerosis, we still believe that the patient developed an internal organ involvement of systemic sclerosis with not only having skin involvement.\n\nWe also admit that we initially missed characteristic findings of bilateral hand sclerosis on examination because we focused only on assessing cardiopulmonary status. An observational study showed that 26% of the inpatient sample had diagnosis and treatment changed substantially as a result of the attending physician's physical examination [14]. Therefore, it cannot be overemphasized that a thorough history taking and comprehensive physical examination are essential for medical practice.\n\n4. Conclusion\nThe association between docetaxel and scleroderma-like skin changes has been well established in the literature. However, we firstly report a case that docetaxel can also cause systemic sclerosis with internal organ involvement that manifested as PAH and microangiopathic kidney disease. Therefore, we may need to consider the possibility of systemic sclerosis and try to look for any skin thickening if a patient develops unexplained PAH or worsening renal function with docetaxel treatment.\n\nCompeting Interests\nAll authors declare no conflict of interests to disclose regarding this study.\n\nFigure 1 Diffuse skin thickening and sclerosis of bilateral hands that cross the metacarpophalangeal joint.\n==== Refs\n1 Wollheim F. A. Classification of systemic sclerosis. Visions and reality Rheumatology 2005 44 10 1212 1216 10.1093/rheumatology/keh671 2-s2.0-26444614639 15870151 \n2 van den Hoogen F. Khanna D. Fransen J. 2013 Classification criteria for systemic sclerosis: an American College of Rheumatology/European League Against Rheumatism collaborative initiative Arthritis & Rheumatism 2013 65 11 2737 2747 10.1002/art.38098 2-s2.0-84886777196 24122180 \n3 Chew L. Chuen V. S. L. Cutaneous reaction associated with weekly docetaxel administration Journal of Oncology Pharmacy Practice 2009 15 1 29 34 10.1177/1078155208096111 2-s2.0-61749096350 18753180 \n4 Battafarano D. F. Zimmerman G. C. Older S. A. Keeling J. H. Burris H. A. Docetaxel (taxotere) associated scleroderma-like changes of the lower extremities: a report of three cases Cancer 1995 76 1 110 115 10.1002/1097-0142(19950701)76:1<110::aid-cncr2820760117>3.0.co;2-9 2-s2.0-0029019350 8630861 \n5 Vignes S. Lebrun-Vignes B. Sclerodermiform aspect of arm lymphoedema after treatment with docetaxel for breast cancer Journal of the European Academy of Dermatology and Venereology 2007 21 8 1131 1133 10.1111/j.1468-3083.2006.02119.x 2-s2.0-34548151560 17714152 \n6 Bouchard S. M. Mohr M. R. Pariser R. J. Taxane-induced morphea in a patient with CREST syndrome Dermatology Reports 2010 2 1 10.4081/dr.2010.e9 2-s2.0-79952464180 \n7 Cleveland M. G. Ajaikumar B. S. Reganti R. Cutaneous fibrosis induced by docetaxel: a case report Cancer 2000 88 5 1078 1081 10.1002/(sici)1097-0142(20000301)88:560;1078::aid-cncr1962;3.0.co;2-t 2-s2.0-0034163486 10699898 \n8 Hassett G. Harnett P. Manolios N. Scleroderma in association with the use of docetaxel (taxotere) for breast cancer Clinical and Experimental Rheumatology 2001 19 2 197 200 2-s2.0-0035032373 11326485 \n9 Wight T. N. Kinsella M. G. Evanko S. P. Potter-Perigo S. Merrilees M. J. Versican and the regulation of cell phenotype in disease Biochimica et Biophysica Acta—General Subjects 2014 1840 8 2441 2451 10.1016/j.bbagen.2013.12.028 2-s2.0-84903380742 \n10 Hesselstrand R. Westergren-Thorsson G. Scheja A. Wildt M. Åkesson A. The association between changes in skin echogenicity and the fibroblast production of biglycan and versican in systemic sclerosis Clinical and Experimental Rheumatology 2002 20 3 301 308 2-s2.0-0036558833 12102465 \n11 Okada K. Endo Y. Miyachi Y. Koike Y. Kuwatsuka Y. Utani A. Glycosaminoglycan and versican deposits in taxane-induced sclerosis British Journal of Dermatology 2015 173 4 1054 1058 10.1111/bjd.13899 2-s2.0-84946489386 25973640 \n12 Hung C.-H. Chan S.-H. Chu P.-M. Tsai K.-L. Docetaxel facilitates endothelial dysfunction through oxidative stress via modulation of protein kinase C beta: the protective effects of sotrastaurin Toxicological Sciences 2015 145 1 59 67 10.1093/toxsci/kfv017 2-s2.0-84929670452 25634538 \n13 Joseph C. G. Darrah E. Shah A. A. Association of the autoimmune disease scleroderma with an immunologic response to cancer Science 2014 343 6167 152 157 10.1126/science.1246886 2-s2.0-84892166613 24310608 \n14 Reilly B. M. Physical examination in the care of medical inpatients: An Observational Study Lancet 2003 362 9390 1100 1105 10.1016/s0140-6736(03)14464-9 2-s2.0-0141863200 14550696\n\n",
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"title": "Docetaxel-Induced Systemic Sclerosis with Internal Organ Involvement Masquerading as Congestive Heart Failure.",
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"abstract": "Nicolau syndrome (NS) is a type of adverse skin reaction occurring after parenteral drug injection. In certain conditions, it can cause ischemic necrosis of the skin and the underlying adipose tissue. The actual cause of NS is not clear though inflammation, vasospasm, and thromboembolic occlusion of blood vessels have been proposed. In this case presentation, we report an interesting case of a 30-year-old man who turned out be human immunodeficiency virus (HIV) positive on investigations, developed extensive purpuric lesions of his skin on left buttock and then spread to the trunk and shoulders after receiving intramuscular injection of paracetamol. With a suggestive history and further supported by clinical examination, a diagnosis of NS following injection of paracetamol was made. Though NS is considered to be rare, at times it can be devastating. Being a common procedure in the life of a health-care professional, the awareness regarding this entity is very essential. Despite intense medical literature search in, we could not find a single report of NS after intramuscular injection of paracetamol in a patient who is HIV positive, thus obliging this communication.",
"affiliations": "Department of Dermatology, STD's and Leprosy, Ellahi Medicare Clinic, Kashmir, India.;Dr. Ram Manohar Lohia Hospital and Post Graduate Institute of Medical Education and Research, New Delhi, India.",
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"fulltext": "\n==== Front\nJ Cutan Aesthet SurgJ Cutan Aesthet SurgJCASJournal of Cutaneous and Aesthetic Surgery0974-20770974-5157Medknow Publications & Media Pvt Ltd India JCAS-11-13610.4103/JCAS.JCAS_53_18Case ReportExtensive Nicolau Syndrome Following Intramuscular Injection of Paracetamol in a Patient Who Is HIV Positive Arif Tasleem Dorjay Konchok 1Department of Dermatology, STD’s and Leprosy, Ellahi Medicare Clinic, Kashmir, India1 Dr. Ram Manohar Lohia Hospital and Post Graduate Institute of Medical Education and Research, New Delhi, IndiaAddress for correspondence: Dr. Tasleem Arif, New Colony Soura, Near Water Supply Control Room, Srinagar, Kashmir 190011, India. E-mail: dr_tasleem_arif@yahoo.comJul-Sep 2018 11 3 136 139 Copyright: © 2018 Journal of Cutaneous and Aesthetic Surgery2018This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Nicolau syndrome (NS) is a type of adverse skin reaction occurring after parenteral drug injection. In certain conditions, it can cause ischemic necrosis of the skin and the underlying adipose tissue. The actual cause of NS is not clear though inflammation, vasospasm, and thromboembolic occlusion of blood vessels have been proposed. In this case presentation, we report an interesting case of a 30-year-old man who turned out be human immunodeficiency virus (HIV) positive on investigations, developed extensive purpuric lesions of his skin on left buttock and then spread to the trunk and shoulders after receiving intramuscular injection of paracetamol. With a suggestive history and further supported by clinical examination, a diagnosis of NS following injection of paracetamol was made. Though NS is considered to be rare, at times it can be devastating. Being a common procedure in the life of a health-care professional, the awareness regarding this entity is very essential. Despite intense medical literature search in, we could not find a single report of NS after intramuscular injection of paracetamol in a patient who is HIV positive, thus obliging this communication.\n\nKeywords:\nIntramuscular injectionNicolau syndromeparacetamolpurpura\n==== Body\nINTRODUCTION\nNicolau syndrome (NS) is a rare complication arising from an inadvertent parenteral drug injection. The first case of NS was published in 1925 in a patient who was suffering from syphilis and who received injection of bismuth via intramuscular (IM) route in the gluteal region.[1] The sequence of events, which usually occurs during NS, includes pain and redness at the site of injection followed by a purpuric patch and in some cases necrosis of skin and subcutaneous tissue.[2] Within a few days, the skin becomes hemorrhagic and forms a necrotic eschar and eventually heals leaving behind an atrophic scar. The exact mechanism leading to NS is unknown; however, an inadvertent drug injection into an artery, which causes the spasm of the injected artery and the consequent formation of emboli have been suggested as the pathophysiological events.[3] The various drugs that have been implicated in the causation of NS include nonsteroidal anti-inflammatory drugs, corticosteroids, local anesthetics, antibiotics, recombinant interferons, sedatives, vaccines, tumor necrosis factor-alpha antagonists, and immunomodulators.[45] In this article, we present a unique case of NS developing after IM injection of paracetamol in a patient who is human immunodeficiency virus (HIV) positive.\n\nCASE REPORT\nA 30-year-old man presented us with chief complaint of reddish-blue discoloration on the left buttock and trunk after receiving IM injection of paracetamol. He experienced pain while the injection was being administered and the pain continued after the injection, after which it regressed and was managed with the use of analgesics. The patient had a history of fever for the last 10 days for which he had taken some oral drugs, and an injection of paracetamol was prescribed to him by the local practitioner. Two days after receiving IM paracetamol in the left buttock, the patient developed reddish discoloration at the injection site, which in a span of 2 days changed to reddish-blue color and spread to the left side of trunk, shoulder, and right shoulder and arm. History of any spontaneous bleeding from any orifice was not reported. History of any joint swelling or any episode of unconsciousness or abnormal body movements was not reported. On physical examination, his vitals were stable. Systemic examination was unremarkable. Cutaneous examination revealed large areas of nonpalpable ecchymotic patches involving left buttock reaching up to the right buttock, left side of trunk, shoulder, and arm and right shoulder, neck, and anterior chest [Figure 1] . On diascopy, the bluish discoloration persisted, confirming the purpura. Laboratory investigations revealed positive enzyme-linked immunosorbent assay for HIV, which was an incidental finding. Rest of his laboratory tests including platelet count and bleeding, clotting, and prothrombin times were unremarkable. He was advised skin biopsy for histopathological examination in view of the extensive purpuric lesions with some lesions distant from the main site of injection and separated by areas of normal skin. However, consent for biopsy was not given. On the basis of history and a suggestive clinical examination, a diagnosis of NS secondary to IM injection of paracetamol was made. He was managed conservatively with oral diclofenac and topical histocalamine lotion. He was referred to HIV medicine department for further management of HIV. As no necrosis occurred in our case, the patient recovered fully in 4 weeks without any complication.\n\nFigure 1 (A) Extensive purpuric patches over left thigh, buttock, left half of trunk, shoulder, and reaching up to the right buttock. (B) Purpuric patches over right shoulder, anterior chest, and neck. (C) Purpuric patches involving left side of abdomen\n\nDISCUSSION\nNS, which is also known by other terms such as “livedo-like dermatitis” and “embolia cutis medicamentosa,” is a rare type of adverse reaction that occurs after parenteral (intra-arterial, IM, or rarely subcutaneous route) drug injection. Usually, the patients complain of pain around the injection site soon after injection. This is followed by the appearance of redness at the site of injection. Later, a bluish discoloration appears forming a hemorrhagic patch, which can break down leading to necrosis and ulceration.[2] However, in our case, there were extensive purpuric lesions but fortunately no necrosis and ulceration occurred.\n\nKim and Chae[6] reviewed the various drugs and vaccines related to NS. These include diclofenac sodium, ibuprofen, piroxicam, salicylate, ketoprofen, ketorolac, benzathine penicillin, bismuth, interferon β, penicillin G, gentamycin, meperidine, hydroxyzine, chlorpheniramine maleate, thiocolchicoside, glatiramer acetate, etanercept, naltrexone, lidocaine, vitamin K, calcium hydroxide, triamcinolone, cyanocobalamin (vitamin B12), Trabit (dexamethasone, phenylbutazone, lidocaine, and salicylamide), diphtheria-pertussis-tetanus (DPT) vaccine, mesotherapy injections, and DPT-polio-Hib vaccine. Diclofenac sodium has been considered as the major drug responsible for NS.[6]\n\nWe believe that it is probably the first case of NS developing after paracetamol injection in a patient who is HIV positive. NS in a patient who is HIV positive after subcutaneous injection of alpha interferon was reported by Rasokat et al.[7] The extensive involvement in our case may be due to the associated HIV infection. But whether it is a true association or not, needs further reports and studies. Kim et al.[8] reported a case of bilateral NS after uterine artery embolization for postpartum bleeding. Similarly, in our case, lesions also spread to the opposite buttock and contralateral shoulder.\n\nAlthough the exact mechanism for NS is unknown, earlier it was thought that immunologic mechanisms, pH, or other properties of the administered drug and faulty injection technique are the causative factors. However, this hypothesis does not stand now in view of various experimental studies.[9] An inadvertent IM injection into an artery leading to arterial spasm and consequent formation of emboli has been proposed as the possible mechanism.[3] Another widely accepted hypothesis in the pathogenesis of NS was vessel damage, acute arterial thrombosis, and subsequent necrosis following paravasal injection of drugs. This hypothesis was supported by Guarneri et al.[10] in their cases of NS following IM injection of ketorolac, tromethamine, and thiocolchicoside. Hence, the physiopathology of NS can be summarized as: (1) vascular or perivascular injection causing tissue inflammation and necrosis, (2) intra-arterial injection causing embolus formation culminating in occlusion of small vessels, (3) arterial spasm because of reactive sympathetic stimuli caused by intra-arterial injection, and (4) needle-induced mechanical trauma. The leakage of drug around artery and neural space has been suggested as the cause of intense pain. Diclofenac as a cyclooxygenase inhibitor inhibits prostaglandin synthesis and causes vasoconstriction. So, pathogenetic mechanism of diclofenac in NS is also suggested by its vasospastic effect.[11] In our case, the patient received injection in his buttock, later he developed lesions on the left side of trunk and shoulder and right shoulder and arm. On literature review, we also found similar cases where lesions spread to distant area from the initial injection site. Alyasin and Sharifian[12] described a case where the initial injection site was left buttock; however, lesions gradually spread to the left leg, thigh, foot, and finally fingers. Similar cases were also reported by Memarian et al.[13]\n\nThe diagnosis of NS relies mainly on history and clinical findings as no specific laboratory investigations are available for it. Skin biopsy is also noncontributory as thrombosis of small- and medium-sized arteries and a nonspecific inflammatory infiltrate and necrosis are reported.[14]\n\nTreatment options include control of pain, use of antibiotics, and dressings depending on the severity of the condition. Surgical methods employing debridement of necrotic tissue and skin grafting may be needed in severe cases. Radical excision of necrotic tissue is important because inadequate debridement leads to poor wound healing.[14] Hence, computerized tomography scan or magnetic resonance imaging is needed to determine the extent of tissue involvement. There is a vital role of systemic antibiotics in its management. A conservative treatment employing pain control and debridement has been considered as the main therapy by Murthy et al.[3] Because of the uncommon nature of disease and lack of clinical trials, a standard treatment regimen with proven benefit cannot be referenced. Supportive treatments such as anticoagulant, pentoxifylline, hyperbaric oxygen, and steroids have been attempted besides the aforementioned conservative methods.[1516]\n\nNS is a complication that can be avoided or minimized. The injection needle that is used should be long enough to reach the muscle compartment. The Z-track injection technique should be followed. This is a method of IM injection into a large muscle using a needle and syringe and it can minimize or prevent NS.[13] This technique of injection seals the medication deeply within the muscle and allows no exit path back into the subcutaneous tissue and skin. First, this is performed by displacing the skin and subcutaneous tissue, 1–1.5 inches (2.5–3.75cm) laterally, by the nondominant hand, before injection and releasing the tissue immediately after the injection. Second, a long needle (long enough to reach the muscle) should be used. A patient weighing 90kg requires a 5–7.5cm (2- or 3-inch) needle and a 45-kg patient requires a 3.18 or 3.68cm (1.25- or 1.45-inch) needle. Third, the injection should be applied in the upper outer quadrant of the buttock. Fourth, before injecting medication, aspiration should be performed to ensure that no blood vessel is hit. Fifth, never inject more than 5mL of medication at a single site when using the Z-track injection technique. Finally, if a larger dose of medication is needed or more than one injection is required, different sites should be chosen by the health-care professional.[1417]\n\nCONCLUSION\nNS is a rare, underestimated but preventable complication of an inadvertent parenteral injection. Proper injection technique and selection of suitable site for injection can prevent this complication.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Nicolau S Dermite livédoïde et gangréneuse de la fesse, consécutive aux injections intra-musculaires, dans la syphilis: à propos d’un cas d’embolie artérielle bismuthique Ann Mal Vener 1925 20 321 39 \n2 Kim KK Nicolau syndrome in patient following diclofenac administration: a case report Ann Dermatol 2011 23 501 3 22148020 \n3 Murthy SC Siddalingappa K Suresh T Nicolau’s syndrome following diclofenac administration: a report of two cases Indian J Dermatol Venereol Leprol 2007 73 429 31 18032871 \n4 Luton K Garcia C Poletti E Koester G Nicolau syndrome: three cases and review Int J Dermatol 2006 45 1326 8 17076716 \n5 Adil M Amin SS Arif T Nicolau’s syndrome: a rare but preventable iatrogenic disease Acta Dermatovenerol Croat 2017 25 251 3 29252181 \n6 Kim KK Chae DS Nicolau syndrome: a literature review World J Dermatol 2015 54 103 7 \n7 Rasokat H Bendick C Wemmer U Steigleder GK [Aseptic skin necrosis after subcutaneous injection of alpha interferon] Dtsch Med Wochenschr 1989 114 458 60 2924699 \n8 Kim TH Lee HH Kim JM Bilateral Nicolau syndrome after uterine artery embolization for postpartum bleeding Acta Obstet Gynecol Scand 2014 93 954 5 24766520 \n9 Guarneri C Polimeni G Nicolau syndrome following etanercept administration Am J Clin Dermatol 2010 11 51 2 \n10 Guarneri C Bevelacqua V Polimeni G Embolia cutis medicamentosa (Nicolau syndrome) QJM 2012 105 1127 8 21990368 \n11 Ezzedine K Vadoud-Seyedi J Heenen M Nicolau syndrome following diclofenac administration Br J Dermatol 2004 150 385 7 14996127 \n12 Alyasin S Sharifian M Nicolau syndrome caused by penicillin injection a report from Iran Shiraz E Medical Journal 2010 11 102 4 \n13 Memarian S Gharib B Gharagozlou M Alimadadi H Ahmadinejad Z Ziaee V Nicolau syndrome due to penicillin injection: a report of 3 cases without long-term complication Case Rep Infect Dis 2016 2016 9082158 27882254 \n14 Lie C Leung F Chow SP Nicolau syndrome following intramuscular diclofenac administration: a case report J Orthop Surg (Hong Kong) 2006 14 104 7 16598099 \n15 Ocak S Ekici B Cam H Taştan Y Nicolau syndrome after intramuscular benzathine penicillin treatment Pediatr Infect Dis J 2006 25 749 16874179 \n16 Ozcan A Senol M Aydin EN Aki T Embolia cutis medicamentosa (Nicolau syndrome): two cases due to different drugs in distinct age groups Clin Drug Investig 2005 25 481 3 \n17 Pullen RL Jr Administering medication by the Z-track method Nursing 2005 35 24\n\n",
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"title": "Extensive Nicolau Syndrome Following Intramuscular Injection of Paracetamol in a Patient Who Is HIV Positive.",
"title_normalized": "extensive nicolau syndrome following intramuscular injection of paracetamol in a patient who is hiv positive"
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"abstract": "CONCLUSIONS\nEntinostat at the selected dose levels in combination with a standard dose of enzalutamide showed a promising safety profile in this small phase I study BACKGROUND: Entinostat inhibits prostate cancer (PCa) growth and suppresses Treg cell function in vitro and in vivo.\n\n\nMETHODS\nThis was a phase I study to explore the safety and preliminary efficacy of entinostat (3 and 5 mg orally per week) in combination with enzalutamide in castration resistant PCa (CRPC). The study was carried out in an open-label two-cohort design. Patients who had developed disease progression on or were eligible for enzalutamide were enrolled in the study. The safety profile of the combination therapy, Prostate specific antigen (PSA) levels, the pharmacokinetics of enzalutamide after entinostat administration, peripheral T-cell subtype (including Treg quantitation), and mononuclear cell (PBMC) histone H3 acetylation were analyzed.\n\n\nRESULTS\nSix patients with metastatic CRPC were enrolled. There was no noticeable increment of fatigue related to entinostat. Toxicities possibly or probably related to entinostat or the combination therapy included grade 3 anemia 1/6 (17%), grade 2 white blood cell (WBC) decrease 1/6 (17%), and other self-limiting grade 1 adverse events (AEs). Median duration of treatment with entinostat was 18 weeks. Entinostat did not affect the steady plasma concentration of enzalutamide. Increased PBMC histone H3 acetylation was observed in blood samples. No evident T-cell subtype changes were detected, including in Treg quantitation.\n\n\nCONCLUSIONS\nEntinostat 5 mg weekly in combination with enzalutamide showed an acceptable safety profile in this small phase I study. A planned phase II part of the trial was terminated because of sponsor withdrawal.",
"affiliations": "Department of Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.;Department of Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.;Department of Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.;Department of Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.;Department of Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.;Department of Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.;Department of Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.;Department of Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.;Department of Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.;Department of Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.",
"authors": "Lin|Jianqing|J|https://orcid.org/0000-0002-0406-690X;Elkon|Jacob|J|;Ricart|Brittany|B|;Palmer|Erica|E|;Zevallos-Delgado|Christian|C|;Noonepalle|Satish|S|;Burgess|Brooke|B|;Siegel|Robert|R|;Ma|Yan|Y|;Villagra|Alejandro|A|",
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"abstract": "We describe the clinicopathologic features of 17 patients who had a hematologic malignancy of various types, were treated, and subsequently developed a lymphoproliferative disorder (LPD). There were 10 men and 7 women with a median age of 59 years (range, 36 to 83 y). The primary hematologic neoplasms included: 5 chronic lymphocytic leukemia/small lymphocytic lymphoma, 3 plasma cell myeloma, 2 acute monoblastic leukemia, and 1 case each of mixed-phenotype acute leukemia, chronic myeloid leukemia, splenic marginal zone lymphoma, follicular lymphoma, mantle cell lymphoma, T-cell prolymphocytic leukemia, and peripheral T-cell lymphoma. All patients were treated with chemotherapy with or without therapeutic antibodies; 3 also underwent autologous stem cell transplantation. The mean interval from initiation of therapy for initial hematologic malignancy to onset of LPD was 66 months (range, 3 to 299 mo). Ten (59%) LPDs were extranodal and 7 (41%) involved nodal tissues. The histologic diagnoses included: 8 diffuse large B-cell lymphoma, 4 classical Hodgkin lymphoma, 3 polymorphic LPD, 1 lymphomatoid granulomatosis, and 1 Epstein-Barr virus (EBV) mucocutaneous ulcer. Fourteen cases were EBV. Following the onset of LPD, chemotherapy was administered to 10 (59%) patients. With a median follow-up of 100 months (range, 5 to 328 mo), 8 (47%) patients are alive and 9 (53%) died. One (6%) patient with lymphomatoid granulomatosis underwent spontaneous remission. On the basis of the clinicopathologic features and high prevalence of EBV infection in this cohort, we believe that these LPDs show similarities with other types of immunodeficiency-associated LPDs. We suggest that cancer therapy-associated LPD be included in future classification systems for immunodeficiency-associated LPDs.",
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"title": "Cancer Therapy-associated Lymphoproliferative Disorders: An Under-recognized Type of Immunodeficiency-associated Lymphoproliferative Disorder.",
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... |
{
"abstract": "A 6 1-year-old man with unresectable multiple hepatic metastases after resection of sigmoid colon carcinoma was treated with irinotecan and infused 5-fluorouracil (5-FU) plus Leucovorin (FOLFIRI). Since the levels of tumor markers increased, the 5-FU dose was increased from 2,700 to 3,000 mg/m2 using a Jackson-type pump and an extended infusion time of 53 hours. The blood level of 5-FU was 507 ng/mL 16 hours after starting the infusion. The pump was then changed to a bottle-type pump with the same dose of 3,000 mg/m2. At 16 hours, the 5-FU level was 964.5 ng/mL. The areas under the concentration vs. time curve (AUC mg・h/L)were 21 and 44 mg・h/L for the Jackson- and bottle-type pumps, respectively. Owing to the development of Grade 3 stomatitis and hand-foot syndrome, 5-FU was reduced to 2,700 mg/m2 with a bottle-type pump. The AUC decreased to 27 mg・h/L, but the liver metastases were reduced and the adverse effects subsided to Grade 1. This case shows that individual dose adjustment of 5-FU to the appropriate AUC based on pharmacokinetic monitoring of the blood 5-FU level can improve the response, reduce adverse effects, and have a clinical benefit.",
"affiliations": "Dept. of Surgery, Niitsu Medical Center Hospital.",
"authors": "Muneoka|Katsuki|K|;Shirai|Yoshio|Y|;Kanda|Junkichi|J|;Sasaki|Masataka|M|;Wakai|Toshifumi|T|;Wakabayashi|Hiroyuki|H|",
"chemical_list": "D020724:Elastomers; D011108:Polymers; C036925:elastomeric polymer; D005472:Fluorouracil",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "42(10)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D004334:Drug Administration Schedule; D020724:Elastomers; D005472:Fluorouracil; D006801:Humans; D007260:Infusion Pumps; D007262:Infusions, Intravenous; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D011108:Polymers; D012811:Sigmoid Neoplasms",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1215-8",
"pmc": null,
"pmid": "26489552",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Improved Response to 5-FU Using Dose Adjustment and Elastomeric Pump Selection Based on Monitoring of the 5-FU Level--A Case Report.",
"title_normalized": "improved response to 5 fu using dose adjustment and elastomeric pump selection based on monitoring of the 5 fu level a case report"
} | [
{
"companynumb": "PHHY2016JP064362",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IRINOTECAN"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Combination therapy with ipilimumab and nivolumab is an adjuvant treatment approach for metastatic melanoma that boasts increased 3-year survival when compared with a single immunotherapy agent. Combination therapy, however, is associated with increased toxicities, especially cutaneous side-effects. Here we present a patient with metastatic melanoma and a sudden eruption of painful nodules on the face and arms 10 days after the administration of the fourth dose of combination ipilimumab/nivolumab. Biopsies demonstrated lymphoid hyperplasia, not clinically or pathologically consistent with an infectious, malignant or autoimmune etiology; a diagnosis of pseudolymphoma secondary to ipilimumab/nivolumab was made. After a steroid taper, the lesions resolved, and the patient was restarted on nivolumab monotherapy 2 weeks later without recurrence of symptoms or disease.",
"affiliations": "Morsani College of Medicine, University of South Florida, Tampa, Florida.;Department of Dermatology and Cutaneous Surgery, University of South Florida, Tampa, Florida.;Department of Dermatology and Cutaneous Surgery, University of South Florida, Tampa, Florida.;Department of Dermatology, Pathology and Cell Biology, University of South Florida, Tampa, Florida.;Cutaneous Oncology Program, H. Lee Moffitt Cancer and Research Center, Tampa, Florida.;Cutaneous Oncology Program, H. Lee Moffitt Cancer and Research Center, Tampa, Florida.;Department of Dermatology and Cutaneous Surgery, University of South Florida, Tampa, Florida.",
"authors": "Ayoubi|Noura|N|https://orcid.org/0000-0001-6462-8620;Haque|Adel|A|;Vera|Nora|N|;Ma|Sophia|S|;Messina|Jane|J|;Khushalani|Nikhil|N|;Seminario-Vidal|Lucia|L|",
"chemical_list": "D000074324:Ipilimumab; D013256:Steroids; D000077594:Nivolumab",
"country": "United States",
"delete": false,
"doi": "10.1111/cup.13604",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0303-6987",
"issue": "47(4)",
"journal": "Journal of cutaneous pathology",
"keywords": "drug rash; ipilimumab; melanoma; nivolumab; oncodermatology; pseudolymphoma",
"medline_ta": "J Cutan Pathol",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D006801:Humans; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma; D016609:Neoplasms, Second Primary; D000077594:Nivolumab; D019310:Pseudolymphoma; D012878:Skin Neoplasms; D013256:Steroids",
"nlm_unique_id": "0425124",
"other_id": null,
"pages": "390-393",
"pmc": null,
"pmid": "31677178",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Ipilimumab/nivolumab-induced pseudolymphoma in a patient with malignant melanoma.",
"title_normalized": "ipilimumab nivolumab induced pseudolymphoma in a patient with malignant melanoma"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2019-113292",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IPILIMUMAB"
},
"drugadd... |
{
"abstract": "BACKGROUND\nHepatitis E virus (HEV) genotype 3 infections can have important clinical consequences.\n\n\nOBJECTIVE\nTo evaluate patients at risk and the effect of treatment strategies, we studied the clinical course and treatment outcome in patients diagnosed with HEV viremia in our hospital.\n\n\nMETHODS\nBetween January 2008 and March 2015 we included all patients with HEV genotype 3 (HEV-3) infections diagnosed by means of quantitative real-time reverse transcription-polymerase chain reaction test (RT-PCR). Clinical data were evaluated retrospectively.\n\n\nRESULTS\nIn total 79 patients were included. Forty-nine patients (62%) were male, median age of all patients was 52 years (range 13-79). Sixty-one (77%) patients were immunocompromised. Three patients (3.8%) had only transient viremia, forty-three (54.5%) cleared the infection within six months and twenty-six (32.9%) developed chronic infection. Five patients (6.3%) were lost to follow-up. All patients developing chronic infection were immunocompromised. Overall, thirteen (16%) patients within this cohort died. Three patients had pre-existent liver diseases and died of liver-related causes. Time between diagnosis and death was shorter for patients with pre-existent liver diseases (p=0.03). Twenty-eight percent of patients on immunosuppressive medication achieved viral clearance after reducing the dose of immunosuppressive therapy. Thirty patients (38.0%) were treated with off-label ribavirin in which 25 (83.3%) a sustained viral response has been documented.\n\n\nCONCLUSIONS\nHEV genotype 3 viremia mainly presents in patients with underlying chronic liver diseases or an impaired immune system. Patients with pre-existent liver diseases are at high risk for complications and even death. The off-label use of ribavirin can cure HEV infection.",
"affiliations": "Erasmus MC, University Medical Center Rotterdam, Department of Gastroenterology and Hepatology, PO Box 2040, 3000CA Rotterdam, The Netherlands.;Erasmus MC, University Medical Center Rotterdam, Department of Viroscience, PO Box 2040, 3000CA Rotterdam, The Netherlands.;Erasmus MC, University Medical Center Rotterdam, Department of Haematology, PO Box 2040, 3000CA Rotterdam, The Netherlands.;Erasmus MC, University Medical Center Rotterdam, Department of Cardiology, PO Box 2040, 3000CA Rotterdam, The Netherlands.;Erasmus MC, University Medical Center Rotterdam, Department of Pulmonology, PO Box 2040, 3000CA Rotterdam, The Netherlands.;Erasmus MC, University Medical Center Rotterdam, Department of Internal Medicine, PO Box 2040, 3000CA Rotterdam, The Netherlands.;Erasmus MC, University Medical Center Rotterdam, Department of Viroscience, PO Box 2040, 3000CA Rotterdam, The Netherlands.;Erasmus MC, University Medical Center Rotterdam, Department of Gastroenterology and Hepatology, PO Box 2040, 3000CA Rotterdam, The Netherlands. Electronic address: r.deman@erasmusmc.nl.",
"authors": "Nijskens|Charlotte M|CM|;Pas|Suzan D|SD|;Cornelissen|Jan|J|;Caliskan|Kadir|K|;Hoek|Rogier A S|RA|;Hesselink|Dennis A|DA|;van der Eijk|Annemiek A|AA|;de Man|Robert A|RA|",
"chemical_list": "D000998:Antiviral Agents",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1386-6532",
"issue": "74()",
"journal": "Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology",
"keywords": "Chronic disease; HEV; Hepatitis E; Pre-existent liver disease; Ribavirin; Solid organ transplant",
"medline_ta": "J Clin Virol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents; D005260:Female; D005838:Genotype; D016751:Hepatitis E; D016752:Hepatitis E virus; D006801:Humans; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D060888:Real-Time Polymerase Chain Reaction; D012189:Retrospective Studies; D016019:Survival Analysis; D062606:Tertiary Care Centers; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9815671",
"other_id": null,
"pages": "82-7",
"pmc": null,
"pmid": "26687439",
"pubdate": "2016-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Hepatitis E virus genotype 3 infection in a tertiary referral center in the Netherlands: Clinical relevance and impact on patient morbidity.",
"title_normalized": "hepatitis e virus genotype 3 infection in a tertiary referral center in the netherlands clinical relevance and impact on patient morbidity"
} | [
{
"companynumb": "NL-KADMON PHARMACEUTICALS, LLC-KAD201601-000087",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugaddi... |
{
"abstract": "OBJECTIVE\nTo report acute visual loss associated with dynamic vascular changes after photodynamic therapy (PDT) combined with intravitreal triamcinolone (IVTA) for the treatment of occult choroidal neovascularization (CNV).\n\n\nMETHODS\nAn 86-year-old woman complained of visual loss in her left eye. Angiographic examination showed a serous pigment epithelium detachment complicated by CNV. She underwent combined treatment with IVTA (4 mg) followed by standard verteporfin PDT administered after a 5-day interval.\n\n\nRESULTS\nThe patient developed vision loss 1 day after PDT. Ophthalmoscopic examination disclosed an acute serous neurosensory retinal detachment. Fluorescein angiography showed a large area of early hypofluorescence in correspondence to and extending beyond the photodynamic spot. Neurosensory retinal vessels involvement with dilation of the retinal arterioles and capillary nonperfusion were also revealed. Indocyanine green angiography showed choroidal infarction within the collateral choroid included in the area of light exposure, with associated nonperfusion of medium and large choroidal vessels being revealed. Five days after PDT, spontaneous severe bleeding with breakthrough into the vitreous occurred, in addition to an RPE tear.\n\n\nCONCLUSIONS\nAcute loss of vision associated with vascular changes in retinal and choroidal circulation represents an uncommon but serious complication following combined PDT and IVTA. These risks should be carefully considered in combination therapies.",
"affiliations": "Department of Ophthalmology, Sant'Antonio Hospital, Padova, Italy. gvofta@libero.it",
"authors": "Lo Giudice|G|G|;De Belvis|V|V|;Piermarocchi|S|S|;Galan|A|A|;Prosdocimo|G|G|",
"chemical_list": "D005938:Glucocorticoids; D014222:Triamcinolone Acetonide; D007208:Indocyanine Green",
"country": "United States",
"delete": false,
"doi": "10.1177/112067210801800429",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1120-6721",
"issue": "18(4)",
"journal": "European journal of ophthalmology",
"keywords": null,
"medline_ta": "Eur J Ophthalmol",
"mesh_terms": "D000208:Acute Disease; D000369:Aged, 80 and over; D002829:Choroid; D020256:Choroidal Neovascularization; D003131:Combined Modality Therapy; D005260:Female; D005451:Fluorescein Angiography; D005938:Glucocorticoids; D006801:Humans; D007208:Indocyanine Green; D007238:Infarction; D007267:Injections; D008268:Macular Degeneration; D010778:Photochemotherapy; D012163:Retinal Detachment; D014222:Triamcinolone Acetonide; D014786:Vision Disorders; D014822:Vitreous Body",
"nlm_unique_id": "9110772",
"other_id": null,
"pages": "652-5",
"pmc": null,
"pmid": "18609494",
"pubdate": "2008",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute visual loss and chorioretinal infarction after photodynamic therapy combined with intravitreal triamcinolone.",
"title_normalized": "acute visual loss and chorioretinal infarction after photodynamic therapy combined with intravitreal triamcinolone"
} | [
{
"companynumb": "IT-SA-2021SA211332",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRIAMCINOLONE ACETONIDE"
},
"drugadditional": "3",
... |
{
"abstract": "With rising use worldwide, pregabalin is increasingly implicated in poisoning deaths. We aimed to investigate the clinical effects and complications of pregabalin poisoning.\n\n\n\nThis is a retrospective review of patients presenting with pregabalin poisoning to two tertiary toxicology units from 1 July 2014 to 30 June 2019. Patients were identified from prospective databases maintained by both units and data were extracted from these in addition to medical records.\n\n\n\nThere were 488 presentations in 413 patients (237 [57%] male) over the five-year period. The median age was 41 years (IQR 31-50 years). Deliberate self-poisonings accounted for 342 (70%) presentations, with 121 (25%) recreational exposures. Recreational exposures increased over the period from 2 (4%) in the first year to 54 (39%) presentations in the final year. The median dose of pregabalin was 1200 mg (IQR 600-3000 mg, range 75-16 800 mg). Co-ingestions occurred in 427 (88%) presentations, with sedating agents being co-ingested in 387 (79%)-most commonly opioids and benzodiazepines in 201 (41%) and 174 (36%) presentations respectively. Coma (GCS < 9) occurred in 89 (18%) cases, with 52 (11%) patients being intubated. Only one (0.2%) of these patients had not co-ingested a sedating agent. Hypotension occurred in 26 (5%) cases, all with co-ingestants. Seizures occurred in 11 (2%) cases, 3/59 (5%) in pregabalin-only overdoses. The median length of stay was 16.5 hours (IQR 10-25 hours).\n\n\n\nPregabalin overdose does not cause severe toxicity, but rather mild sedation and, uncommonly, seizures. Coma is common in the presence of sedating co-ingestants. Recreational use is increasing.",
"affiliations": "Clinical Toxicology Unit, Princess Alexandra Hospital, Brisbane, Queensland, Australia.;Clinical Toxicology Unit, Princess Alexandra Hospital, Brisbane, Queensland, Australia.;Clinical Toxicology Unit, Princess Alexandra Hospital, Brisbane, Queensland, Australia.;Clinical Toxicology Research Group, University of Newcastle, Newcastle, New South Wales, Australia.",
"authors": "Isoardi|Katherine Z|KZ|0000-0002-1176-7923;Polkinghorne|Gregory|G|;Harris|Keith|K|;Isbister|Geoffrey K|GK|0000-0003-1519-7419",
"chemical_list": "D000701:Analgesics, Opioid; D001569:Benzodiazepines; D000069583:Pregabalin",
"country": "England",
"delete": false,
"doi": "10.1111/bcp.14348",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0306-5251",
"issue": "86(12)",
"journal": "British journal of clinical pharmacology",
"keywords": "drug abuse; overdose and poisoning; toxicology",
"medline_ta": "Br J Clin Pharmacol",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D001569:Benzodiazepines; D062787:Drug Overdose; D005260:Female; D006801:Humans; D008297:Male; D011041:Poisoning; D000069583:Pregabalin; D012189:Retrospective Studies",
"nlm_unique_id": "7503323",
"other_id": null,
"pages": "2435-2440",
"pmc": null,
"pmid": "32374500",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "28315808;17719135;30712302;16433872;29264838;28493329;29297045;28144823;20373065;31601126;26951495;25929508;30098227;18668385;32374500;24515527;17448068;28988943",
"title": "Pregabalin poisoning and rising recreational use: a retrospective observational series.",
"title_normalized": "pregabalin poisoning and rising recreational use a retrospective observational series"
} | [
{
"companynumb": "AU-ALKEM LABORATORIES LIMITED-AU-ALKEM-2020-02144",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREGABALIN"
},
"druga... |
{
"abstract": "African tick bite fever is the most commonly encountered travel-associated rickettsiosis, occurring in as many as 5% of travelers returning from rural subequatorial Africa. This case report illustrates that rifampin represents an effective alternative to doxycycline for treatment of African tick bite fever in some selective situations.",
"affiliations": "Division of Infectious Diseases, Duke University Medical Center, Durham, North Carolina.;Rickettsial Zoonoses Branch, Centers for Disease Control and Prevention, Atlanta, Georgia.;ViiV Healthcare, Research Triangle Park, North Carolina.;Rickettsial Zoonoses Branch, Centers for Disease Control and Prevention, Atlanta, Georgia.;Rickettsial Zoonoses Branch, Centers for Disease Control and Prevention, Atlanta, Georgia.;Rickettsial Zoonoses Branch, Centers for Disease Control and Prevention, Atlanta, Georgia.;Rickettsial Zoonoses Branch, Centers for Disease Control and Prevention, Atlanta, Georgia.;Division of Infectious Diseases, Duke University Medical Center, Durham, North Carolina.",
"authors": "Strand|Andrew|A|;Paddock|Christopher D|CD|;Rinehart|Alex R|AR|;Condit|Marah E|ME|;Marus|Jessica R|JR|;Gillani|Shezeen|S|;Chung|Ida H|IH|;Fowler|Vance G|VG|",
"chemical_list": "D000900:Anti-Bacterial Agents; D004318:Doxycycline; D012293:Rifampin",
"country": "United States",
"delete": false,
"doi": "10.1093/cid/cix363",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-4838",
"issue": "65(9)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": "African tick bite fever; Rickettsia africae; rifampin",
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000900:Anti-Bacterial Agents; D004318:Doxycycline; D006801:Humans; D008297:Male; D008875:Middle Aged; D012281:Rickettsia; D012293:Rifampin; D000073605:Spotted Fever Group Rickettsiosis",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "1582-1584",
"pmc": null,
"pmid": "28505276",
"pubdate": "2017-10-16",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "6548581;18387179;16242016;12766836;24092850;15546086;1856496;1810178;12949322;10447334;15541225;1671856;25385549;16449002;25118103;27172113;9382560;11550121;23135935;9660979;17353249;3104481;4863911;16291409;24314770;11939395;12954562;8862558;10508014;3144922;12803376;8426619;9675481",
"title": "African Tick Bite Fever Treated Successfully With Rifampin in a Patient With Doxycycline Intolerance.",
"title_normalized": "african tick bite fever treated successfully with rifampin in a patient with doxycycline intolerance"
} | [
{
"companynumb": "US-GALDERMA-US17011691",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXYCYCLINE"
},
"drugadditional": "3",
... |
{
"abstract": "The aim of this paper is to describe the third pregnancy trimester, delivery and puerperium in patient with idiopathic pulmonary hypertension.\n\n\n\na 30-year-old primigravida with idiopathic pulmonary hypertension was qualified for emergency Caesarean section. In the post partum period no improvement in managing pulmonary arterial hypertension was achieved. Because of progressive respiratory and circulatory failure as well as the pulmonary artery pressure exceeding the systemic pressure the AV ECMO was applied on postoperative day 6. During the ECMO period the emergency laparotomy due to bleeding was necessary. The further course of ICU treatment was uneventful.\n\n\n\nIn described case things are left to chance or goodwill of specialists and final outcome depend on happy coincidences.",
"affiliations": "Cardiologic Intensive Care Unit, Prof. Leszek Giec Upper Silesian Medical Centre, Medical University of Silesia, Katowice, ul. Ziołowa 45-47, 40-635 Katowice, Poland.;Department of Cardiac Anaesthesia and Intensive Therapy, Medical University of Silesia, Ziołowa 45/47, 40-635 Katowice, Poland.;Cardiologic Intensive Care Unit, Prof. Leszek Giec Upper Silesian Medical Centre, Medical University of Silesia, Katowice, ul. Ziołowa 45-47, 40-635 Katowice, Poland.;Cardiologic Intensive Care Unit, Prof. Leszek Giec Upper Silesian Medical Centre, Medical University of Silesia, Katowice, ul. Ziołowa 45-47, 40-635 Katowice, Poland.;Department of Cardiac Surgery, Medical University of Silesia, Katowice, Poland.;Department of Gynaecology and Obstetrics,, Upper Silesian Medical Centre, Medical University of Silesia, Ziołowa 45-47, 40-635 Katowice, Poland.;Department of Gynaecology and Obstetrics,, Upper Silesian Medical Centre, Medical University of Silesia, Ziołowa 45-47, 40-635 Katowice, Poland.;1st Department of Cardiology, Medical University of Silesia, Katowice, Poland.;1st Department of Cardiology, Medical University of Silesia, Katowice, Poland.;Department of Cardiac Anaesthesia and Intensive Therapy, Medical University of Silesia, Ziołowa 45/47, 40-635 Katowice, Poland. kucewiczewa@op.pl.",
"authors": "Maciejewski|Tomasz|T|;Darocha|Tomasz|T|;Kiermasz|Kazimierz|K|;Budziarz|Barbara|B|;Duraj|Piotr|P|;Szanecki|Wojciech|W|;Mackiewicz|Mirosława|M|;Myszor|Jarosław|J|;Mizia-Stec|Katarzyna|K|;Kucewicz-Czech|Ewa|E|",
"chemical_list": null,
"country": "Poland",
"delete": false,
"doi": "10.5603/AIT.a2019.0001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1642-5758",
"issue": "51(1)",
"journal": "Anaesthesiology intensive therapy",
"keywords": null,
"medline_ta": "Anaesthesiol Intensive Ther",
"mesh_terms": "D000328:Adult; D002585:Cesarean Section; D004630:Emergencies; D015199:Extracorporeal Membrane Oxygenation; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D011181:Postnatal Care; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular",
"nlm_unique_id": "101472620",
"other_id": null,
"pages": "70-71",
"pmc": null,
"pmid": "30667036",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Emergency caesarean section delivery and puerperium in a patient with severe idiopathic pulmonary arterial hypertension - a case report.",
"title_normalized": "emergency caesarean section delivery and puerperium in a patient with severe idiopathic pulmonary arterial hypertension a case report"
} | [
{
"companynumb": "PL-PFIZER INC-2019180760",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ILOPROST"
},
"drugadditional": "3",
... |
{
"abstract": "Aortopulmonary window (APW) is a rare congenital heart defect with abnormal communication between the ascending aorta and the pulmonary trunk with two separate semilunar valves. We present an autopsy case report wherein a young primigravida woman presented with progressive breathlessness and central cyanosis at 21 weeks of gestation. Echocardiography performed in the emergency room revealed elevated right-sided cardiac pressures suggestive of severe pulmonary hypertension; however, no structural cardiac defect was discernible. The patient succumbed to congestive cardiac failure and progressive hypoxia within 5 days of hospitalization. The autopsy revealed a Type I aortopulmonary window (2 cm) with patent ductus arteriosus. The lungs showed changes of severe pulmonary hypertension with superadded bronchopneumonia. This report underscores a rare presentation of APW, undiagnosed until pregnancy, leading to the Eisenmenger syndrome and death.",
"affiliations": "Post Graduate Institute of Medical Education & Research (PGIMER), Departments of Histopathology, Chandigarh, India.;Post Graduate Institute of Medical Education & Research (PGIMER), Departments of Histopathology, Chandigarh, India.;Post Graduate Institute of Medical Education & Research (PGIMER), Departments of Internal Medicine, Chandigarh, India.;Post Graduate Institute of Medical Education & Research (PGIMER), Departments of Internal Medicine, Chandigarh, India.;Post Graduate Institute of Medical Education & Research (PGIMER), Departments of Histopathology, Chandigarh, India.",
"authors": "Thirunavukkarasu|Balamurugan|B|0000-0002-5583-1720;Kithan|Lijanthung S|LS|0000-0001-9946-4902;Kumar|Nikhil|N|0000-0003-2601-696X;Jain|Arihant|A|0000-0001-9495-9789;Bal|Amanjit|A|0000-0002-1457-8589",
"chemical_list": null,
"country": "Brazil",
"delete": false,
"doi": "10.4322/acr.2021.265",
"fulltext": "\n==== Front\nAutops Case Rep\nAutops Case Rep\nacrep\nAutopsy & Case Reports\n2236-1960\nHospital Universitário da Universidade de São Paulo\n\nacrep085920\n00203\n10.4322/acr.2021.265\nAutopsy Case Report and Review\nFatal outcome of congenital aortopulmonary window with patent ductus arteriosus complicating pregnancy\nhttp://orcid.org/0000-0002-5583-1720\nThirunavukkarasu Balamurugan 1\nhttp://orcid.org/0000-0001-9946-4902\nKithan Lijanthung S. 1\nhttp://orcid.org/0000-0003-2601-696X\nKumar Nikhil 2\nhttp://orcid.org/0000-0001-9495-9789\nJain Arihant 2\nhttp://orcid.org/0000-0002-1457-8589\nBal Amanjit 1\n1 Post Graduate Institute of Medical Education & Research (PGIMER), Departments of Histopathology, Chandigarh, India\n2 Post Graduate Institute of Medical Education & Research (PGIMER), Departments of Internal Medicine, Chandigarh, India\nAuthors’ contributions: Balamurugan Thirunavukkarasu was involved in data collection, literature review and drafting of the manuscript. Amanjit Bal contributed to the drafting of the manuscript and supervised it. Balamurugan Thirunavukkarasu, Lijanthung S. Kithan, and Amanjit Bal were involved in the diagnosis on autopsy. Nikhil Kumar and Arihant Jain managed the patient clinically. All authors have read and approved the manuscript.\n\nConflict of interest: None.\n\nCorrespondence Amanjit Bal Post Graduate Institute of Medical Education & Research (PGIMER), Department of Histopathology Research Block A, Sector 12, Pincode: 160012, Chandigarh, India Phone: +91 70 87008134 / Fax: +91 172 2744401 docaman5@hotmail.com\n15 4 2021\n2021\n11 e202126511 10 2020\n11 2 2021\nCopyright © 2021 The Authors.\n2021\nThe Authors.\nhttps://creativecommons.org/licenses/by/4.0/ 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.\nABSTRACT\n\nAortopulmonary window (APW) is a rare congenital heart defect with abnormal communication between the ascending aorta and the pulmonary trunk with two separate semilunar valves. We present an autopsy case report wherein a young primigravida woman presented with progressive breathlessness and central cyanosis at 21 weeks of gestation. Echocardiography performed in the emergency room revealed elevated right-sided cardiac pressures suggestive of severe pulmonary hypertension; however, no structural cardiac defect was discernible. The patient succumbed to congestive cardiac failure and progressive hypoxia within 5 days of hospitalization. The autopsy revealed a Type I aortopulmonary window (2 cm) with patent ductus arteriosus. The lungs showed changes of severe pulmonary hypertension with superadded bronchopneumonia. This report underscores a rare presentation of APW, undiagnosed until pregnancy, leading to the Eisenmenger syndrome and death.\n\nKeywords\n\nAortopulmonary window\nHeart defects, Congenital\nHypertension, Pulmonary\nAutopsy\n==== Body\nINTRODUCTION\n\nAortopulmonary window (APW) is a rare congenital heart defect that accounts for 0.1-0.2% of all congenital heart defects. 1 - 3 It is characterized by abnormal communication between the ascending aorta and pulmonary trunk with two separate aortic and pulmonary valves producing a left-to-right shunt. The presentation time can be variable, ranging from the prenatal period to as late as the seventh decade. 4 Surgical correction at an early stage can prevent the development of irreversible pulmonary hypertension (PHT) and Eisenmenger syndrome. 5 We describe an adult case of APW associated with patent ductus arteriosus who first presented at 21 weeks of gestation with cyanosis and rapidly succumbed to her illness.\n\nCASE REPORT\n\nA 23-year-old primigravida with no known previous illness presented at 21 weeks of gestation with progressive new-onset shortness of breath, dizziness on exertion, and cyanosis for 3 months. Examination revealed a respiratory rate of 32/min, a heart rate of 110/min, and SpO2 of 27% on room air. She had bilateral, symmetrical, Grade 2 clubbing fingers and toes along with cyanosis on lips, fingers, and nails that persisted despite oxygen supplementation. There was a parasternal heave with loud P2. Investigations revealed hemoglobin of 13.7g/dl (reference range [RR]; 12-15 g/dl), leukocyte count of 18x109/L (RR; 4.5-11 x109/L) and platelet count of 67x109/L (RR; 150-400 x109/L) and chest x-ray showed cardiomegaly. Transthoracic echocardiogram showed a dilated right atrium (RA) and right ventricle (RV) with moderate tricuspid regurgitation. The main pulmonary artery was dilated to 23mm, and the pulmonary acceleration time was 59ms indicating severe pulmonary hypertension (<60ms – Severe PHT). No definite atrial septal defect, ventricular septal defect, or other anomalies were seen. A possibility of primary pulmonary hypertension was kept, and the patient was started on Sildenafil 40mg three times a day. The patient had an intrauterine death with spontaneous labor and expulsion of the fetus on 2nd day of hospitalization. Despite mechanical ventilation, the patient had persistent hypoxia and refractory shock, to which she succumbed on the third day of hospitalization. A partial autopsy was performed after written consent.\n\nAUTOPSY FINDINGS\n\nOn the gross examination, the heart weighed 260 grams (mean RR; 276 g), and the apex was rounded and mainly formed by the right ventricle (Figure 1A). There was a right atrial dilatation with marked right ventricular hypertrophy (wall thickness of 1.2 cm [RR 0.35-0.40 cm]) (Figure 1B). A large aortopulmonary window connecting the main pulmonary artery and the ascending aorta (Type I) in the proximal region, measuring 2 cm in the greatest dimension, was noted (Figure 2AC). In addition, there was a patent ductus arteriosus (Figure 2D). The left atrium and atrioventricular valves were unremarkable. The left ventricular wall thickness was 1.3 cm (RR; 1.05-1.25 cm). The pulmonary and aortic valves were separate and normally developed (Figure 2C). No atrial or ventricular septal defect was seen. The microscopic examination from the right ventricle showed cytoplasmic eosinophilia and mild anisonucleosis, confirming right ventricular hypertrophy (Figure 1C).\n\nFigure 1 A – External view: Right ventricle forming the apex indicating severe enlargement. White arrow – Lack of separation between the aorta and pulmonary trunk; B – Apical slice indicating severe right ventricular hypertrophy; C – Microscopy showing hypertrophic cardiac myocytes.\n\nFigure 2 Aortopulmonary window. A – Anterior view (arrow pointed); B – Right lateral view showing Type 1 defect; C – Superior view with the probe placed in the defect and showing intact semilunar valves; D – Patent ductus arteriosus (Probe placed in situ with an arrow pointed).\n\nBoth lungs were heavy, weighing 800 g (mean RR; 730 g), and the cut surface showed prominent broncho-vascular markings. There were multiple bronchiolocentric nodules (5mm) predominantly seen in the lower lobes (Figure 3A). Multiple sections showed a spectrum of changes related to pulmonary hypertension. The pre-acinar and intra-acinar pulmonary artery branches showed eccentric myointimal proliferation with complete occlusion of the lumen. In addition, the plexiform lesions with intraluminal fibrin deposition were occasionally seen (Figure 3BD). Sections studied from the nodules showed bronchopneumonia composed of neutrophilic infiltrate in the alveoli.\n\nFigure 3 A – Cut surface of lung shows prominent bronchovascular marking with multiple small nodules; B – Pulmonary artery hypertension in the form of myointimal proliferation with obliteration of lumen (H&E, 200X); C – Masson trichrome stain (200X); D – Plexiform lesion (Masson trichrome, 200X).\n\nThe special stains did not highlight any bacterial or fungal profiles. No evidence of amniotic fluid embolism or pulmonary embolism was noted. Sections from the liver, spleen, and pancreas were unremarkable.\n\nThe final autopsy diagnosis was a Type 1 aortopulmonary window with patent ductus arteriosus. The lung showed changes of severe pulmonary arteriopathy with superadded bronchopneumonia. The fetal autopsy was performed but did not show any congenital malformations, including cardiac defect.\n\nDISCUSSION\n\nThe aortopulmonary window arises due to embryonic failure of the fusion of two opposing conotruncal ridge or spiral septum, which separates the truncus arteriosus into the aorta and pulmonary artery. The defect causes left to right shunt and was first described by John Elliotson. 6 Few classification schemes exist for APW based on the location of the defect. 7 , 8 Mori et al. 7 have classified APW as proximal or type I, distal or type II, and total or type III defect. Our case had an oval defect just above the semilunar valve (proximal defect), placing it in Type I category. 7 Classification by the Society of Thoracic Surgeons is another common classification system, which is followed. 8 Associations with other cardiac anomalies have been described in nearly one-third to half of cases, of which the most common is interrupted aortic arch. 3 , 9 Other associated anomalies include patent ductus arteriosus, coronary artery anomalies, ventricular septal defect, atrial septal defect, tetralogy of Fallot, and transposition of great arteries. 10 - 12 In a series of 42 pediatric cases of APW, 16 cases (38%) had associated patent ductus arteriosus. 11 APW with PDA first presenting in adult has been rarely reported in only one case report, to the best of our knowledge. 13\n\nThe usual course of APW varies according to the size of the defect and its associated anomaly. A large defect can lead to the left-right shunt causing cardiac failure, pulmonary hypertension, Eisenmenger syndrome, and death in infancy or early childhood. 13 Timely diagnosis of APW by prenatal echocardiography can facilitate timely referral for surgical repair prior to the development of irreversible Eisenmenger syndrome that has high mortality up to 40%. 14 Undiagnosed cases may have poor weight gain and recurrent respiratory illness. Cardiovascular diseases have been reported in 1-4% of pregnancies, of which few can lead to severe morbidity and mortality. 15 Clinical diagnosis of the aortopulmonary window should be suspected in adult patients with pulmonary hypertension after excluding the other causes. 2D echocardiography has a variable sensitivity of 37-57% in APW, depending on factors like the type of instrument, operator experience, type of anomaly (Proximal > Distal defect), and the presence of pulmonary hypertension. Our case had very high PA pressure, and therefore though there were an anatomic APW and PDA, but there would have been no flow across the shunt and, therefore, not visible on echocardiography. Like the current case, APW may be missed at the initial presentation, unless there is a high threshold of suspicion. 16 , 17 The diagnosis by 2DE should be made by visualizing the aortopulmonary septum in two or more different planes with the best visualization in a high parasternal short-axis view. Doppler and color flow mapping add to the sensitivity of echocardiography. Transesophageal echocardiography and magnetic resonance angiography may be useful in a difficult case. Though the role of non-invasive techniques have increased drastically in recent times, cardiac catheterization can definitely help in cases of complex anomalies and in cases with established pulmonary hypertension. 13 , 18\n\nThe index patient survived into adulthood without any significant illness. Survival into adulthood with such a lethal defect is an intriguing and enigmatic phenomenon. The influencing factors include the patient’s physiological, anatomical, and psychological adaptation, associated co-morbidities, cardiac remodeling, and other associated cardiac anomalies. 19 These patients develop Eisenmenger at a very early age of less than 5 years. The patient might not become symptomatic ever due to multiple reasons like non-regression of high infantile PA pressures. Once they develop Eisenmenger because of reduced L→R shunt, they become symptomatically better with respect to heart failure symptoms. Pregnancy-associated hemodynamic changes include increased plasma volume, cardiac output, dilutional anemia, and reduction in systemic vascular resistance (SVR). 20 Decreased SVR during pregnancy leads to an increase in right to left shunt, subsequently leading to reduced pulmonary perfusion and hypoxia. Hence, the mortality of this patient is due to right ventricular failure due to very high PA pressures, which got accentuated because of pneumonia, in our case.\n\nThere is scarce literature regarding the feto-maternal outcomes of pregnancy with uncorrected APW. To date, four cases have been described to the best of our knowledge and are summarized in Table 1. Two cases had an uneventful pregnancy and postpartum period. 4 , 21 One case had a clinical profile similar to the present case; however, the patient survived the pregnancy and delivered the child by a cesarean section. 22 In another case, the pregnancy was terminated, and the patient expired years later. 19\n\nTable 1 Adult cases of Aortopulmonary window – related to or post-pregnancy\n\nAuthor\tAge of diagnosis (years)\tMode of diagnosis\tMaternal outcome\tFetal outcome\t\nSu-Mei and Ju-Le 4\t40\tEchocardiography\tAsymptomatic for 50 years; Died at 60 years of age due to biventricular failure;\tDelivered three children during her lifetime which was uneventful\t\nAggarwal et al. 21\t25\tCECT chest#\tDiagnosed immediate postpartum – alive\tSuccessfully completed 1st pregnancy\t\nKose et al. 22\t27\tCardiac catheterization\tAsymptomatic since birth; Diagnosed at 27 weeks of gestation;\tSuccessfully delivered baby at 35th week\t\nNiles and Schmidt 19\t39\tCardiac catheterization and later autopsy\tSymptomatic since early childhood; Died at 46 years of age\tTerminated pregnancy at age of 20 years\t\nCurrent case\t23\tAutopsy\tSymptomatic during 2nd trimester of pregnancy – Died due to cardiac failure and Eisenmenger syndrome\tSpontaneous abortion\t\n# CECT: Contrast-enhanced computed tomography.\n\nTreatment of APW depends on the size of the defect, associated anomalies such as the interrupted aortic arch, and anomalous origin of coronary arteries. The defect can be repaired via an incision in the window, through the aorta, or through the pulmonary artery and closed with an appropriately sized patch. Catheter-based closure is appropriate in small-sized defects. 9\n\nCONCLUSION\n\nThis report highlights an autopsy-based demonstration of an undiagnosed case of the aortopulmonary window with patent ductus arteriosus in its untreated natural course. In her early twenties, this adult patient had established pulmonary hypertension with a reversal of shunt that worsened due to the hemodynamic alterations of pregnancy and superadded pneumonia. A high index of suspicion can lead to timely diagnosis and surgical management.\n\nHow to cite: Thirunavukkarasu B, Kithan LS, Kumar N, Jain A, Bal A. Fatal outcome of congenital aortopulmonary window with patent ductus arteriosus complicating pregnancy. Autops Case Rep [Internet]. 2021;11:e2021265. https://doi.org/10.4322/acr.2021.265\n\nThis study carried out at the Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.\n\nEthics statement: Informed consent by the next of kin was retained by the institution where the autopsy was performed.\n\nFinancial support: None.\n==== Refs\nREFERENCES\n\n1 Kutsche LM Van Mierop LHS Anatomy and pathogenesis of aorticopulmonary septal defect Am J Cardiol 1987 59 5 443 447 10.1016/0002-9149(87)90953-2 3812313\n2 Talner CN Report of the New England Regional Infant Cardiac Program, by Donald C. Fyler, MD, Pediatrics, 1980;65(suppl):375-461 Pediatrics 1998 102 1 Pt 2 258 259 9651450\n3 Šamánek M Voříšková M Congenital heart disease among 815,569 children born between 1980 and 1990 and their 15-year survival: a prospective bohemia survival study Pediatr Cardiol 1999 20 6 411 417 10.1007/s002469900502 10556387\n4 Su-Mei AK Ju-Le T Large unrepaired aortopulmonary window: survival into the seventh decade Echocardiography 2007 24 1 71 73 10.1111/j.1540-8175.2006.00353.x 17214626\n5 Backer C Mavroudis C Surgical management of aortopulmonary window: a 40-year experience Eur J Cardiothorac Surg 2002 21 5 773 779 10.1016/S1010-7940(02)00056-8 12062263\n6 Elliotson J Case of malformation of the pulmonary artery and aorta Lancet 1830 1 247 251\n7 Mori K Ando M Takao A Ishikawa S Imai Y Distal type of aortopulmonary window: report of 4 cases Br Heart J 1978 40 6 681 689 10.1136/hrt.40.6.681 656242\n8 Jacobs JP Quintessenza JA Gaynor JW Burke RP Mavroudis C Congenital heart surgery nomenclature and database project: aortopulmonary window Ann Thorac Surg 2000 69 4 Suppl S44 9 10.1016/S0003-4975(99)01236-9 10798415\n9 Barnes ME Mitchell ME Tweddell JS Aortopulmonary window Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2011 14 1 67 74 10.1053/j.pcsu.2011.01.017 21444051\n10 Backer C Aortopulmonary window and aortic origin of a pulmonary artery. Mavroudis C Backer C Pediatric cardiac surgery. Philadelphia Mosby 2003\n11 Bagtharia R Trivedi KR Burkhart HM et al Outcomes for patients with an aortopulmonary window, and the impact of associated cardiovascular lesions Cardiol Young 2004 14 5 473 480 10.1017/S1047951104005025 15680067\n12 Agius PV Rushworth A Connolly N Anomalous origin of left coronary artery from pulmonary artery associated with an aorto-pulmonary septal defect Br Heart J 1970 32 5 708 710 10.1136/hrt.32.5.708 5470055\n13 Chouaib H Fellat N Hatem S Aortopulmonary window associated with a patent ductus arteriosus in an adult Sch J Med Case Reports 2020 08 03 410 416 10.36347/sjmcr.2020.v08i03.043\n14 Tongprasert F Sittiwangkul R Jatavan P Tongsong T Prenatal diagnosis of aortopulmonary window: a case series and literature review J Ultrasound Med 2017 36 8 1733 1738 10.7863/ultra.16.08025 28393388\n15 Elkayam U Goland S Pieper PG Silversides CK High-risk cardiac disease in pregnancy J Am Coll Cardiol 2016 68 4 396 410 10.1016/j.jacc.2016.05.048 27443437\n16 Soares AM Atik E Cortêz TM et al Aortopulmonary window: clinical and surgical assessment of 18 cases Arq Bras Cardiol 1999 73 1 59 74 10.1590/S0066-782X1999000700006 10684142\n17 Balaji S Burch M Sullivan ID Accuracy of cross-sectional echocardiography in diagnosis of aortopulmonary window Am J Cardiol 1991 67 7 650 653 10.1016/0002-9149(91)90910-D 2000804\n18 Ghaderian M Aortopulmonary window in infants Heart Views 2012 13 3 103 106 10.4103/1995-705X.102153 23181179\n19 Niles NR Schmidt WA Aortopulmonary septal defect and longevity Chest 1980 78 2 336 338 10.1378/chest.78.2.336 7398426\n20 Hemnes AR Kiely DG Cockrill BA et al Statement on Pregnancy in Pulmonary Hypertension from the Pulmonary Vascular Research Institute Pulm Circ 2015 5 3 435 465 10.1086/682230 26401246\n21 Aggarwal H Gupta T Jain D et al Aortopulmonary window: a rare presentation in post‐partum female Biomed Res 2011 22 345 347\n22 Kose M Ucar S Emet S Akpinar TS Yalin K A case of aortopulmonary window: asymptomatic until the first pregnancy Case Rep Cardiol 2015 2015 935253 10.1155/2015/935253 26457208\n\n",
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"title": "Fatal outcome of congenital aortopulmonary window with patent ductus arteriosus complicating pregnancy.",
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"abstract": "Vancomycin-induced immune thrombocytopenia (ITP) is a rare, potentially life-threatening complication from an antibiotic frequently used in medical practice. We report a case of an 81-year-old male with recent removal of an infected right knee prosthesis and insertion of an articulating antibiotic spacer, presenting from rehabilitation for severe thrombocytopenia (1 X 103/µL). The patient's thrombocytopenia was initially falsely attributed to rifampin-induced ITP, a much more common cause of drug-induced thrombocytopenia. Only later, after a second precipitous drop in platelet count, vancomycin was correctly identified as the culprit. The patient's serum was tested for drug-dependent platelet antibodies with and without vancomycin. A positive reaction for IgG was detected by flow cytometry in the absence of vancomycin, which was potentiated in the presence of vancomycin. The result indicated the presence of vancomycin-dependent and nondrug-dependent platelet reactive antibodies and confirmed the diagnosis of vancomycin-induced ITP. In this case, the correct diagnosis was masked by the simultaneous administration of two drugs that cause drug-induced ITP and highlights the importance of early recognition of rare, vancomycin-induced ITP.",
"affiliations": "Internal Medicine, Staten Island University Hospital, Northwell Health, New York, USA.;Hematology/Oncology, Staten Island University Hospital, New York, USA.;Hematology/Oncology, Staten Island University Hospital, Northwell Health, New York, USA.",
"authors": "MacDougall|Kira N|KN|;Parylo|Sara|S|;Sokoloff|Alisa|A|",
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"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.7940\nInternal Medicine\nInfectious Disease\nHematology\nA Case of Vancomycin-Induced Immune Thrombocytopenia\nMuacevic Alexander Adler John R MacDougall Kira N 1 Parylo Sara 2 Sokoloff Alisa 3 \n1 \nInternal Medicine, Staten Island University Hospital, Northwell Health, New York, USA \n\n2 \nHematology/Oncology, Staten Island University Hospital, New York, USA \n\n3 \nHematology/Oncology, Staten Island University Hospital, Northwell Health, New York, USA \n\nKira N. MacDougall kmacdougall1@northwell.edu\n3 5 2020 \n5 2020 \n12 5 e794020 4 2020 2 5 2020 Copyright © 2020, MacDougall et al.2020MacDougall et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/31164-a-case-of-vancomycin-induced-immune-thrombocytopeniaVancomycin-induced immune thrombocytopenia (ITP) is a rare, potentially life-threatening complication from an antibiotic frequently used in medical practice. We report a case of an 81-year-old male with recent removal of an infected right knee prosthesis and insertion of an articulating antibiotic spacer, presenting from rehabilitation for severe thrombocytopenia (1 X 103/µL). The patient’s thrombocytopenia was initially falsely attributed to rifampin-induced ITP, a much more common cause of drug-induced thrombocytopenia. Only later, after a second precipitous drop in platelet count, vancomycin was correctly identified as the culprit. The patient’s serum was tested for drug-dependent platelet antibodies with and without vancomycin. A positive reaction for IgG was detected by flow cytometry in the absence of vancomycin, which was potentiated in the presence of vancomycin. The result indicated the presence of vancomycin-dependent and nondrug-dependent platelet reactive antibodies and confirmed the diagnosis of vancomycin-induced ITP. In this case, the correct diagnosis was masked by the simultaneous administration of two drugs that cause drug-induced ITP and highlights the importance of early recognition of rare, vancomycin-induced ITP.\n\nimmune thrombocytopeniavancomycinvancomycin-induced immune thrombocytopeniadrug-induced immune thrombocytopeniaThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nIn the hospitalized patient, acquired thrombocytopenia is a relatively common clinical phenomenon that poses a unique diagnostic challenge due to the broad differential diagnosis. One such etiology is drug-induced thrombocytopenia, which can occur by several mechanisms including direct bone marrow suppression, organ toxicity, or drug-induced immune thrombocytopenia (DITP). DITP is caused by drug-dependent platelet antibodies that cause accelerated platelet destruction by the reticuloendothelial system, often resulting in severe thrombocytopenia, and in some cases, life-threatening bleeding [1].\n\nThe drug classes most commonly implicated in DITP are quinines, sulfonamides, nonsteroidal anti-inflammatory drugs, anticonvulsants, disease-modifying antirheumatic drugs, and diuretics [2]. There are only a few rare cases in the literature of vancomycin being implicated as a cause of antibody-mediated thrombocytopenia [3-8]. Prior to a pivotal study conducted by Von Drygalski et al., there was only limited evidence that the mechanism was immune mediated [9]. We are now able to detect drug-dependent antiplatelet antibodies by flow cytometry and diagnose vancomycin-induced immune thrombocytopenia (ITP). Due to the frequency of vancomycin use, it is important to expand our knowledge on the subject and educate ourselves regarding the management of this potentially life-threatening condition.\n\nCase presentation\nAn 81-year-old male was transferred to the medical service from inpatient physical rehabilitation after routine blood work revealed severe thrombocytopenia. He was undergoing rehabilitation following removal of an infected right knee prosthesis and insertion of an articulating antibiotic spacer. His medical history includes hypertension, dyslipidemia, and a chronic right popliteal deep vein thrombosis. Following the surgical intervention, the patient was discharged to the inpatient physical rehabilitation floor and started on cefepime 2,000 mg intravenously every eight hours, vancomycin 1,500 mg intravenously every 12 hours, and rifampin 300 mg intravenously every 12 hours.\n\nPrior to the initiation of antibiotic therapy, platelet count was 172 X 103/µL (Table 1). Routine lab work done in the rehabilitation unit showed a precipitous drop in platelets from 170 X 103/µL on hospital day 8 to 88 X 103/µL on hospital day 9, and then to 1 X 103/µL on hospital day 10 (Figure 1).Repeat blood work confirmed a platelet count of 1 X 103/µL. At no point did the patient receive any heparin-based products. The hematology consultants reviewed the peripheral smear which demonstrated very few platelets and no schistocytes. The patient denied any bleeding events, hemoptysis, hematemesis, melena, or hematochezia. To the patient’s knowledge, he had never had thrombocytopenia before. Physical exam revealed minor petechia on his right lower extremity.\n\nTable 1 Laboratory Data on Admission \nWBC = white blood cell; RBC = red blood cell; Hb = hemoglobin; Hct = hematocrit.\n\nWBC\t12.36\tK/µL\tSodium\t142\tmEq/L\t\n Neutrophils\t62.4\t%\tPotassium\t4.1\tmEq/L\t\n Lymphocytes\t21.3\t%\tChloride\t105\tmEq/L\t\n Monocytes\t13.8\t%\tBlood urea nitrogen\t10\tmg/dL\t\n Eosinophils\t1.8\t%\tCreatinine\t0.8\tmg/dL\t\n Basophils\t0.3\t%\tGlucose\t116\tmg/dL\t\nRBC\t3.48\tM/µL\tCalcium\t8.6\tmg/dL\t\nHb\t10.6\tg/dL\t \t \t \t\nHct\t31.9\t%\t \t \t \t\nPlatelets\t172\tK/µL\t \t \t \t\nFigure 1 Platelet Count in Relation to Vancomycin Administration\nFollowing transfusion with one unit of platelets, repeat complete blood count revealed a platelet count of 2 X 103/µL the following day. Lack of improvement following transfusion suggested ITP. The patient was then started on prednisone at 1 mg/kg and intravenous immunoglobulin (IVIG) at 0.4g/kg over the next four days. The patient’s medications were reviewed and rifampin, well known for causing ITP, was immediately discontinued. Our infectious disease consultants recommended switching to daptomycin 8 mg/kg intravenously every 24 hours. At this time, cefepime and vancomycin were also discontinued. The platelet count recovered over the next five days, and the patient’s thrombocytopenia was incorrectly attributed to rifampin-induced ITP.\n\nAntibiotic therapy was again changed in anticipation for the patient’s discharge home. On the final day of hospitalization, the patient’s platelets improved to 88 X 103/µL. Daptomycin was discontinued, and the patient was re-started on vancomycin 1,250 mg intravenously every 12 hours to complete a six-week course and prednisone 90 mg daily. The following day, outpatient blood work revealed a platelet count of 24 X 103/µL and the patient was re-admitted for refractory ITP with plans to initiate rituximab 375 mg/m2 weekly x 4 doses. At this point, review of the literature revealed rare case reports of vancomycin-induced ITP and vancomycin was considered as the causative agent and was discontinued. In the following days, platelets subsequently rebounded to 41 X 103/µL, 60 X 103/µL, 182 X 103/µL, and 278 X 103/µL. The patient had no clinically significant bleeding episodes during these events. The patient’s thrombocytopenia resolved, and the patient was discharged on doxycycline 100 mg intravenously every 12 hours with a presumptive diagnosis of vancomycin-induced ITP.\n\nVancomycin-induced platelet antibody testing was sent to an outside laboratory. The patient’s serum was tested for drug-dependent platelet antibodies with and without vancomycin. A positive reaction for IgG was detected by flow cytometry in the absence of vancomycin which was potentiated in the presence of vancomycin. These results indicate the presence of vancomycin-dependent and nondrug-dependent platelet reactive antibodies and confirm the diagnosis of vancomycin-induced ITP.\n\nDiscussion\nWe present the case of an 81-year-old male being treated with a combination of cefepime, rifampin, and vancomycin following removal of an infected right knee prosthesis and insertion of an articulating antibiotic spacer. He was found to have severe thrombocytopenia on routine blood work, which improved after discontinuation of rifampin and vancomycin. The medical team initially suspected rifampin-induced ITP. However, upon re-administration of vancomycin, platelet count again plummeted. Due to the rarity of vancomycin-induced ITP, it was not initially included in the differential diagnosis. Only after a second drop in platelet count was this unlikely cause of thrombocytopenia suspected. The diagnosis was later confirmed by the detection of vancomycin-dependent antiplatelet antibody by flow cytometry.\n\nThis case is unique for several reasons. First, the simultaneous administration of two drugs that cause DITP complicated the clinical picture. Second, the absence of clinically significant bleeding is unusual compared to many previous cases of DITP described in the literature. Finally, in addition to the vancomycin-dependent antiplatelet antibody detected by flow cytometry, we have documented a clear temporal relationship of platelet decline upon exposure and re-exposure to vancomycin.\n\nDITP is a unique clinical syndrome that is caused by drug-dependent platelet antibodies that promote clearance by the reticuloendothelial system. Epidemiologic studies suggest that approximately 10 persons per million are affected by DITP [2]. Historically, quinine and its isomer quinidine have been associated with drug-induced thrombocytopenia [10]. However, with advances in technology and the detection of drug-dependent antiplatelet antibodies by flow cytometry, more drugs are being identified.\n\nDITP should be considered in any patient who presents with severe, unexplained thrombocytopenia. A thorough history, including all present and past drug exposures, is essential in establishing this diagnosis. DITP occurs five to ten days after initiation of a new drug, or within hours after re-exposure [1]. Severe thrombocytopenia with a platelet count less than 20 X 103/µL is typically observed [1]. Positive laboratory testing demonstrating drug-dependent antiplatelet antibodies confirms the diagnosis. After discontinuing the offending drug, thrombocytopenia usually begins to recover within one to two days, with complete recovery after one week [11]. In patient with severe thrombocytopenia and bleeding, other supportive measures including high-dose IVIG and corticosteroids may be indicated. Most importantly, in patients with confirmed DITP, patients must be counseled to avoid the drug indefinitely, as drug-dependent antibodies may persist in the blood for years [11]. \n\nConclusions\nThis case implicates vancomycin-dependent antiplatelet antibodies as the cause of the patient’s severe thrombocytopenia. Vancomycin-induced ITP is rare and can easily be overlooked. Given the frequency of vancomycin use in today’s clinical practice, increased awareness of this potentially life-threatening condition is warranted.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Approach to the diagnosis and management of drug-induced immune thrombocytopenia Transfus Med Rev Arnold DM Nazi I Warkentin TE 137 145 27 2013 23845922 \n2 Drug-induced immune thrombocytopenia Drug Saf van den Bemt PM Meyboom RH Egberts AC 1243 1252 27 2004 15588119 \n3 Vancomycin-induced immune thrombocytopenia proven by the detection of vancomycin-dependent anti-platelet antibody with flow cytometry Intern Med Yamanouchi J Hato T Shiraishi S Takeuchi K Yakushijin Y Yasukawa M 3035 3038 55 2016 27746445 \n4 A masked case of vancomycin-induced immune thrombocytopenia Am J Med Sci Schueler SA Shet NS Stienstra N Chen DC 636 351 2016 27238931 \n5 Acute vancomycin-dependent immune thrombocytopenia as an anamnestic response Platelets Kenney B Tormey CA 379 383 19 2008 18791945 \n6 Vancomycin-induced thrombocytopenia without isolation of a drug-dependent antibody Pharmacotherapy Ruggero MA Abdelghany O Topal JE 321 325 32 2012 \n7 Vancomycin-dependent antibodies associated with thrombocytopenia and refractoriness to platelet transfusion in patients with leukemia Blood Christie DJ van Buren N Lennon SS Putnam JL 518 523 75 1990 https://pdfs.semanticscholar.org/f541/b04050838da7035c80095cc247ee7768f6b7.pdf 2295006 \n8 Thrombocytopenia induced by vancomycin-dependent platelet antibody Vox Sang Mizon P Kiefel V Mannessier L Mueller-Eckhardt C Goudemand J 49 51 73 1997 9269071 \n9 Vancomycin-induced immune thrombocytopenia N Engl J Med Von Drygalski A Curtis BR Bougie DW 904 910 356 2007 17329697 \n10 Spontaneous reports of thrombocytopenia in association with quinine: clinical attributes and timing related to regulatory action Am J Hematol Brinker AD Beitz J 313 317 70 2002 12210813 \n11 Drug-induced thrombocytopenia: pathogenesis, evaluation, and management Hematology Am Soc Hematol Educ Program George JN Aster RH 153 158 2009 2009\n\n",
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"affiliations": "Department of Medical Oncology, The Canberra Hospital, Garran, ACT, Australia.;Department of Radiology, Royal North Shore Hospital, St Leonards, NSW, Australia.;Department of Anatomical Pathology, The Canberra Hospital, Garran, ACT, Australia.;Department of Medical Oncology, The Canberra Hospital, Garran, ACT, Australia.",
"authors": "Prasanna|Thiru|T|;Briggs|Greg|G|;Jain|Sanjiv|S|;Yip|Desmond|D|",
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"title": "Massive fatal pulmonary haemorrhage during bevacizumab treatment following microwave ablation therapy for oligometastatic lung metastasis from rectal cancer.",
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"abstract": "Treatment with proteasome inhibitors like carfilzomib in patients with multiple myeloma (MM) can induce thrombotic microangiopathy (TMA) characterized by neurological symptoms, acute kidney injury, hemolysis and thrombocytopenia. Successful treatment with the monoclonal antibody eculizumab was described for these patients, but reports of ideal management and definitive treatment protocols are lacking.\n\n\n\nThe first case describes a 43-years-old IgG-kappa-MM patient that developed TMA during the first course of carfilzomib-lenalidomide-dexamethasone (KRd) consolidation after autologous stem cell transplantation (ASCT). In the second case, a 59-years-old IgG-kappa-MM patient showed late-onset TMA during the fourth and last cycle of elotuzumab-KRd consolidation within the DSMM XVII study of the German study group MM (DSMM; clinicalTrials.gov Identifier: NCT03948035). Concurrently, he suffered from influenza A/B infection. Both patients had a high TMA-index for a poor prognosis of TMA. Therapeutically, in both patients plasma exchange (TPE) was initiated as soon as TMA was diagnosed. In patient #1, dialysis became necessary. For both patients, only when the complement inhibitor eculizumab was administered, kidney function and blood values impressively improved.\n\n\n\nIn this small case series, two patients with MM developed TMA due to carfilzomib treatment (CFZ-TMA), the second patient as a late-onset form. Even though TMA could have been elicited by influenza in the second patient and occurred after ASCT in both patients, with cases of TMA post-transplantation in MM being described, a relation of TMA and carfilzomib treatment was most likely. In both patients, treatment with eculizumab over two months efficiently treated TMA without recurrence and with both patients remaining responsive months after TMA onset. Taken together, we describe two cases of TMA in MM patients on carfilzomib-combination treatment, showing similar courses of this severe adverse reaction, with good responses to two months of eculizumab treatment.",
"affiliations": "Department of Medicine I (Hematology, Oncology and Stem Cell Transplantation), Medical Center, Faculty of Medicine, University of Freiburg, Hugstetter Strasse 53, D-79106, Freiburg, Germany.;Department of Internal Medicine 5 - Hematology/Oncology, University Hospital of Erlangen, Erlangen, Germany.;Department of Medicine I (Hematology, Oncology and Stem Cell Transplantation), Medical Center, Faculty of Medicine, University of Freiburg, Hugstetter Strasse 53, D-79106, Freiburg, Germany.;Department of Internal Medicine 4 - Nephrology, University Hospital of Erlangen, Erlangen, Germany.;Department of Medicine IV, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.;Department of Internal Medicine 5 - Hematology/Oncology, University Hospital of Erlangen, Erlangen, Germany.;Department of Medicine I (Hematology, Oncology and Stem Cell Transplantation), Medical Center, Faculty of Medicine, University of Freiburg, Hugstetter Strasse 53, D-79106, Freiburg, Germany. monika.engelhardt@uniklinik-freiburg.de.",
"authors": "Rassner|Michael|M|;Baur|Rebecca|R|;Wäsch|Ralph|R|;Schiffer|Mario|M|;Schneider|Johanna|J|;Mackensen|Andreas|A|;Engelhardt|Monika|M|",
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"fulltext": "\n==== Front\nBMC Nephrol\nBMC Nephrol\nBMC Nephrology\n1471-2369 BioMed Central London \n\n2226\n10.1186/s12882-020-02226-5\nCase Report\nTwo cases of carfilzomib‐induced thrombotic microangiopathy successfully treated with Eculizumab in multiple myeloma\nRassner Michael 1 Baur Rebecca 2 Wäsch Ralph 1 Schiffer Mario 3 Schneider Johanna 4 Mackensen Andreas 2 Engelhardt Monika monika.engelhardt@uniklinik-freiburg.de 1 1 grid.5963.9Department of Medicine I (Hematology, Oncology and Stem Cell Transplantation), Medical Center, Faculty of Medicine, University of Freiburg, Hugstetter Strasse 53, D-79106 Freiburg, Germany \n2 grid.411668.c0000 0000 9935 6525Department of Internal Medicine 5 - Hematology/Oncology, University Hospital of Erlangen, Erlangen, Germany \n3 grid.411668.c0000 0000 9935 6525Department of Internal Medicine 4 - Nephrology, University Hospital of Erlangen, Erlangen, Germany \n4 grid.5963.9Department of Medicine IV, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany \n18 1 2021 \n18 1 2021 \n2021 \n22 3216 7 2020 25 12 2020 © The Author(s) 2021Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nTreatment with proteasome inhibitors like carfilzomib in patients with multiple myeloma (MM) can induce thrombotic microangiopathy (TMA) characterized by neurological symptoms, acute kidney injury, hemolysis and thrombocytopenia. Successful treatment with the monoclonal antibody eculizumab was described for these patients, but reports of ideal management and definitive treatment protocols are lacking.\n\nCase Presentation\nThe first case describes a 43-years-old IgG-kappa-MM patient that developed TMA during the first course of carfilzomib-lenalidomide-dexamethasone (KRd) consolidation after autologous stem cell transplantation (ASCT). In the second case, a 59-years-old IgG-kappa-MM patient showed late-onset TMA during the fourth and last cycle of elotuzumab-KRd consolidation within the DSMM XVII study of the German study group MM (DSMM; clinicalTrials.gov Identifier: NCT03948035). Concurrently, he suffered from influenza A/B infection. Both patients had a high TMA-index for a poor prognosis of TMA. Therapeutically, in both patients plasma exchange (TPE) was initiated as soon as TMA was diagnosed. In patient #1, dialysis became necessary. For both patients, only when the complement inhibitor eculizumab was administered, kidney function and blood values impressively improved.\n\nConclusion\nIn this small case series, two patients with MM developed TMA due to carfilzomib treatment (CFZ-TMA), the second patient as a late-onset form. Even though TMA could have been elicited by influenza in the second patient and occurred after ASCT in both patients, with cases of TMA post-transplantation in MM being described, a relation of TMA and carfilzomib treatment was most likely. In both patients, treatment with eculizumab over two months efficiently treated TMA without recurrence and with both patients remaining responsive months after TMA onset. Taken together, we describe two cases of TMA in MM patients on carfilzomib-combination treatment, showing similar courses of this severe adverse reaction, with good responses to two months of eculizumab treatment.\n\nKeywords\nMultiple myeloma (MM)Thombotic microangiopathy (TMA)EculizumabCarfilzomibCase reportissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\nThrombotic microangiopathy (TMA) is a rare cause of anemia in multiple myeloma (MM) patients, but can occasionally be elicited by common anti-myeloma drugs, especially by proteasome-inhibitors (PI) like carfilzomib (CFZ) [1–3]. Reports about TMA in MM induced by CFZ and optimal therapeutic approaches are scarce. Recently, single case reports described successful treatment of TMA in MM with the terminal complement pathway inhibitor eculizumab [1, 2, 4–6]. Definitive treatment recommendations, however, are lacking. Below we describe two cases of CFZ-induced TMA, that were successfully treated by eculizumab and provide evidence about precise therapeutic work-flow and possible interventions.\n\nCase 1\nA 43-year old male patient was diagnosed with IgG-kappa-MM in August 2018. At admission, we found extensive osteolysis and an acute kidney failure with a serum-creatinine of 4.2 mg/dl [0.67–1.17] (GFR 15 ml/min; MDRD) without previous history of impaired kidney function. With highly elevated serum free kappa light chains (kappa-SFLC) 3645 mg/l [0.35–15.10] and 4.2 g/d [< 0.15] urinary protein excretion, in the absence of albuminuria, cast nephropathy was assumed as the most likely cause of acute kidney failure. Since there was no sign of further organ injury, amyloidosis seemed unlikely, as well MIDD (monoclonal immunoglobulin deposition disease), which is often accompanied by amyloidosis and presents with albuminuria. The type of renal injury was not further determined by kidney puncture. The M-protein was elevated with 37 g/l, IgG 52.3 g/l [6.1-16.16], k/l-ratio 864 [0.46-4], hemoglobin (Hb) 9.5 g/dl [13.5–17.5], β2-microglobulin 8.7 mg/dl [0-2.34], serum calcium and LDH were normal. The bone marrow plasma cell (BMPC) infiltration was 15%, FISH excluded high-risk cytogenetics. Following the ISS grading system, we diagnosed an IgG-kappa-MM stage III (Durie & Salmon stage IIIB) and symptomatic myeloma with 3/4 CRAB criteria (anemia, renal impairment, bone lesions). The revised myeloma comorbidity index (R-MCI: 1/9 = fit/low-risk) revealed a fit patient [7–9]. Due to the CRAB-criteria, specifically renal impairment, chemotherapy was initiated with one cycle of bortezomib, doxorubicin, dexamethasone (BAD) followed by two cycles of bortezomib, cyclophosphamide, dexamethasone (VCD) after improvement of the kidney function and resolved urinary proteinuria. Since M-protein reduction was insufficient (21.4 g/l), the regimen was switched a second time to CFZ, lenalidomide and dexamethasone (KRd). After two cycles KRd, a partial remission (PR; M-protein 5.3 g/l, IgG 6.4 g/l) was achieved and high-dose melphalan (200 mg/m²) chemotherapy with autologous stem cell transplantation (ASCT) was performed. On day (d) 42 post ASCT IgG levels were increasing again (21.1 g/l). Based on the distinct improvement of the myeloma markers after KRd and a missing additional response to ASCT, our MM-tumor board decided to apply three consolidation cycles of KRd. In May 2019, the 3rd KRd cycle (1st consolidation cycle after ASCT) was initiated. At d2 of CFZ, the patient developed fever, dyspnea and malaise. Platelets were 11Tsd/µl, Hb 10.8 g/dl, LDH 1836U/l, haptoglobin < 150 mg/l, unconjugated bilirubin 2.7 mg/dl, the creatinine rose from 0.72 to 2.07 mg/dl [0.67–1.17] (GFR > 60 to 35 ml/min) (Fig. 1a) and urinary proteinuria increased from normal values to 52 g/l [< 0.135]. In the peripheral blood smear, 11‰ schistocytes were detected and an altered complement profile with reduced C3 and C4 levels was found (C3 77.6md/dl, C4 9.9 mg/dl). TMA-Index (LDH/platelets ratio) was elevated to 166. These findings (schistocytes > 10‰, elevated creatinine and TMA-Index) have been described as poor prognostic factors for transplant associated-TMA (TA-TMA) [10]. Of note, two days earlier, lab results had been normal (Fig. 1a). Chest CT scan showed bilateral infiltrates, matching pulmonary hemorrhage (Fig. 2). Due to the acute development of hemolysis, together with acute kidney injury, unsuspicious ATAMTS13 activity (61%) [50–110], normal ADAMTS13 antigen (0.48 IU/ml) [0.35–1.2] and direct Coombs test being negative, we suspected medication-induced TMA. Therapeutic plasma exchange (TPE) was initiated by replacement with fresh frozen plasma (FFP) on a daily regimen and on account of declining kidney function with development of acute kidney injury stage 3 according to the acute Kidney Injury Network (AKIN), dialysis was necessary one day later. After six days of TPE neither LDH nor platelets improved. Assuming CFZ-induced TMA, we administered eculizumab (900 mg) along with meningococcal vaccination and initiation of antibiotic prophylaxis. Five days later, LDH declined to 818U/l and platelet counts improved to 58Tsd/µl without transfusions. We continued eculizumab (900 mg) weekly. After the fourth application, dialysis could be discontinued. Platelet counts normalized within two months after treatment initiation of eculizumab and there were no further signs of TMA, thus eculizumab was terminated (Fig. 1a). One year after TMA diagnosis and KRd consolidation, our patient remains in PR of his MM and CR of the CFZ-induced TMA.\nFig. 1 Course of CFZ-TMA in the two patients. a Case #1: This patient developed acute kidney injury, fever and pulmonary hemorrhage during the first consolidation with carfilzomib, lenalidomide and dexamethasone (KRd) after ASCT. Laboratory findings (thrombocytopenia) and schistocytosis of 11‰ were consistent with thrombotic microangiopathy (TMA). Therapeutic plasma exchange (TPE) was immediately initiated, but shortly after dialysis was necessary. As blood values did not improve, we finally administered eculizumab for a total of seven doses and saw a rapid response in LDH, platelet number and kidney function with our patient being still in PR. b Case #2: This patient, who is treated in the DSMM XVII study (Arm A: Elotuzumab-KRd) developed head ache, malignant hypertension and laboratory distortions (thrombocytopenia, increase of LDH and acute kidney injury) consistent with TMA. After a short period of TPE, eculizumab was infused (total of six infusions). Blood values improved but kidney function remains decreased\n\nFig. 2 a Chest-CT in patient case 1, d1 of CFZ-TMA onset: Bipulmonary extensive ground-glass opacities in all lung fields, mostly omitting the periphery and predominantly occurring in the right lung. b Mechanism of CFZ-TMA: Within the proximal complement activation C3 is cleaved by the C3 convertase to anaphylactic 3a and C3b. C3b then cleaves C5 to C5a and C5b, the latter together with C6-C9 forming the membrane attack complex (MAC) within the terminal pathway. Activity of the C3 convertase is regulated by complement factor H and regulated proteins. Proteasome inhibition blocks CFH [11]. The monoclonal antibody eculizumab counteracts the resulting overactivation of C3b by binding C5\n\n\n\nCase 2\nThe second 59-year-old male patient was diagnosed with IgG-kappa-MM in 11/2018. CT scan revealed osteolysis of the sacrum, pelvis and vertebrae. Calcium and creatinine were normal and the Hb was slightly decreased (13.3 g/dl). IgG was 38.4 g/l, k-SFLC 182 mg/l, k/l-ratio 60.5. BM biopsy revealed 40% PC infiltration. Cytogenetics were favorable (trisomy 5p15, 9q22, 11q13 und 15q22). The ISS and R-ISS were both I, Durie & Salmon stage was IIIA and symptomatic MM was diagnosed with 1/4 CRAB symptoms. The patient was classified as fit for ASCT (R-MCI-score: 2/9 = fit) [7–9]. We included the patient into the DSMM XVII study of the German study group MM (DSMM; clinicalTrials.gov Identifier: NCT03948035). Induction with elotuzumab, CFZ, lenalidomide and dexamethasone (E-KRd, 6 cycles) and ASCT with melphalan 200 mg/m2 were performed and due to repeated respiratory infections (boca- and corona (CoV NL 63) virus) dose reductions of elotuzumab and lenalidomide were executed. Before ASCT, kappa-SFLC decreased to 12.8 mg/l (vgPR).\n\nIn 01/20, within the last (4th) cycle of E-KRd consolidation, the patient developed fever and acute kidney failure with creatinine 1.7 mg/dl (GFR 40 ml/min, MRDRD; baseline-creatinine: 1 mg/dl). Prerenal genesis was assumed (fractional sodium excretion < 1%) and fluids were infused. However, creatinine elevation did not resolve finally reaching acute kidney injury stage 3 according to AKIN and proteinuria reached 6.2 g/d. The patient developed headache and high blood pressure (BP 220/105 mmHg). Platelets and Hb gradually decreased (Fig. 1b), haptoglobin was < 5 mg/dl. In the peripheral blood smear, 44‰ schistocytes were visible; ADAMTS13 activity and antigen were normal (58% and 0.40 IU/ml, respectively) and Coombs test negative. Blood culture additionally showed Staphylococcus epidermidis due to port infection and throat swab detected influenza A (H3N2) and B.\n\nSince TMA was diagnosed (LDH/platelets ratio 88.3), high-dose glucocorticoids and TPE were applied (before completion of diagnostics). Without substantial improvement, five days after first plasmapheresis our patient received eculizumab (Fig. 1b), starting at 900 mg. A total of 11 sessions of plasma exchange at a daily basis were performed with FFP as replacement (Fig. 1b). Parameters of hemolysis rapidly improved, so that glucocorticoids could be expeditiously reduced and eculizumab was terminated after four cycles with 900 mg/weekly and two doses with 1200 mg/every two weeks (Fig. 1b).\n\nIn 05/19, the patient showed VGPR of his MM, the BMPC infiltration even CR (polyclonal PCs of 5%) and gradual renal function improvement (eGFR improved from 10 to 32 ml/min). Maintenance therapy with reduced doses of elotuzumab-lenalidomide (E-R: lenalidomide with 5 mg d1-28) was successfully initiated and TMA has remained in CR.\n\nDiscussion and conclusion\nHemolysis is a rather rare cause for anemia in MM [12]. When anemia is accompanied with thrombocytopenia, acute kidney injury, high blood pressure, neurological or unexplained extrarenal symptoms TMA should be considered. TMA includes a group of etiologically diverse diseases: Primary TMA, which include atypical HUS (aHUS) or thrombotic thrombocytopenic purpura (TTP) and secondary TMA and infection-associated TMA, involving Shiga-toxin-producing Escherichia coli-associated hemolytic uremic syndrome (STEC-HUS) [6, 13, 14]. TTP, in contrast to other TMA forms, is defined by decreased activity of the vWF-cleaving enzyme ADAMTS13 [6]. Unlike “typical” HUS, which is triggered by infections with STEC, complement mediated TMA is driven by uncontrolled complement activation and affected patients frequently harbor mutations in complement regulatory proteins (Fig. 2b) [15]. Secondary TMA is elicited by medication, malignancy, pregnancy, malignant hypertension, transplantations, infections or associated to autoimmune diseases [6, 10, 12–14]. As reviewed recently [6], TMA in MM can be elicited by ASCT- or allogeneic-SCT, MM progression, or anti-myeloma therapy. Drug-induced TMA (DITMA) may occur in MM due to PIs bortezomib or CFZ [3, 16, 17]. CFZ-TMA can appear early after onset of the drug, but also as late as two years after first administration [1, 2]. CFZ-TMA is probably driven by complement activation of the alternative pathway in terms of complement-mediated TMA [2–4, 18]. Blasco et al. described three cases in which plasma samples from patients with CFZ-TMA, led to depositions of complex membrane attack complex (C5b-9) of on endothelial cells, suggesting a complement overactivation [4]. Supporting this assumption, proteasome inhibition has been found to block Factor H, consequently leading to complement activation (Fig. 2b) [11]. Bortezomib-induced cases of TMA are attributed to decreased activity of ADAMTS13 [19, 20]. However, the majority of bortezomib-induced cases of TMA/TTP had only slightly decreased ADAMTS13 activity and PI-induced TMA in MM might be generally based on pathological overactivation of the alternative complement pathway rather than TTP [6]. In patient #2, TMA was either induced by CFZ or influenza A or B [15, 21]. Also a combination of both preexistent vascular endothelial injury due to CFZ and transient complement activation during influenza infection was eagerly discussed within our group. In this respect, eculizumab could be effective in patients treated with concurrent PI treatment, infection and TMA.\n\nIn patient #2, in contrast to patient #1, C3 and C4 levels were normal; CH50 and C5b-9, the terminal pathway of the complement pathway were, however, not assessed. The fast response to eculizumab and the lacking effect of TPE seemed to argue for pathological complement activation, but it cannot be ruled out that the classical or the alternative complement pathway was involved. Importantly, both patients developed TMA several weeks after ASCT. Since TA-TMA was described to occur in a complement-dependent manner, like complement mediated TMA [10], a combination of TMA-triggers is likewise conceivable.\n\nTaken together, several factors might have induced TMA in our patients: ASCT, genetic predispositions, viral infections and the underlying CFZ treatment. Thus, definite causality could ot be entirely proven. The major criticism of our study may be missing additional in vitro studies of complement activation and the unavailability of renal biopsies for further diagnostics. Kidney biopsies had been discussed interdisciplinary in our weekly MM tumor board, however, in the acute clinical setting, the potential biopsy risk, especially bleeding, was judged to outweigh potential benefits and on top, both patients had declined kidney biopsies.\n\nIn respect to therapy for TMA in MM, definitive clinical practical guidelines do not exist [6]. For DITMA, the causative drug must be discontinued promptly, high-dose glucocorticoids are given and plasmapheresis is performed [2, 6]. In CFZ-TMA, successful treatment with eculizumab, a terminal complement pathway inhibitor, was described in six cases to our knowledge [1, 2, 4, 5, 22]. Nevertheless, reports of TMA in MM remain scarce, and the definitive treatment regimen as well as definitive duration of treatment are unclear [6]: Portuguese and Lipe (2018), Moliz et al. (2019) and Blasco et al. (2020) administered eculizumab for up to three weekly doses [2, 4, 22], whereas Bhutani et al. (2020) for four months [1]. In our two cases, only after eculizumab initiation, hemolysis and creatinine levels improved impressively (Fig. 1A,B), plus the application period of two months of eculizumab was efficient without relapsing TMA, thus appears possible to be shorter than four months. On the other hand a shorter treatment period, as reported by Portuguese and Lipe, might be insufficient as one of their eculizumab-treated patients stayed on hemodialysis with this regime [22].\n\nTPE is generally recommended for TMA. Plasma exchange, however, is not without side effects, and can remove therapeutic antibodies from the circulation, thus its concurrent use is not recommended [6, 10]. Interestingly, in our cases the success of eculizumab was not fully dependent on the termination of TPE, since in patient #2 TPE was continued during the first two eculizumab doses. In this respect, concerns, that TPE would remove eculizumab from the blood or restore C5-levels available for activation, seem unfounded. On the other hand, a significant improvement of creatinine-levels and platelets was only achieved after termination of TPE in patient #2 (Fig. 1B). Thus, irrespective of the cause of TMA in MM patients under PI treatment or shortly after ASCT, eculizumab rather than TPE could be considered as standard first-line therapy [2, 6] (Fig. 3). Increased susceptibility to meningococcal infection during eculizumab treatment has to be considered and vaccination should be implemented [23]. As soon as ADAMTS13 activity is proven to be within the normal range (50–150%) and TTP is excluded, further treatment decisions can be drawn [6]. Additionally, in our experience short-term use of eculizumab was sufficient for effective TMA treatment. Furthermore, eculizumab treatment did not worsen MM parameters in neither of our patients.\nFig. 3 Guideline for diagnostic and therapeutic approach for TMA in MM: Whenever clinical and laboratory findings are consistent with TMA, one should rapidly terminate possible causative drugs, initiate therapeutic plasma exchange (TPE) and apply a first dose of eculizumab. As soon as ADAMTS13 activity is determined further therapeutic decisions can be drawn\n\n\n\nTaken together, CFZ-induced TMA is a serious event and should be assumed in treated MM patients with rapid acute kidney failure and hemolysis. Fast treatment initiation with eculizumab can reverse pathological complement system activation and prevent organ damage. As shown in our patients, early initiated, short-term treatment with eculizumab can sufficiently terminate CFZ-TMA and counteract TMA-poor prognostic factors.\n\nAbbreviations\naHUSAtypical hemolytic uremic syndrome\n\nAKINAcute kidney injury network\n\nASCTAutologous stem cell transplantation\n\nBMBone marrow\n\nCFZ-TMACarfilzomib-induced thrombotic microangiopathy\n\nCRComplete response\n\nDITMADrug-induced thrombotic microangiopathy\n\nFFPFresh frozen plasma\n\nTMAThrombotic microangiopathy\n\nTPETherapeutic plasma exchange\n\nTTPThrombotic thrombocytopenic purpura\n\nMMMultiple myeloma\n\nPCPlasma cell\n\nPIProteasome inhibitor\n\nSTECShiga-toxin-producing E.coli\n\nvgPRVery good partial response\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nMichael Rassner, Rebecca Baur, Andreas Mackensen and Monika Engelhardt contributed equally to this work.\n\nAcknowledgements\nWe would like to thank both patients for consent of publication of their educational cases within this work.\n\nAuthors’ contributions\nMR and RB treated the patients, drafted and wrote the manuscript; JS, MS and RW treated the patient and revised the manuscript; AM and ME treated the patient, initiated and wrote the manuscript. All authors read and approved the final manuscript.\n\nFunding\nThere was no funding received to support this research. Open Access funding enabled and organized by Projekt DEAL.\n\nAvailability of data and materials\nNot applicable.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWe have obtained written consent for publication from both patients presented in this case report.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Bhutani D Assal A Mapara MY Prinzing S Lentzsch S Case Report: Carfilzomib-induced Thrombotic Microangiopathy With Complement Activation Treated Successfully With Eculizumab Clin Lymphoma Myeloma Leuk 2020 20 e155 7 10.1016/j.clml.2020.01.016 32098724 \n2. Moliz C Gutiérrez E Cavero T Redondo B Praga M Eculizumab as a treatment for atypical hemolytic syndrome secondary to carfilzomib Nefrologia 2019 39 86 8 10.1016/j.nefro.2018.02.005 29716757 \n3. Mehta N, Saxena A, Niesvizky R. Bortezomib-induced thrombotic thrombocytopaenic purpura. BMJ Case Rep. 2012;2012.\n4. Blasco M, Martínez-Roca A, Rodríguez-Lobato LG, Garcia-Herrera A, Rosiñol L, Castro P, et al. Complement as the enabler of carfilzomib-induced thrombotic microangiopathy. Br J Haematol. 2020.\n5. Gosain R Gill A Fuqua J Volz LH Kessans Knable MR Bycroft R Gemcitabine and carfilzomib induced thrombotic microangiopathy: eculizumab as a life-saving treatment Clinical Case Reports 2017 5 1926 30 10.1002/ccr3.1214 29225827 \n6. Portuguese AJ Gleber C Passero FC Lipe B A review of thrombotic microangiopathies in multiple myeloma Leuk Res 2019 85 106195 10.1016/j.leukres.2019.106195 31404728 \n7. Engelhardt M Dold SM Ihorst G Zober A Moller M Reinhardt H Geriatric assessment in multiple myeloma patients: validation of the International Myeloma Working Group (IMWG) score and comparison with other common comorbidity scores Haematologica 2016 101 1110 9 10.3324/haematol.2016.148189 27479825 \n8. Engelhardt M Domm A-S Dold SM Ihorst G Reinhardt H Zober A A concise revised Myeloma Comorbidity Index as a valid prognostic instrument in a large cohort of 801 multiple myeloma patients Haematologica 2017 102 910 21 10.3324/haematol.2016.162693 28154088 \n9. Engelhardt M Ihorst G Duque-Afonso J Wedding U Spät-Schwalbe E Goede V Structured assessment of frailty in multiple myeloma as a paradigm of individualized treatment algorithms in cancer patients at advanced age Haematologica 2020 105 1183 8 10.3324/haematol.2019.242958 32241848 \n10. Khosla J Yeh AC Spitzer TR Dey BR Hematopoietic stem cell transplant-associated thrombotic microangiopathy: current paradigm and novel therapies Bone Marrow Transplant 2018 53 129 37 10.1038/bmt.2017.207 28967899 \n11. Liu Z Qin T Zhou J Taylor A Sparrow JR Shang F Impairment of the Ubiquitin-Proteasome Pathway in RPE Alters the Expression of Inflammation Related Genes Adv Exp Med Biol 2014 801 237 50 10.1007/978-1-4614-3209-8_31 24664704 \n12. Rassner M, Jung J, Schneider J, Wäsch R, Engelhardt M. Dapsone-induced hemolytic anemia in multiple myeloma – a case report of various differential diagnoses. Clinical Lymphoma Myeloma and Leukemia. 2020;S2152265020303190.\n13. Aigner C Schmidt A Gaggl M Sunder-Plassmann G An updated classification of thrombotic microangiopathies and treatment of complement gene variant-mediated thrombotic microangiopathy Clinical Kidney Journal 2019 12 333 7 10.1093/ckj/sfz040 31198225 \n14. Brocklebank V Wood KM Kavanagh D Thrombotic Microangiopathy and the Kidney Clinical journal of the American Society of Nephrology: CJASN 2018 13 300 17 10.2215/CJN.00620117 29042465 \n15. van Hoeve K Vandermeulen C Van Ranst M Levtchenko E van den Heuvel L Mekahli D Occurrence of atypical HUS associated with influenza B Eur J Pediatr 2017 176 449 54 10.1007/s00431-017-2856-5 28110418 \n16. Haddadin M Al-Sadawi M Madanat S Tam E Taiwo E Luhrs C Late Presentation of Carfilzomib Associated Thrombotic Microangiopathy Am J Med Case Rep 2019 7 240 3 10.12691/ajmcr-7-10-5 31457071 \n17. Yui JC Van Keer J Weiss BM Waxman AJ Palmer MB D’Agati VD Proteasome inhibitor associated thrombotic microangiopathy Am J Hematol 2016 91 E348 52 10.1002/ajh.24447 27286661 \n18. Caprioli J Noris M Brioschi S Pianetti G Castelletti F Bettinaglio P Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome Blood 2006 108 1267 79 10.1182/blood-2005-10-007252 16621965 \n19. Chan K-L Filshie R Nandurkar H Quach H Thrombotic microangiopathy complicating bortezomib-based therapy for multiple myeloma Leuk Lymphoma 2015 56 2185 6 10.3109/10428194.2014.977887 25547654 \n20. Pettitt AR Clark RE Thrombotic microangiopathy following bone marrow transplantation Bone Marrow Transplant 1994 14 495 504 7858524 \n21. Bitzan M Zieg J Influenza-associated thrombotic microangiopathies Pediatr Nephrol 2018 33 2009 25 10.1007/s00467-017-3783-4 28884355 \n22. Portuguese AJ Lipe B Carfilzomib-induced aHUS responds to early eculizumab and may be associated with heterozygous CFHR3-CFHR1 deletion Blood Adv 2018 2 3443 6 10.1182/bloodadvances.2018027532 30518536 \n23. Crew PE McNamara L Waldron PE McCulley L Jones SC Bersoff-Matcha SJ Unusual Neisseria species as a cause of infection in patients taking eculizumab J Infect 2019 78 113 8 10.1016/j.jinf.2018.10.015 30408494\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2369",
"issue": "22(1)",
"journal": "BMC nephrology",
"keywords": "Carfilzomib; Case report; Eculizumab; Multiple myeloma (MM); Thombotic microangiopathy (TMA)",
"medline_ta": "BMC Nephrol",
"mesh_terms": null,
"nlm_unique_id": "100967793",
"other_id": null,
"pages": "32",
"pmc": null,
"pmid": "33461512",
"pubdate": "2021-01-18",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "32241848;31198225;7858524;22854237;28110418;29042465;32098724;28884355;31404728;28154088;27479825;31457071;28967899;24664704;25547654;30518536;32753123;16621965;29225827;27286661;30408494;32469083;29716757",
"title": "Two cases of carfilzomib-induced thrombotic microangiopathy successfully treated with Eculizumab in multiple myeloma.",
"title_normalized": "two cases of carfilzomib induced thrombotic microangiopathy successfully treated with eculizumab in multiple myeloma"
} | [
{
"companynumb": "DE-AMGEN-DEUSP2021012565",
"fulfillexpeditecriteria": "2",
"occurcountry": "DE",
"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARFILZOMIB"
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"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nDrug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare and potentially life-threatening drug reaction. Allopurinol is one of the most frequently reported drugs accounting for DRESS syndrome development. In contrast to allopurinol, DRESS syndrome induced by teicoplanin has not been reported frequently.\n\n\nMETHODS\nA 50-year-old woman was admitted to receive FLAG chemotherapy regimen (fludarabine, cytarabine (high-dose Ara-C), granulocyte colony-stimulating factor) for relapsed acute lymphoblastic leukaemia (ALL) treatment. Allopurinol was initiated at a dose of 300 mg per day 48 hours before chemotherapy regimen initiation, for tumour lysis syndrome prophylaxis. Seven days after allopurinol initiation, the patient presented with fever, dyspnoea, shortening of breath, facial oedema, generalized pruritus, erythema and macular rash affecting the face, abdomen, trunk, upper and lower limbs and an elevation in hepatic enzymes. Allopurinol was immediately discontinued and intravenous hydrocortisone was started concomitantly alongside other supportive measures. About 72 hours later, pruritus, erythema and rash were ameliorated and abnormalities in liver tests were improved. Afterwards, teicoplanin administration led to severe deterioration of pruritus, erythema and rash; subsequently, serum alanine aminotransferase increased again and episodes of worsening dyspnea occurred. Signs of hypersensitivity reaction were reduced by discontinuation of teicoplanin and supportive care.\n\n\nCONCLUSIONS\nWe report a case of allopurinol-induced DRESS syndrome, which was exacerbated by administration of teicoplanin. It can be suggested that the administration of drugs with high possibility of hypersensitivity reactions should be avoided during the acute phase of DRESS syndrome.",
"affiliations": "Clinical Pharmacy Department, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.;Research Center for Rational Use of Drugs, and Clinical Pharmacy Department, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.;Hematology-Oncology and SCT Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.;Clinical Pharmacy Department, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.",
"authors": "Taghvaye Masoumi|H|H|;Hadjibabaie|M|M|;Zarif-Yeganeh|M|M|;Arasteh|O|O|",
"chemical_list": "D000900:Anti-Bacterial Agents; D006074:Gout Suppressants; D003561:Cytarabine; D016179:Granulocyte Colony-Stimulating Factor; D017334:Teicoplanin; D000493:Allopurinol; D014740:Vidarabine",
"country": "England",
"delete": false,
"doi": "10.1111/jcpt.12556",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-4727",
"issue": "42(5)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "allopurinol; drug reaction with eosinophilia and systemic symptoms; teicoplanin",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": "D000493:Allopurinol; D000900:Anti-Bacterial Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D003561:Cytarabine; D063926:Drug Hypersensitivity Syndrome; D005260:Female; D006074:Gout Suppressants; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D017334:Teicoplanin; D014740:Vidarabine",
"nlm_unique_id": "8704308",
"other_id": null,
"pages": "642-645",
"pmc": null,
"pmid": "28556959",
"pubdate": "2017-10",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Exacerbation of allopurinol-induced drug reaction with eosinophilia and systemic symptoms by teicoplanin: A case report.",
"title_normalized": "exacerbation of allopurinol induced drug reaction with eosinophilia and systemic symptoms by teicoplanin a case report"
} | [
{
"companynumb": "IR-NORTHSTAR HEALTHCARE HOLDINGS-IR-2017NSR000211",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ALLOPURINOL"
},
"drug... |
{
"abstract": "We report findings in five patients who presented with venous thrombosis and thrombocytopenia 7 to 10 days after receiving the first dose of the ChAdOx1 nCoV-19 adenoviral vector vaccine against coronavirus disease 2019 (Covid-19). The patients were health care workers who were 32 to 54 years of age. All the patients had high levels of antibodies to platelet factor 4-polyanion complexes; however, they had had no previous exposure to heparin. Because the five cases occurred in a population of more than 130,000 vaccinated persons, we propose that they represent a rare vaccine-related variant of spontaneous heparin-induced thrombocytopenia that we refer to as vaccine-induced immune thrombotic thrombocytopenia.",
"affiliations": "From the Departments of Hematology (N.H.S., G.E.T., P.A.H.), Immunology (L.A.M., F.L.-J.), Neurosurgery (M.W.), Neurology (A.-H.A.), and Radiology and Nuclear Medicine (T.H.S.), and the Research Institute of Internal Medicine (N.H.S., A.E.M., P.A.H.), Oslo University Hospital, and the Faculty of Medicine (A.E.M., G.E.T., P.A.H.), the KG Jebsen Center for B Cell Malignancy (L.A.M., G.E.T.), Institute of Clinical Medicine, and the ImmunoLingo Convergence Center (F.L.-J.), University of Oslo, the Department of Hematology, Akershus University Hospital, Lørenskog (N.H.S.), and the Norwegian National Unit for Platelet Immunology, Division of Diagnostics, University Hospital of North Norway, Tromsø (I.H.S., M.T.A.) - all in Norway.;From the Departments of Hematology (N.H.S., G.E.T., P.A.H.), Immunology (L.A.M., F.L.-J.), Neurosurgery (M.W.), Neurology (A.-H.A.), and Radiology and Nuclear Medicine (T.H.S.), and the Research Institute of Internal Medicine (N.H.S., A.E.M., P.A.H.), Oslo University Hospital, and the Faculty of Medicine (A.E.M., G.E.T., P.A.H.), the KG Jebsen Center for B Cell Malignancy (L.A.M., G.E.T.), Institute of Clinical Medicine, and the ImmunoLingo Convergence Center (F.L.-J.), University of Oslo, the Department of Hematology, Akershus University Hospital, Lørenskog (N.H.S.), and the Norwegian National Unit for Platelet Immunology, Division of Diagnostics, University Hospital of North Norway, Tromsø (I.H.S., M.T.A.) - all in Norway.;From the Departments of Hematology (N.H.S., G.E.T., P.A.H.), Immunology (L.A.M., F.L.-J.), Neurosurgery (M.W.), Neurology (A.-H.A.), and Radiology and Nuclear Medicine (T.H.S.), and the Research Institute of Internal Medicine (N.H.S., A.E.M., P.A.H.), Oslo University Hospital, and the Faculty of Medicine (A.E.M., G.E.T., P.A.H.), the KG Jebsen Center for B Cell Malignancy (L.A.M., G.E.T.), Institute of Clinical Medicine, and the ImmunoLingo Convergence Center (F.L.-J.), University of Oslo, the Department of Hematology, Akershus University Hospital, Lørenskog (N.H.S.), and the Norwegian National Unit for Platelet Immunology, Division of Diagnostics, University Hospital of North Norway, Tromsø (I.H.S., M.T.A.) - all in Norway.;From the Departments of Hematology (N.H.S., G.E.T., P.A.H.), Immunology (L.A.M., F.L.-J.), Neurosurgery (M.W.), Neurology (A.-H.A.), and Radiology and Nuclear Medicine (T.H.S.), and the Research Institute of Internal Medicine (N.H.S., A.E.M., P.A.H.), Oslo University Hospital, and the Faculty of Medicine (A.E.M., G.E.T., P.A.H.), the KG Jebsen Center for B Cell Malignancy (L.A.M., G.E.T.), Institute of Clinical Medicine, and the ImmunoLingo Convergence Center (F.L.-J.), University of Oslo, the Department of Hematology, Akershus University Hospital, Lørenskog (N.H.S.), and the Norwegian National Unit for Platelet Immunology, Division of Diagnostics, University Hospital of North Norway, Tromsø (I.H.S., M.T.A.) - all in Norway.;From the Departments of Hematology (N.H.S., G.E.T., P.A.H.), Immunology (L.A.M., F.L.-J.), Neurosurgery (M.W.), Neurology (A.-H.A.), and Radiology and Nuclear Medicine (T.H.S.), and the Research Institute of Internal Medicine (N.H.S., A.E.M., P.A.H.), Oslo University Hospital, and the Faculty of Medicine (A.E.M., G.E.T., P.A.H.), the KG Jebsen Center for B Cell Malignancy (L.A.M., G.E.T.), Institute of Clinical Medicine, and the ImmunoLingo Convergence Center (F.L.-J.), University of Oslo, the Department of Hematology, Akershus University Hospital, Lørenskog (N.H.S.), and the Norwegian National Unit for Platelet Immunology, Division of Diagnostics, University Hospital of North Norway, Tromsø (I.H.S., M.T.A.) - all in Norway.;From the Departments of Hematology (N.H.S., G.E.T., P.A.H.), Immunology (L.A.M., F.L.-J.), Neurosurgery (M.W.), Neurology (A.-H.A.), and Radiology and Nuclear Medicine (T.H.S.), and the Research Institute of Internal Medicine (N.H.S., A.E.M., P.A.H.), Oslo University Hospital, and the Faculty of Medicine (A.E.M., G.E.T., P.A.H.), the KG Jebsen Center for B Cell Malignancy (L.A.M., G.E.T.), Institute of Clinical Medicine, and the ImmunoLingo Convergence Center (F.L.-J.), University of Oslo, the Department of Hematology, Akershus University Hospital, Lørenskog (N.H.S.), and the Norwegian National Unit for Platelet Immunology, Division of Diagnostics, University Hospital of North Norway, Tromsø (I.H.S., M.T.A.) - all in Norway.;From the Departments of Hematology (N.H.S., G.E.T., P.A.H.), Immunology (L.A.M., F.L.-J.), Neurosurgery (M.W.), Neurology (A.-H.A.), and Radiology and Nuclear Medicine (T.H.S.), and the Research Institute of Internal Medicine (N.H.S., A.E.M., P.A.H.), Oslo University Hospital, and the Faculty of Medicine (A.E.M., G.E.T., P.A.H.), the KG Jebsen Center for B Cell Malignancy (L.A.M., G.E.T.), Institute of Clinical Medicine, and the ImmunoLingo Convergence Center (F.L.-J.), University of Oslo, the Department of Hematology, Akershus University Hospital, Lørenskog (N.H.S.), and the Norwegian National Unit for Platelet Immunology, Division of Diagnostics, University Hospital of North Norway, Tromsø (I.H.S., M.T.A.) - all in Norway.;From the Departments of Hematology (N.H.S., G.E.T., P.A.H.), Immunology (L.A.M., F.L.-J.), Neurosurgery (M.W.), Neurology (A.-H.A.), and Radiology and Nuclear Medicine (T.H.S.), and the Research Institute of Internal Medicine (N.H.S., A.E.M., P.A.H.), Oslo University Hospital, and the Faculty of Medicine (A.E.M., G.E.T., P.A.H.), the KG Jebsen Center for B Cell Malignancy (L.A.M., G.E.T.), Institute of Clinical Medicine, and the ImmunoLingo Convergence Center (F.L.-J.), University of Oslo, the Department of Hematology, Akershus University Hospital, Lørenskog (N.H.S.), and the Norwegian National Unit for Platelet Immunology, Division of Diagnostics, University Hospital of North Norway, Tromsø (I.H.S., M.T.A.) - all in Norway.;From the Departments of Hematology (N.H.S., G.E.T., P.A.H.), Immunology (L.A.M., F.L.-J.), Neurosurgery (M.W.), Neurology (A.-H.A.), and Radiology and Nuclear Medicine (T.H.S.), and the Research Institute of Internal Medicine (N.H.S., A.E.M., P.A.H.), Oslo University Hospital, and the Faculty of Medicine (A.E.M., G.E.T., P.A.H.), the KG Jebsen Center for B Cell Malignancy (L.A.M., G.E.T.), Institute of Clinical Medicine, and the ImmunoLingo Convergence Center (F.L.-J.), University of Oslo, the Department of Hematology, Akershus University Hospital, Lørenskog (N.H.S.), and the Norwegian National Unit for Platelet Immunology, Division of Diagnostics, University Hospital of North Norway, Tromsø (I.H.S., M.T.A.) - all in Norway.;From the Departments of Hematology (N.H.S., G.E.T., P.A.H.), Immunology (L.A.M., F.L.-J.), Neurosurgery (M.W.), Neurology (A.-H.A.), and Radiology and Nuclear Medicine (T.H.S.), and the Research Institute of Internal Medicine (N.H.S., A.E.M., P.A.H.), Oslo University Hospital, and the Faculty of Medicine (A.E.M., G.E.T., P.A.H.), the KG Jebsen Center for B Cell Malignancy (L.A.M., G.E.T.), Institute of Clinical Medicine, and the ImmunoLingo Convergence Center (F.L.-J.), University of Oslo, the Department of Hematology, Akershus University Hospital, Lørenskog (N.H.S.), and the Norwegian National Unit for Platelet Immunology, Division of Diagnostics, University Hospital of North Norway, Tromsø (I.H.S., M.T.A.) - all in Norway.;From the Departments of Hematology (N.H.S., G.E.T., P.A.H.), Immunology (L.A.M., F.L.-J.), Neurosurgery (M.W.), Neurology (A.-H.A.), and Radiology and Nuclear Medicine (T.H.S.), and the Research Institute of Internal Medicine (N.H.S., A.E.M., P.A.H.), Oslo University Hospital, and the Faculty of Medicine (A.E.M., G.E.T., P.A.H.), the KG Jebsen Center for B Cell Malignancy (L.A.M., G.E.T.), Institute of Clinical Medicine, and the ImmunoLingo Convergence Center (F.L.-J.), University of Oslo, the Department of Hematology, Akershus University Hospital, Lørenskog (N.H.S.), and the Norwegian National Unit for Platelet Immunology, Division of Diagnostics, University Hospital of North Norway, Tromsø (I.H.S., M.T.A.) - all in Norway.",
"authors": "Schultz|Nina H|NH|0000-0001-9194-4952;Sørvoll|Ingvild H|IH|;Michelsen|Annika E|AE|;Munthe|Ludvig A|LA|;Lund-Johansen|Fridtjof|F|;Ahlen|Maria T|MT|;Wiedmann|Markus|M|;Aamodt|Anne-Hege|AH|;Skattør|Thor H|TH|;Tjønnfjord|Geir E|GE|;Holme|Pål A|PA|",
"chemical_list": "D001323:Autoantibodies; D000086663:COVID-19 Vaccines; D010978:Platelet Factor 4; D000090985:ChAdOx1 nCoV-19",
"country": "United States",
"delete": false,
"doi": "10.1056/NEJMoa2104882",
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"issn_linking": "0028-4793",
"issue": "384(22)",
"journal": "The New England journal of medicine",
"keywords": null,
"medline_ta": "N Engl J Med",
"mesh_terms": "D000328:Adult; D001323:Autoantibodies; D001327:Autoimmune Diseases; D001774:Blood Chemical Analysis; D000086663:COVID-19 Vaccines; D000090985:ChAdOx1 nCoV-19; D004797:Enzyme-Linked Immunosorbent Assay; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation; D010976:Platelet Count; D010978:Platelet Factor 4; D013921:Thrombocytopenia; D013927:Thrombosis",
"nlm_unique_id": "0255562",
"other_id": null,
"pages": "2124-2130",
"pmc": null,
"pmid": "33835768",
"pubdate": "2021-06-03",
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"abstract": "Multiple opioids are known to trigger mast cell degranulation. We report the case of a neonate with blistering skin lesions at birth who died of multi-organ failure after administration of morphine. Given the excessive histamine release and potential complications associated with morphine administration, alternative opioids and adjuvants should be considered in infants presenting with evidence of bullous or infiltrative skin lesions until mastocytosis is ruled out.",
"affiliations": "Pritzker School of Medicine, University of Chicago, Chicago, Illinois.;Department of Pathology, University of Connecticut, Farmington, Connecticut.;Department of Pediatrics, Division of Pain and Palliative Medicine, University of Connecticut, Farmington, Connecticut.;Department of Pediatrics, Division of Neonatology, University of Connecticut, Farmington, Connecticut.",
"authors": "Hussain|Aamir|A|https://orcid.org/0000-0002-5110-8244;Sanders|Melinda|M|;Riotte|Clare|C|;Hussain|Naveed|N|",
"chemical_list": "D000701:Analgesics, Opioid; D009020:Morphine",
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"issue": "36(3)",
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"keywords": "blistering skin lesions; mast cell degranulation; mastocytosis; neonatology; opioid use; opioid use in neonates",
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D000701:Analgesics, Opioid; D017809:Fatal Outcome; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D034701:Mastocytosis, Cutaneous; D009020:Morphine; D009102:Multiple Organ Failure",
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"title": "Full-term newborn infant with blistering skin lesions-Caution regarding use of pain medications.",
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"abstract": "A 26-year-old woman was diagnosed with and treated for systemic lupus erythematosus (SLE) in 2002. She was admitted 11 years later with nephrotic-range proteinuria and lupus nephritis and received two doses of rituximab after failing on steroids and mycophenolate mofetil. Four months later, she presented with fever and joint pain/swelling. Gram stains, joint aspirates, and blood culture all yielded negative results for bacteria. She was discharged after treatment for a possible flare of lupus, but two weeks later, she presented again with a cough and shortness of breath in addition to the flare symptoms. Synovial fluid Smears, and cultures yielded positive results for Mycobacterium tuberculosis; similarly, sputum polymerase chain reaction test and culture confirmed pulmonary tuberculosis. Tuberculosis is difficult to diagnose in SLE patients; it may present like or precipitate SLE flare. In this patient a presumed SLE flare turned out to be an aggressive miliary, disseminated tuberculosis.",
"affiliations": "Infectious Diseases Unit, PSMMC, Riyadh, Saudi Arabia, P.O. Box 7897, Riyadh, 11159, Saudi Arabia.;Infectious Diseases Unit, PSMMC, Riyadh, Saudi Arabia, P.O. Box 7897, Riyadh, 11159, Saudi Arabia.;Infectious Diseases Unit, PSMMC, Riyadh, Saudi Arabia, P.O. Box 7897, Riyadh, 11159, Saudi Arabia.;Rheumatology Division, PSMMC, Riyadh, Saudi Arabia, P.O. Box 7897, Riyadh, 11159, Saudi Arabia.",
"authors": "Elzein|Fatehi|F|;Elzein|Ahmed|A|;Mohammed|Nazik|N|;Alswailem|Ramiz|R|",
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"fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(18)30246-610.1016/j.rmcr.2018.09.005Case ReportMiliary tuberculosis mimicking systemic lupus erythematosus flare Elzein Fatehi fatehielzein@gmail.coma∗Elzein Ahmed aMohammed Nazik aAlswailem Ramiz ba Infectious Diseases Unit, PSMMC, Riyadh, Saudi Arabia, P.O. Box 7897, Riyadh, 11159, Saudi Arabiab Rheumatology Division, PSMMC, Riyadh, Saudi Arabia, P.O. Box 7897, Riyadh, 11159, Saudi Arabia∗ Corresponding author. fatehielzein@gmail.com11 9 2018 2018 11 9 2018 25 216 219 20 8 2018 7 9 2018 7 9 2018 © 2018 The Authors. Published by Elsevier Ltd.2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).A 26-year-old woman was diagnosed with and treated for systemic lupus erythematosus (SLE) in 2002. She was admitted 11 years later with nephrotic-range proteinuria and lupus nephritis and received two doses of rituximab after failing on steroids and mycophenolate mofetil. Four months later, she presented with fever and joint pain/swelling. Gram stains, joint aspirates, and blood culture all yielded negative results for bacteria. She was discharged after treatment for a possible flare of lupus, but two weeks later, she presented again with a cough and shortness of breath in addition to the flare symptoms. Synovial fluid Smears, and cultures yielded positive results for Mycobacterium tuberculosis; similarly, sputum polymerase chain reaction test and culture confirmed pulmonary tuberculosis. Tuberculosis is difficult to diagnose in SLE patients; it may present like or precipitate SLE flare. In this patient a presumed SLE flare turned out to be an aggressive miliary, disseminated tuberculosis.\n==== Body\n1 Background\nThe risk of infections, including tuberculosis, is increased in patients with systemic lupus erythematosus. This risk is influenced by the degree of immunosuppression, presence of nephropathy as well as the prevalence of tuberculosis. A review by Sebastiani et al. noted that the relative frequency of tuberculosis in patients with systemic lupus erythematosus differed from 50 out of 100,000 patients (in Turkey) to 2450 out of 100,000 patients (in India) [1].Many factors increase the risk of developing tuberculosis in patients with systemic lupus erythematosus, including deficiency in immunoglobulins and complement, defective phagocytic function, and decreased cellular immunity. Furthermore, Ribero et al. [2] suggest that molecular mimicry could be a contributory factor; for example, antigenic similarity exists between cell wall glycolipids of Mycobacterium tuberculosis (MTB) and DNA. They also note that heat-shock proteins 60 and 65 of MTB might act as super-antigens that trigger an autoimmune response. Additionally, the use of corticosteroids and the increasing use of biological agents, anti-tumour necrosis factor (anti-TNF) therapy, increase this risk. The average daily dose, cumulative dose and pulse steroids therapy are important determinant for increasing risk of tuberculosis. The adjusted odds ratio for the development of tuberculosis was 7.7 (95% CI 2.8,21.4) for doses greater then 15mg/day as compared to 2.8 (95% CI 1.0,7.9) for doses less than 15mg/day. An increase in the cumulative dose of steroids by one gram is postulated to increase the risk by 23% while treatment with pulse steroids therapy is found to be more common among patients who developed tuberculosis in SLE patients [3,4]. In contrast, the association between use of rituximab (a chimeric human/mouse antibody) and reactivation of tuberculosis has not been widely reported. The adjusted ORs for rituximab, infliximab, and adalimumab were 1.4, 2.4, and 4.7, respectively. Interestingly, rituximab is more commonly associated with nontuberculous mycobacteria (NTM) when compared with the anti-TNF increased risk of tuberculosis. Two patients with inflammatory myopathies acquired severe NTM infections while undergoing treatment with rituximab [5,6]. On the other hand, systemic lupus erythematosus itself is associated with a higher risk of NTM. Reminiscent of human immunodeficiency virus, NTM tends to occur later in the clinical course of systemic lupus erythematosus than MTB infection. Advanced immunosuppression is suggested as a predisposing cause [7].\n\n2 Case presentation\nA 26-year-old woman was diagnosed with systemic lupus erythematosus in 2002 and was treated with prednisolone, mycophenolate, and hydroxychloroquine. In September 2013, she was admitted with nephrotic-range proteinuria. Renal biopsy confirmed class IV lupus nephritis. After failure of treatment with mycophenolate mofetil, enalapril, and high doses of steroids, she received two 1000-mg doses of rituximab one month apart. Prior to receiving rituximab, a chest x-ray showed normal findings, but a tuberculin skin test (TST) was not performed. A pre-employment TST performed in 2010 showed negative findings. Following rituximab she was maintained on 10–15 mg prednisolone daily. Four months after the second dose of rituximab, she presented with fever as well as pain and swelling in her right knee and left elbow. Her temperature was 39 °C and erythrocyte sedimentation rate was 117 mm/hr. Gram stains and culture of aspirates from the knee and elbow joints yielded negative results for bacteria, as did a blood culture. A combination of methylprednisolone and intravenous ceftriaxone was given for a possible flare of lupus. Her condition improved, and she was discharged home. Two weeks later, she presented with similar symptoms accompanied by cough and shortness of breath. The patient's temperature was 38.3 °C. Both her right knee and left elbow joints were erythematous and tender; her other joints were normal.\n\n3 Investigations\nThe anti-nuclear antibody titre was 1:2560 (normal <1:40); anti-double-stranded DNA level, 110 IU/mL (normal: 0–200); creatinine, 57 μmol/L; serum calcium, 2.63 mmol/L (normal: 2.06–2.44); and vitamin D, 43.6 nmol/L (optimal ≥75). A plain x-ray of the left elbow showed cranial displacement of a proximal fractured fragment of the olecranon process with intra-articular extension associated with swelling of the olecranon bursa (Fig. 1A). Magnetic resonance imaging scan (MRI)of left elbow joint showing avulsion fracture involving the olecranon process (White arrow) with possible underlying osteomyelitis of the avulsed fragment in addition to synovitis and reactive bursitis of the left elbow joint (Fig. 1B).Fig. 1 A: Plain x-ray of the left elbow showed cranial displacement of a proximal fractured fragment of the olecranon process (red arrow) with an intra-articular extension associated with olecranon bursa swelling. Fig. 1B: Magnetic resonance imaging scan (MRI)of left elbow joint showing avulsion fracture involving the olecranon process (White arrow). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)\n\nFig. 1\n\nMRI of the right knee joint revealed arthritis with synovial thickening, rice pad in the suprapatellar pouch, and large lateral femoral condyle erosion in addition to severe bone marrow edema involving almost the entire lateral femoral condyle. MRI findings were highly suggestive of tuberculous arthritis (Fig. 2). A computed tomography (CT)-guided biopsy confirmed acute-on-chronic osteomyelitis of the right knee. A synovial fluid smear yielded positive results for acid-fast bacilli, and culture confirmed MTB.Fig. 2 MRI of the right knee joint revealed arthritis with synovial thickening, rice pad in the suprapatellar pouch (white arrows), and large lateral femoral condyle erosion in addition to severe bone marrow edema involving almost the entire lateral femoral condyle (orange arrow). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)\n\nFig. 2\n\nAn initial chest radiograph was reported as normal; conversely, a CT scan of the chest showed marked miliary nodular shadowing consistent with miliary tuberculosis (Fig. 3). Sputum smear yielded negative findings for acid-fast bacilli; however, sputum polymerase chain reaction (PCR) test using a GeneXpert system (Cepheid, Sunnyvale, CA, USA) yielded positive results for MTB. The gene mutation for rifampicin resistance was not detected. A fully sensitive MTB was isolated from both the sputum and synovial fluid culture.Fig. 3 Computed tomography scan of the chest showing marked miliary nodular shadowing consistent with miliary tuberculosis.\n\nFig. 3\n\n4 Treatment\nThe patient was treated with an initial phase of isoniazid 300 mg, rifampicin 600 mg, ethambutol 1.2 g, pyrazinamide 1.5 g, and pyridoxine 40 mg, all given once daily for two months; the same doses of isoniazid, rifampicin, and pyridoxine were then continued for another 7 months.\n\n5 Outcome and follow-up\nThe patient made a remarkable recovery and has had no relapse of tuberculosis for almost 4 years.\n\n6 Discussion\nThis patient's presentation highlights a number of interesting issues. She had underlying systemic lupus erythematosus nephropathy, was receiving steroid treatment, and had received recent courses of rituximab therapy. The complicating tuberculosis was severe; with miliary dissemination masquerading as a systemic lupus erythematosus flare. Despite having a low vitamin D level, her serum calcium level was high, but regressed on anti-tuberculosis treatment.\n\nShe presented with fever, arthritis, and negative synovial fluid culture, which erroneously indicated treatment with pulse steroid therapy for possible active systemic lupus erythematosus. However, tuberculosis can masquerade as a systemic lupus erythematosus flare, with similar laboratory findings as well as shared symptoms including fever, arthritis, and central nervous system manifestations. Moreover, a previous study showed an increased risk of precipitating systemic lupus erythematosus flares among patients with tuberculosis [8]. In some cases, tuberculosis’ presentation can mimic an initial presentation of SLE. Justin Li et al., describe a 19 years old patient who fulfilled the American college of Rheumatology (ACR) and systemic lupus international collaborating clinics (SLICC) criteria. Her ANA, anti-RO, anti-LA, and anticardiolipin antibodies were all positive. Furthermore, skin biopsy showed IgM containing granular deposits consistent with connective tissue disease. Bronchoalveolar lavage for a worsening pulmonary infiltrate ultimately recovered MTB on culture. Following treatment with anti-TB medications, she showed resolution of disseminated and military TB changes as well as disappearance of all antibodies [9]. Thus, tuberculosis diagnosis in patients with active systemic lupus erythematosus is difficult; misdiagnosis can result in delay of tuberculosis treatment that can vary from months to years in some cases [10].\n\nVitamin D deficiency has been related to a heightened risk of tuberculosis in systemic lupus erythematosus patients. Remarkably, anti-vitamin D antibodies are known to be present in patients with systemic lupus erythematosus [11].Inflammatory and immune response to tuberculosis are modulated by vitamin D. Furthermore, vitamin D also mediates the release of the human cathelicidin antimicrobial peptides. A likely association between vitamin D deficiency and impaired host defence to MTB was reported in the 1980s [12]. Vitamin D deficiency has been detected in 8.5–62.7% of patients with tuberculosis living in Africa [13]. A meta-analysis revealed hypovitaminosis D to be linked with higher risk of active tuberculosis [14].Additionally, vitamin D receptor polymorphisms and increased susceptibility to MTB infection have been previously reported. Smear or culture conversion time in patients with pulmonary tuberculosis have been reported to be related to vitamin D receptor polymorphisms [15]. Therefore, further studies are required before vitamin D is routinely used in these patients.\n\nRituximab specifically binds to the CD20 antigen of B cells. It also leads to the depletion of peripheral blood B cells as well as bone marrow and synovial B cells, subsequently reducing the levels of immunoglobulin M and G [16]. Evidence is growing that B cells play a role in the defence against Mycobacterial infections. In an animal study, B cell-deficient mice were found to be more vulnerable to MTB infection, which was corrected by infusion of B cells into these mice [17]. Furthermore, studies have shown that B cells are decreased in number and impaired in function in patient with tuberculosis [18].However, tuberculosis is extremely rare among patients on rituximab, with few case reports present in the literature. The concomitant use of high dose steroids (prednisolone dose >15 mg/day) while receiving rituximab, was found to be associated with the development of serious infections. Notably, renal impairment and greater total dose of rituximab are linked to an increased susceptibility to infection during rituximab therapy [6].\n\nIn conclusion, the patient described in this case report had multiple predispositions to tuberculosis including systemic lupus erythematosus, SLE nephropathy, immunosuppressive therapy, and low Vitamin D levels. Although the concurrent manifestation of miliary tuberculosis and administration of rituximab make it plausible to assume rituximab as an added risk, it is very difficult to dichotomise its contribution among these factors.\n\n7 Learning points/take home messages\n• Patients with systemic lupus erythematosus are at increased risk of tuberculosis.\n\n• Tuberculosis can mimic an initial presentation of SLE, a flare or precipitate SLE disease.\n\n• High dose, cumulative dose and steroid pulse therapy are responsible for most cases. Rituximab is not usually associated with reactivation; however a high index of suspicion is needed when such patients present with tuberculosis symptoms.\n\n• Further studies are needed to assess the relationship between vitamin D and tuberculosis in patients with systemic lupus erythematosus.\n\n\n\nAppendix A Supplementary data\nThe following is the supplementary data related to this article:Multimedia component 1\nMultimedia component 1 \n\nAppendix A Supplementary data related to this article can be found at https://doi.org/10.1016/j.rmcr.2018.09.005.\n==== Refs\nReferences\n1 Risk E. Opportunistic Infections in Systemic Lupus Erythematosus S Pecial R Eport 2012 275–9 \n2 Ribeiro F.R.E.M. Szyper-Kravitz M. Klumb E.M. Lannes G. Ribeiro F.R.E.M. Albuquerque E.M.M. Can lupus flares be associated with tuberculosis infection? Clin. Rev. Allergy Immunol. 38 2–3 2010 163 168 19548122 \n3 Tam L.S. Li E.K. Wong S.M. Szeto C.C. Risk factors and clinical features for tuberculosis among patients with systemic lupus erythematosus in Hong Kong Scand. J. Rheumatol. 31 5 2002 Jan 1 296 300 12455821 \n4 Jick S.S. Lieberman E.S. Rahman M.U. Choi H.K. Glucocorticoid use, other associated factors, and the risk of tuberculosis Arthritis Care Res. Offic. J. Am. Coll. Rheumatol. 55 1 2006 Feb 15 19 26 \n5 Lutt J.R. Pisculli M.L. Weinblatt M.E. Deodhar A. Winthrop K.L. Severe nontuberculous mycobacterial infection in 2 patients receiving rituximab for refractory myositis the journal of Rheumatology is a monthly international serial edited by Earl D . Silverman featuring research articles on clinical subjects from scient J. Rheumotol. 35 8 2008 1683 1686 \n6 Nixon A. Ogden L. Woywodt A. Dhaygude A. Infectious complications of rituximab therapy in renal disease Clin. Kidney J. 10 4 2017 Jul 6 455 460 28852481 \n7 Mok M.Y. Wong S.S. Chan T.M. Fong D.Y. Wong W.S. Lau C.S. Non-tuberculous mycobacterial infection in patients with systemic lupus erythematosus Rheumatology 46 2 2006 Jul 22 280 284 16861709 \n8 Lin Y.C. Liang S.J. Liu Y.H. Hsu W.H. Shih C.M. Sung F.C. Chen W. Tuberculosis as a risk factor for systemic lupus erythematosus: results of a nationwide study in Taiwan Rheumatol. Int. 32 6 2012 Jun 1 1669 1673 21416237 \n9 Li J.C. Fong W. Wijaya L. Leung Y.Y. Disseminated tuberculosis masquerading as a presentation of systemic lupus erythematosus Int. J. Rheum. Dis. 21 1 2018 Jan 352 355 28971575 \n10 Sayarlioglu M. Inanc M. Kamali S. Cefle A. Karaman O. Gul A. Ocal L. Aral O. Konice M. Tuberculosis in Turkish patients with systemic lupus erythematosus: increased frequency of extrapulmonary localization Lupus 13 4 2004 Apr 274 278 15176665 \n11 Carvalho J.F. Blank M. Kiss E. Tarr T. Amital H. Shoenfeld Y. Anti-vitamin D, vitamin D in SLE: preliminary results Annals of the New York Academy of Sciences 2007 550 557 \n12 Hospital L. Hypothesis a possible link between vitamin D deficiency and impaired host defence to mycobacterium tuberculosis: the pattern in the United Kingdom Group 66 1985 301 306 \n13 Kibirige D. Mutebi E. Ssekitoleko R. Worodria W. Mayanja-Kizza H. Vitamin D deficiency among adult patients with tuberculosis: a cross sectional study from a national referral hospital in Uganda BMC Res. Notes 6 1 2013 1 (Available from: BMC Research Notes) 23281703 \n14 Nnoaham K.E. Clarke A. Low serum vitamin D levels and tuberculosis: a systematic review and meta-analysis Int. J. Epidemiol. 37 1 2008 113 119 Available from: https://academic.oup.com/ije/article-lookup/doi/10.1093/ije/dym247 18245055 \n15 Magee M.J. Sun Y.V. Brust J.C.M. Shah N.S. Ning Y. Allana S. Polymorphisms in the vitamin D receptor gene are associated with reduced rate of sputum culture conversion in multidrug-resistant tuberculosis patients in South Africa PLoS One 12 7 2017 e0180916 Available from: http://dx.plos.org/10.1371/journal.pone.0180916 \n16 Buch M.H. Smolen J.S. Betteridge N. Breedveld F.C. Burmester G. Dörner T. Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis Ann. Rheum. Dis. 70 6 2011 909 920 21378402 \n17 Maglione P.J. Chan J. How B cells shape the immune response against Mycobacterium tuberculosis Eur. J. Immunol. 39 2009 676 686 Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2760469&tool=pmcentrez&rendertype=abstract 19283721 \n18 Joosten S.A. van Meijgaarden K.E. del Nonno F. Baiocchini A. Petrone L. Vanini V. Patients with tuberculosis have a dysfunctional circulating B-cell compartment, which normalizes following successful treatment PLoS Pathog. 12 6 2016 Jun 15 e1005687\n\n",
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"title": "Miliary tuberculosis mimicking systemic lupus erythematosus flare.",
"title_normalized": "miliary tuberculosis mimicking systemic lupus erythematosus flare"
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"abstract": "Presented are updated results of allogeneic hematopoietic stem cell transplantations (HSCTs) in 25 adult patients with acute lymphoblastic leukemia (ALL) in complete remission (CR) after a reduced intensity conditioning (RIC) combining fludarabine (150 mg/m2) and melphalan (140 mg/m2) with thymoglobulin (4.5 mg/kg or recently 4.0 mg/kg) followed by early initiation of reduction and withdrawal of prophylactic posttransplant immunosuppression. The median post-transplant follow-up was 32 (range, 4-87) months. Stable engraftment of donor's hematopoiesis was achieved in all patients. Acute graft versus host disease (GVHD) as well as the chronic one were equally observed in four cases (16%). Five patients (20%) relapsed with ALL in the median of 9 (range, 3-15) months after HSCT. During the above post-transplant follow-up, 4 recipients (16%) died. Disease progression and posttransplant complications were the cause of death in three (12%) and one (4%) of them, respectively. The probabilities of 2-year event-free (EFS) and overall survival (OS) were 70.3% (95% CI 51.9-88.7%) and 86.1% (95% CI 71.6-100%), respectively. Presented study confirmed our previously reported promising results and this approach may be considered as an alternative to traditional HSCTs performed in high-risk patients with ALL.",
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"authors": "Raida|L|L|;Kuba|A|A|;Rusinakova|Z|Z|;Szotkowska|R|R|;Skoumalova|I|I|;Faber|E|E|;Szotkowski|T|T|;Rohon|P|P|;Hubacek|J|J|;Indrak|K|K|;Pikalova|Z|Z|;Jarosova|M|M|;Divoka|M|M|;Langova|K|K|;Papajik|T|T|",
"chemical_list": "D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents; C512542:thymoglobulin; D014740:Vidarabine; C024352:fludarabine; D008558:Melphalan",
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"abstract": "Background: Kawasaki disease (KD) is an acute vasculitis that mainly affects the coronary arteries. This inflammation can cause coronary artery aneurysms (CAAs). Patients with KD need cardiac assessment for risk stratification for the development of myocardial ischemia, based on Z-score (luminal diameter of the coronary artery corrected for body surface area). Echocardiography is the primary imaging modality in KD but has several important limitations. Coronary computed tomographic angiography (cCTA) and Cardiac MRI (CMR) are non-invasive imaging modalities and of additional value for assessment of CAAs with a high diagnostic yield. The objective of this single center, retrospective study is to explore the diagnostic potential of coronary artery assessment of cCTA vs. CMR in children with KD. Methods and Results: Out of 965 KD patients from our database, a total of 111 cCTAs (104 patients) and 311 CMR (225 patients) have been performed since 2010. For comparison, we identified 54 KD patients who had undergone both cCTA and CMR. CMR only identified eight patients with CAAs compared to 14 patients by cCTA. CMR missed 50% of the CAAs identified by cCTA. Conclusions: Our single center study demonstrates that cCTA may be a more sensitive diagnostic tool to detect CAAs in KD patients, compared to CMR.",
"affiliations": "Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children's Hospital, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, Netherlands.;Department of Radiology and Nuclear Medicine, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, Netherlands.;Department of Pediatric Cardiology, Emma Children's Hospital, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, Netherlands.;Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children's Hospital, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, Netherlands.",
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"doi": "10.3389/fped.2021.630462",
"fulltext": "\n==== Front\nFront Pediatr\nFront Pediatr\nFront. Pediatr.\nFrontiers in Pediatrics\n2296-2360\nFrontiers Media S.A.\n\n10.3389/fped.2021.630462\nPediatrics\nOriginal Research\nCT Angiography or Cardiac MRI for Detection of Coronary Artery Aneurysms in Kawasaki Disease\nvan Stijn-Bringas Dimitriades Diana 1*\n\nPlanken Nils 2\nKuipers Irene 3†\n\nKuijpers Taco 1†\n1Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children's Hospital, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, Netherlands\n2Department of Radiology and Nuclear Medicine, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, Netherlands\n3Department of Pediatric Cardiology, Emma Children's Hospital, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, Netherlands\nEdited by: Rolando Cimaz, University of Milan, Italy\n\nReviewed by: Robert Tulloh, University of Bristol, United Kingdom; Ozgur Kasapcopur, Istanbul University-Cerrahpasa, Turkey\n\n*Correspondence: Diana van Stijn-Bringas Dimitriades d.vanstijn@amsterdamumc.nl\nThis article was submitted to Pediatric Rheumatology, a section of the journal Frontiers in Pediatrics\n\n†These authors have contributed equally to this work and share co-senior authorship\n\n04 2 2021\n2021\n9 63046217 11 2020\n11 1 2021\nCopyright © 2021 van Stijn-Bringas Dimitriades, Planken, Kuipers and Kuijpers.\n2021\nvan Stijn-Bringas Dimitriades, Planken, Kuipers and Kuijpers\nThis 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.\nBackground: Kawasaki disease (KD) is an acute vasculitis that mainly affects the coronary arteries. This inflammation can cause coronary artery aneurysms (CAAs). Patients with KD need cardiac assessment for risk stratification for the development of myocardial ischemia, based on Z-score (luminal diameter of the coronary artery corrected for body surface area). Echocardiography is the primary imaging modality in KD but has several important limitations. Coronary computed tomographic angiography (cCTA) and Cardiac MRI (CMR) are non-invasive imaging modalities and of additional value for assessment of CAAs with a high diagnostic yield. The objective of this single center, retrospective study is to explore the diagnostic potential of coronary artery assessment of cCTA vs. CMR in children with KD.\n\nMethods and Results: Out of 965 KD patients from our database, a total of 111 cCTAs (104 patients) and 311 CMR (225 patients) have been performed since 2010. For comparison, we identified 54 KD patients who had undergone both cCTA and CMR. CMR only identified eight patients with CAAs compared to 14 patients by cCTA. CMR missed 50% of the CAAs identified by cCTA.\n\nConclusions: Our single center study demonstrates that cCTA may be a more sensitive diagnostic tool to detect CAAs in KD patients, compared to CMR.\n\nKawasaki disease\nimaging\ncardiac MRI\ncoronary computed tomographic angiography\ncoronary artery aneurysms\ncoronary artery assessment\n==== Body\nIntroduction\n\nKawasaki disease (KD) is an acute vasculitis of the medium-and-small-sized arteries of unknown etiology. To date, KD is the most common acquired pediatric heart disease in Western society (1). The vasculitis mainly affects the coronary arteries and the inflammation can cause coronary artery aneurysms (CAAs). Due to the formation of CAAs, CAA-related secondary complications can occur such as thrombosis, calcification, and stenosis/occlusion which can lead to myocardial ischemia. The occurrence of stenosis and thrombosis may well be inherent to the size of the CAA (2). Currently, echocardiography is used as the primary imaging modality in KD, and is a good first, rapid, and non-invasive screening tool in the acute phase. According to the American Heart Association (AHA) guidelines of 2017, additional imaging should be considered during follow-up after the patient has been categorized (by echocardiography) with a CAA (Z-score ≥ 2.5) (3), due to an associated increased risk for myocardial ischemia. This is where the Japanese Circulation Society (JCS) differs in their recommendations from the AHA. Low diagnostic accuracy of echocardiography due to limited visualization of distal coronary segments may result in underestimation of the CAA burden and may increase the risk for secondary complications (4). Therefore, the JCS suggests performing additional imaging in the convalescent phase (5) for a more accurate categorization of CAA severity.\n\nInvasive Coronary Angiography (CAG), coronary computed tomographic angiography (cCTA) and Cardiac MRI (CMR) have been suggested as alternatives complementary to echocardiography by the AHA guidelines of 2017. Invasive CAG is not routinely used because of its invasive nature and risk of complications. In a recent overview, the need for guidance for the long-term management of KD patients was emphasized, suggesting non-invasive modalities such as echocardiography and CMR, and only when other modalities cannot be used, to consider low radiation dose computed tomography (CT) (6). As the limitations of echocardiography are known, we have been performing additional imaging such as cCTA and CMR, in selected patients in our national referral center (7). In our previous study we have demonstrated the relevance of routine additional imaging for coronary artery assessment by evaluating echocardiography and cCTA for the detection of CAAs, secondary coronary artery pathology, and radiation exposure (4). In the current study, we took the approach to investigate CAA detection with cCTA and CMR, if imaging results were both available in the same patient during follow-up. The aim of this retrospective single-center study is to compare the diagnostic yield of cCTA and CMR in clinical practice for the detection of CAAs in KD patients.\n\nMethods\n\nStudy Population\n\nPatients that met the AHA diagnostic criteria for KD, and presented to the follow-up of the national referral center for KD in the Netherlands and underwent CMR and cCTA between the year 2008 and 2020, were retrospectively included in this study. The AHA diagnostic criteria for KD are: persistent fever for ≥5 days and ≥4 of the five clinical features (rash, conjunctivitis, cervical lymphadenopathy, oral changes, and extremity changes) in the case of complete KD and, for incomplete KD, if fewer than 4 of the clinical features with prolonged unexplained fever and compatible echocardiography and/or laboratory findings are present. As cCTA and CMR are not part of the routine cardiac assessment in patients with KD, these patients are a selected subset of the KD population. The majority of these patients had been previously diagnosed with CAA upon echocardiography. It is exactly this group of patients (with proximal coronary artery pathology upon echocardiography) that has the risk for potentially missed distal coronary artery involvement upon echocardiography, since the patients with no proximal involvement have no reports on having distal involvement (4). The primary objectives for additional imaging in these patients were: i.e., to verify whether CAAs could be missed in the distal parts of the coronary arteries, beyond the window of inspection by echocardiography, and—at the same time—to look for secondary coronary artery pathology (such as stenosis, occlusion, calcification, or thrombus formation). Beta-blockers were used if patients were older than the age of 12 and had a heart rate above 70–75 beats per minute (BPM) prior to the imaging. Clinical information about the acute phase and of the follow-up was extracted from medical records. Institutional Review Board approval was obtained.\n\nCMR\n\nMagnetic resonance imaging (MRI) images were acquired using a 1.5-T whole body MRI scanner with cardiac software (Siemens, Magnetom, Avanto; Siemens, Erlangen, and Germany). The imaging protocol included a navigator gated, ECG-triggered, non-contrast enhanced magnetic resonance coronary angiography (MRA) series, using a 3D echo time (TE)/repetition time (TR) optimized steady state free precession sequence with a fat saturated prepulse and T2 preparation (FOV 340–400 mm, base resolution 288 pixels. This resulted in a 3D image with a resolution of ~0.6 × 0.6 × 1.0 mm/pixel, encompassing the entire coronary tree. Acceptance window of the navigator was set to 2 mm. ECG triggering was set to the period of diastasis in the heart cycle. Imaging results were discussed in a multi-disciplinary team, consisting of a radiologist, cardiologist, pediatric cardiologist, and pediatric immunologist (all with expertise in KD).\n\ncCTA\n\nFor cCTA a dual-source 2 × 192-slice multidetector CT scanner (Siemens Somatom Force, Erlangen, Germany) was used from November 2015. Before 2015, the cCTA images were acquired using a 64-slice CT scanner (Philips, Brilliance64). For both scanners a prospective ECG-triggered step-and-shoot protocol was used and images were reconstructed with a slice-thickness of 0.6 and 0.9 mm, respectively. Contrast medium (Ultravist 300 mg/ml, Bayer Healthcare Pharmaceuticals) was administered intravenously. The total iodine dose and iodine delivery rate were adjusted for body weight. The scan delay was determined using a test bolus, after which 4 s were added for the scan delay of the main bolus. A multidisciplinary team including a radiologist, cardiologist, pediatric cardiologist, and pediatric immunologist (with expertise in KD) discussed the results, as reported previously (4).\n\nMeasurements\n\nCoronary artery diameters were measured and the CAAs Z-score was calculated according to the McCrindle/Boston model (8). There is no current alternative to the standardized measures of CAA obtained by echocardiography (9). Hence, we have used these values as the best available substrate, recognizing that they are obtained by measuring different components of the coronary arteries (internal appearance of wall to wall on echocardiography, rather than luminal diameter of contract on cCTA/CMR). A Z-score ≥ 3 was considered to be an aneurysm (as compared to a Z-score ≥ 2.5, which is normally used). By using a cut-off of a Z-score ≥ 3 instead of a Z-score ≥ 2.5 we aimed to increase specificity because a Z-score ≥ 2.5 in 1 coronary artery branch occurs in 0.6% of afebrile children and a Z-score ≥ 3.0 occurs in 0.1% (3). Also a study found that coronary artery dimensions in febrile children (non-KD) are larger than those in afebrile children, but smaller than in febrile KD patients (9). Even though not performed at the same age, majority of the imaging took place in the stable phase of the disease (i.e., more than 2 years after onset of disease) when remodeling is not expected anymore. Thereafter, discrepancies in outcome (number of detected CAAs) were considered the result of a lack of diagnostic accuracy. The left main coronary artery (LMCA), left anterior descending artery (LAD), right coronary artery (RCA), and circumflex (Cx) were evaluated. A CAA in the Cx was defined as luminal diameter ≥ 4.0 mm (10). Not only luminal dimensions were visualized, also myocardial ischemia, vascular stenosis, occlusion, vessel wall calcification and intravascular thrombosis were reported. Stenosis was defined as a narrowed lumen which influences the blood flow while an occlusion is a complete blockage of the lumen with no reserve flow. When on CMR, the coronary arteries were not visualized distinctly enough to make accurate and reliable measurements, coronary arteries were classified as NORMAL/ABNORMAL by two independent radiologists, blinded for the initial echocardiography and any additional imaging.\n\nStatistics\n\nWe generated demographic characteristics of KD patients who underwent both cCTA and CMR, presented as numbers with percentages and, where appropriate, with their mean or median and ranges (Table 1).\n\nTable 1 Demographics and characteristics of 54 KD patients with imaging performed both by cCTA and CMR.\n\nDemographics\tn = 54\tRemarks\t\nMale\tn = 43\t\t\nFemale\tn = 11\t\t\nAge in years at onset KD (median, range)\t3.1 (0.12–11.15)\tAge-at-onset was unknown in two patients.\t\nMissed diagnosis, no treatment\tn = 7\tNo treatment (IVIG/prednisone) received in seven cases, of which two did receive ASA.\t\nDay of treatment after onset of fever (median, range)\t8 (4–26)\tIn 2 patients the day of treatment was unclear.\t\nTreatment > 10 days after fever onset\tn = 11\t\t\nNon-responder to 1st IVIG\tn = 11\tPersistent fever > 48 h after IVIG treatment.\t\nΔTime in years (time between CMR and cCTA) (median, range)\t3 (0–7)\tIn 3 patients the cCTA was performed after the CMR. ΔTime in years (time between cCTA and CMR) for these patients was 1, 1, and 4 years.\t\nCAA Z-score acute stage\t\t\t\n• Z-score > 10* (giant)\tn = 12\t\t\n• Z-score 3–10* (small- to medium-sized aneurysms)\tn = 13\t\t\n• Z-score <3* (no aneurysm)\tn = 23\t\t\n• Unknown\tn = 6\t\t\n* CAA status is based on prior echocardiography results in the acute phase of KD.\n\nResults\n\nStudy Population\n\nWe collected the cCTA and CMR results from 54 pediatric KD patients who had undergone both imaging techniques during the follow-up and we compared the imaging results retrospectively, of which nine were performed before 2015. All of the CMRs were executed prior to cCTA, except for three cases. The majority of the study population in which both cCTA and CMR scanning has been performed, was male (80%). The median age at onset of disease was 3.1 years (range 0.12–11.15). A total of 12 patients (22%) had giant aneurysms (Z-score ≥ 10) following the acute presentation with clinical KD (Table 1). Classic KD diagnosis presenting with ≥4 of the 5 principal clinical features was present in the majority of cases (74%), incomplete KD was present in a minority (20%), and in the remaining three patients (6%) the clinical features at the acute stage of the disease were unknown. Most patients had been treated adequately with oral acetylsalicylic acid (ASA) and high-dose intravenous immunoglobulin (IVIG) [once (67%), or twice (20%)], whereas a minority of cases (13%) was initially missed and did not receive any treatment. The difference in median age for cCTA when compared to CMR [16.5 years (1–59) vs. 12 years (0–57)], medians, and ranges), is in part explained by the earlier availability of the non-invasive CMR modality whereas the third generation dual-source cCTA only became available in 2015. Anesthesia was used in two patients for CMR as well as for cCTA because of their young age. The remaining patients were scanned while conscious and alert, medication to manage heart rhythm (i.e., beta-blockers) were not routinely used, only when the heart rate exceeded 70–75 beats per minute. The two patients with a history of coronary artery bypass grafting (CABG) were excluded from analysis.\n\nCAA Detection\n\nWith respect to the accuracy of coronary abnormalities we identified a total of 30 CAAs in 14 patients upon cCTA against 15 CAAs upon CMR in eight patients (Table 2). When the CAAs, visualized by cCTA were considered valid and true, the distribution of CAAs missed by CMR was as followed: four CAAs in the LMCA, three CAAs in the RCA, seven CAAs in the LAD, and one CAA in the Cx. There was no clear cut-off in diameter above which the CMR was able to detect the CAAs (Table 3), but predominantly determined by imaging quality overall instead.\n\nTable 2 Total CAAs detected by cCTA vs CMR.\n\nCoronary artery\tCAA on cCTA\tCAA on CMR\t\nLMCA\t7\t3\t\nRCA\t12\t7\t\nLAD\t10\t3\t\nCx\t1\t0\t\n\nTable 3 CAAs missed by CMR, with accompanying Z-scores calculated from the luminal diameters acquired by cCTA.\n\nLMCA in mm (Z score)\tRCA in mm (Z-score)\tLAD in mm (Z-score)\tCx in mm\t\n5 (1.25)a\t4 (3.3)\t4 (3.0)\t7\t\n6 (4.26)\t7.4 (9.15)\t4 (2.52)b\t\t\n\t6 (3.88)\t6.4 (7.69)\t\t\n\t\t9 (29.92)\t\t\n\t\t7 (6.52)\t\t\n\t\t5 (3.07)\t\t\na Patient was overweight (BMI 35.1) which strongly affected the calculation of his Z-score.\n\nb Borderline Z-score of 2.52, but with an irregular wall and an internal diameter of >1.5 times that of the adjacent segment, hence counted as CAA.\n\nIn one patient, the CMR detected four CAAs in the RCA and one CAA in the Cx, while the cCTA detected only three CAAs in the RCA and a normal Cx. The delay between CMR and cCTA was 10 months. A month prior to the cCTA a CAG was performed, the results of the CAG were in concordance with the cCTA. Imaging in this patient was performed in the 1st year after onset of disease [also referred to as the dynamic phase (4, 11)] therefore, this discrepancy is most likely due to remodeling.\n\nThe CMR detected CAAs in three patients which actually had no CAAs in the coronary artery tree upon cCTA (neither in echocardiography) whereas the CMR detected a CAA in the LAD (1 patient) and in the Cx (2 patients). The delay between CMR and cCTA was 61, 67, and 59 months. However, imaging in these patients was performed long after onset of disease (>2 years), also referred to as the static phase (4), making the contribution of remodeling or normalization much less likely as the explanation for these discrepancies.\n\ncCTA and CMR; Logistics and Failure Rates\n\nDiagnostic failure rates to accurately assess the presence of vascular lesions in these patients by either cCTA or CMR were 9.6% (a total of nine coronary arteries were failed to visualize in five patients) and 59.6% (a total of 108 coronary arteries were failed to visualize in 31 patients), respectively, when both modalities were compared with each other. The main reason that CMR data acquisition failed to accurately assess the presence of a vascular lesion and therefore 1 or more coronary arteries could not be interpreted, more often than in cCTA, was due to motion artifacts caused by (i.e.,) irregular breathing and insufficient image quality; all but two patients were subsequently assessed successfully by cCTA. The cCTA gave insufficient results in five cases (without anesthesia) because of motion artifact (4) and so-called “streaking” due to beam hardening and scatter (1). In three patients the coronary artery segments which were visualized insufficiently by cCTA could be assessed by CMR or echocardiography and were unaffected. In the other two patients the Cx was not visualized well-enough either by cCTA, CMR and echocardiography. These latter two patients had no history of CAAs in any of the other coronary branches though.\n\nCAA-Related Secondary Complications\n\nImaging by cCTA was able to detect additional vascular pathology in nine patients with coronary features such as calcification (n = 8), stenosis (n = 4), occlusion (n = 1) which were not observed by routine CMR. Coronary artery thrombosis (n = 3) was detected only once by CMR. In three patients CMR enabled us to identify myocardial infarction, cCTA revealed signs of myocardial infarction in two of these patients but with much less accuracy.\n\nClinical Repercussions\n\nAs a consequence of the insufficient performance of CMR, of the eight patients diagnosed with CAA upon CMR, four patients had a second or third CAA that were identified by cCTA and not by CMR. This did not lead to a change of CAA classification, in other words, the missed CAA did not exceed the other visible CAA in Z-score and therefore did not have clinical repercussions. CMR missed CAAs in three additional patients because of diagnostic failure (mainly due to motion artifact as mentioned before) which led to subsequent imaging by cCTA. Of these, one patient needed to start acetylsalicylic acid based on the new results of the cCTA. Finally, in the last three patients redefinition by cCTA of initially missed CAAs led to a different classification, i.e., from “no CAA” to “small CAA” in two patients and near giant CAA (Z-score 9.15) in one patient (Figure 1, Table 3). This last patient needed to start acetylsalicylic acid and also underwent subsequent CMR cardiac stress testing to detect possible myocardial damage, as she was pregnant at the moment of redefinition by cCTA, which showed no myocardial ischemia.\n\nFigure 1 cCTA imaging (a) and CMR imaging (b) of KD patient with near giant CAA (*) in RCA. Calcification and partial coronary artery thrombus are only visible upon cCTA.\n\nDiscussion\n\nOur study in KD indicates that cCTA is the better modality to assess the coronary artery lesions in clinical practice when compared to CMR, and can be used for a more precise risk stratification and monitoring during follow-up of patients.\n\nThird generation dual-source cCTA has proven to be of great value for the evaluation of the luminal diameter of the coronary artery compared to invasive coronary angiography in adults (12, 13) and in KD patients (14) as well as the detection of CAAs and CAA-related secondary complications in KD (4, 15–17). The strength of cCTA lies predominantly in visualizing the anatomy and therefore to detect aneurysms, stenosis, calcification, and thrombosis. Other benefits of the third dual-source cCTA are the low radiation exposure and fast acquisition time leading to a lower burden on the pediatric population. Therefore, third generation dual-source cCTA appears to be a good candidate for coronary artery assessment in KD, i.e., risk stratification for the development of myocardial ischemia. However, CMR does not expose patients to radiation, unlike CT imaging and CAG. There is consensus that radiation exposure (due to imaging), is associated with an increase in lifetime cancer risk, especially in children and should be kept to a minimum (18, 19). Recent guidelines consider this radiation exposure and therefore mention CMR as a good imaging technique in KD (6), however, our data suggest cCTA is the more preferred modality for the visualization vascular morphology, thrombus formation and calcified lesions. CMR is valuable to visualize tissue characteristics and physiology, and has been used to demonstrate and in particular ischemia and tissue damage following myocardial infarction in KD (20, 21). Other imaging methods to evaluate cardiac function are being investigated as well (22). Current development in CT scanning techniques may enable cardiac function assessment in the future at low-dose radiation exposure (23, 24), but to date however, CMR remains the most suitable and best imaging modality for the evaluation of cardiac function and for detection of ischemia and infarction.\n\nDifferences in applicability and accuracy between CMR and cCTA have been described in the past in adults with coronary artery disease (CAD) (25). These patients mainly presented with obstructive CAD due to plaque formation and may not be comparable with our pediatric population with KD. Previous studies have attempted to determine the clinical applicability of either CT or CMR for the risk stratification (4, 12–17, 21, 26–29), but there are no comparative imaging studies available for KD to date.\n\nUpon comparison of both modalities in daily practice, our data shows that cCTA outperforms CMR in the detection of CAAs. CMR showed a higher diagnostic failure rate for coronary artery assessment mainly due to motion artifacts caused by protracted acquisition time, compared to cCTA (respectively, 59.6 vs. 9.6%). To note, suboptimal images were rated as “diagnostic failure,” as these suboptimal images led to the under-reporting of CAAs. The CAAs missed by CMR were more frequently localized in the LAD, followed by the LCA and RCA; of which three were missed because of inadequate performance.\n\nBecause echocardiography also had not been able to detect these CAAs, two patients went undertreated for 5 and 2 years, until their medium-sized CAAs were detected and oral medication was (re)started. In four patients, the CAA classification changed from normal to “small CAA,” which needed no further medication. The four patients in whom additional CAAs were detected that had been missed upon CMR, were already taking oral aspirin, but will be monitored by repeated cCTA during follow-up as a consequence. Important factors that contribute in the higher CAA detection rate by cCTA are high spatial resolution of the cCTA (0.6 mm/pixel vs. 0.6 × 0.6 × 1 mm/pixel in MRI), and high temporal resolution. This higher spatial resolution also contributes to the detection of additional coronary artery pathology (i.e., calcification, stenosis, and thrombosis), while CMR was inaccurate or unable to do so. These CAA-related secondary complications are relevant to be properly diagnosed for treatment considerations during follow-up. Another important factor for accurate coronary artery assessment is heart rate. A higher heart rate is a disadvantage for accurate coronary artery assessment. In our study, the average age of the children undergoing cCTA, and as a consequence their heart rate (since younger children on average have a higher heart rate than older children), was higher than in those that were imaged by CMR. Instead of the heart rate at start, longer acquisition time, and variability in heart rate upon CMR is probably the reason for a higher failure rate and lack of sufficient accuracy in CAA detection in KD. Stricter regulation of heart rate, managed by beta-blockers, could improve the diagnostic accuracy of CMR.\n\nLimitations\n\nRetrospective analysis introduces variation of the data, having not been systematically collected in a predefined prospective manner. In our case, patients have been selected based on the prerequisite of having complementary imaging with both CMR and cCTA data available in the same patients. Most often these patients were known to have CAAs as previously visualized in the (sub)acute stage upon echocardiography. Thus, our patient cohort does not represent a normal unselected KD population. This, however, may not be a disadvantage because it is exactly this subgroup of patients that should be routinely monitored more closely. Despite the fact that most imaging was performed in the stable phase in which remodeling of coronary artery lesions is not expected anymore, the delay between both imaging techniques may have been of influence on our results. Since there were no luminal diameters available for some of the coronary arteries on CMR, the arteries were scored as “normal” or “abnormal” based on the experienced eye. This approach was considered the most realistic for subsequent comparisons between the two imaging groups (i.e., cCTA and CMR). The inability to measure the exact coronary artery diameter on CMR supports our first suspicion that CMR could have a lower diagnostic accuracy compared to cCTA.\n\nFinally, we calculated the Z-scores using the McCrindle/Boston model, although not formally validated for being used for imaging by cCTA and CMR.\n\nConclusion\n\nOur study in KD shows that cCTA is an excellent imaging modality to assess the coronary artery tree at great resolution. cCTA detects CAAs more frequent and with greater detail when compared to CMR. Therefore, we recommend to perform cCTA in addition to echocardiography in CAA positive KD patients to detect and classify CAAs.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.\n\nEthics Statement\n\nEthical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.\n\nAuthor Contributions\n\nDS-BD conceptualized the study, collected data, and drafted the initial manuscript. IK and TK contributed equally as co-senior authors and conceptualized the study, coordinated, and supervised data collection and reviewed the manuscript for important intellectual content and revised the manuscript. NP conceptualized the study and reviewed for important intellectual content and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.\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\nWe are grateful to Dr. M. van den Hof for statistical advice.\n\nAbbreviations\n\nAHA American Heart Association\n\nASA acetylsalicylic acid\n\nBPM beats per minute\n\nCAAs Coronary artery aneurysms\n\nCABG coronary artery bypass grafting\n\nCAD coronary artery disease\n\nCAG coronary angiography\n\ncCTA coronary computed tomographic angiography\n\nCMR cardiac magnetic resonance imaging\n\nCT computed tomography\n\nCx circumflex\n\nIVIG intravenous immunoglobulin\n\nJCS Japanese Circulation Society\n\nKD Kawasaki disease\n\nLAD left anterior descending artery\n\nLMCA left main coronary artery\n\nMRA magnetic resonance coronary angiography\n\nMRI magnetic resonance imaging\n\nRCA right coronary artery\n\nTE echo time\n\nTR repetition time.\n\nFunding. 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"keywords": "Kawasaki disease; cardiac MRI; coronary artery aneurysms; coronary artery assessment; coronary computed tomographic angiography; imaging",
"medline_ta": "Front Pediatr",
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"title": "CT Angiography or Cardiac MRI for Detection of Coronary Artery Aneurysms in Kawasaki Disease.",
"title_normalized": "ct angiography or cardiac mri for detection of coronary artery aneurysms in kawasaki disease"
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"abstract": "BACKGROUND\nWhile Legionella is a common cause of pneumonia, extrapulmonary infections like arthritis are scarce. Here, we describe a case of monoarthritis due to Legionella bozemanii, with no history of pneumonia. We provide a literature review of the 9 previously published Legionella arthritis and highlight a dichotomous epidemiology suggesting different physiopathological pathways leading to joint infection.\n\n\nMETHODS\nA 56-year old woman under immunosuppressive treatment by oral and intra-articular corticosteroids, methotrexate, and tocilizumab for an anti-synthetase syndrome was hospitalized for worsening pain and swelling of the left wrist for 3 days. Clinical examination showed left wrist synovitis and no fever. The arthritis occurred a few days after an accidental fall on wet asphalt responsible for a cutaneous wound followed by a corticosteroid intra-articular injection. Due to both the negativity of conventional culture of articular fluid and suspicion of infection, 16S rRNA and specific PCRs were performed leading to the identification of L. bozemanii. Legionella-specific culture of the articular fluid was performed retrospectively and isolated L. bozemanii. The empiric antibiotic therapy was switched for oral levofloxacin and rifampin and the patient recovered after a 12-week treatment.\n\n\nCONCLUSIONS\nWe report a case of L. bozemanii monoarthritis in an immunosuppressed woman, following a fall on wet asphalt and intra-articular corticosteroid injection. The review of the literature found that the clinical presentation reveals the mode of infection and the bacterial species. Monoarthritis more likely occurred after inoculation in patients under immunosuppressive therapy and were associated with non-Legionella pneumophila serogroup 1 (Lp1) strains that predominate in the environment. Polyarthritis were more likely secondary legionellosis localizations after blood spread of Lp1, the most frequently found in pneumonia. In both settings, 16S rRNA and Legionella-specific PCR were key factors for the diagnosis.",
"affiliations": "Hospices Civils de Lyon, Groupement Hospitalier Nord, Institut des Agents Infectieux, Laboratoire de Bactériologie, Lyon, France.;Hospices Civils de Lyon, Groupement Hospitalier Nord, Institut des Agents Infectieux, Laboratoire de Bactériologie, Lyon, France.;Hospices Civils de Lyon, Groupement Hospitalier Sud, Hôpital Lyon Sud, Service de Rhumatologie, Pierre-Bénite, France.;Hospices Civils de Lyon, Groupement Hospitalier Nord, Institut des Agents Infectieux, Laboratoire de Bactériologie, Lyon, France.;Hospices Civils de Lyon, Groupement Hospitalier Nord, Institut des Agents Infectieux, Centre National de Référence des Légionelles, Lyon, France.;Hospices Civils de Lyon, Groupement Hospitalier Nord, Institut des Agents Infectieux, Laboratoire de Bactériologie, Lyon, France.;Hospices Civils de Lyon, Groupement Hospitalier Nord, Institut des Agents Infectieux, Laboratoire de Bactériologie, Lyon, France. ghislaine.descours@univ-lyon1.fr.",
"authors": "Ibranosyan|Marine|M|;Beraud|Laetitia|L|;Lemaire|Hélène|H|;Ranc|Anne-Gaëlle|AG|;Ginevra|Christophe|C|;Jarraud|Sophie|S|;Descours|Ghislaine|G|http://orcid.org/0000-0001-5745-5186",
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"fulltext": "\n==== Front\nBMC Infect DisBMC Infect. DisBMC Infectious Diseases1471-2334BioMed Central London 448810.1186/s12879-019-4488-zCase ReportThe clinical presentation of Legionella arthritis reveals the mode of infection and the bacterial species: case report and literature review Ibranosyan Marine marine.ibranosyan@chu-lyon.fr 1Beraud Laetitia laetitia.beraud@chu-lyon.fr 12Lemaire Hélène helene.lemaire@chu-lyon.fr 34Ranc Anne-Gaëlle anne-gaelle.ranc@chu-lyon.fr 12Ginevra Christophe christophe.ginevra@chu-lyon.fr 2567Jarraud Sophie sophie.jarraud@univ-lyon1.fr 12567http://orcid.org/0000-0001-5745-5186Descours Ghislaine +33 (0)472 071 650ghislaine.descours@univ-lyon1.fr 125671 0000 0001 2163 3825grid.413852.9Hospices Civils de Lyon, Groupement Hospitalier Nord, Institut des Agents Infectieux, Laboratoire de Bactériologie, Lyon, France 2 0000 0001 2163 3825grid.413852.9Hospices Civils de Lyon, Groupement Hospitalier Nord, Institut des Agents Infectieux, Centre National de Référence des Légionelles, Lyon, France 3 0000 0001 0288 2594grid.411430.3Hospices Civils de Lyon, Groupement Hospitalier Sud, Hôpital Lyon Sud, Service de Rhumatologie, Pierre-Bénite, France 4 0000 0001 2198 4166grid.412180.eHospices Civils de Lyon, Groupement Hospitalier Centre, Hôpital Edouard Herriot, Service de Rhumatologie, Lyon, France 5 0000 0004 0450 6033grid.462394.eCIRI, Centre International de Recherche en Infectiologie, Equipe Pathogénèse des Légionelles, Lyon, France 6 0000 0001 2175 9188grid.15140.31Inserm, U1111, Université Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, Lyon, France 7 0000 0001 2150 7757grid.7849.2Univ Lyon 1, Lyon, France 21 10 2019 21 10 2019 2019 19 8644 6 2019 20 9 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nWhile Legionella is a common cause of pneumonia, extrapulmonary infections like arthritis are scarce. Here, we describe a case of monoarthritis due to Legionella bozemanii, with no history of pneumonia. We provide a literature review of the 9 previously published Legionella arthritis and highlight a dichotomous epidemiology suggesting different physiopathological pathways leading to joint infection.\n\nCase presentation\nA 56-year old woman under immunosuppressive treatment by oral and intra-articular corticosteroids, methotrexate, and tocilizumab for an anti-synthetase syndrome was hospitalized for worsening pain and swelling of the left wrist for 3 days. Clinical examination showed left wrist synovitis and no fever. The arthritis occurred a few days after an accidental fall on wet asphalt responsible for a cutaneous wound followed by a corticosteroid intra-articular injection. Due to both the negativity of conventional culture of articular fluid and suspicion of infection, 16S rRNA and specific PCRs were performed leading to the identification of L. bozemanii. Legionella-specific culture of the articular fluid was performed retrospectively and isolated L. bozemanii. The empiric antibiotic therapy was switched for oral levofloxacin and rifampin and the patient recovered after a 12-week treatment.\n\nConclusion\nWe report a case of L. bozemanii monoarthritis in an immunosuppressed woman, following a fall on wet asphalt and intra-articular corticosteroid injection. The review of the literature found that the clinical presentation reveals the mode of infection and the bacterial species. Monoarthritis more likely occurred after inoculation in patients under immunosuppressive therapy and were associated with non-Legionella pneumophila serogroup 1 (Lp1) strains that predominate in the environment. Polyarthritis were more likely secondary legionellosis localizations after blood spread of Lp1, the most frequently found in pneumonia. In both settings, 16S rRNA and Legionella-specific PCR were key factors for the diagnosis.\n\nKeywords\nLegionella bozemaniiArthritisImmunosuppressionCorticosteroidTocilizumabMethotrexateInoculation16S rRNA PCRExtrapulmonary infectionsissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nLegionnaires’ disease (LD), a severe pneumonia caused by Legionella, represents 2–9% of cases of community-acquired pneumonia. There are more than 70 species and serogroups, but Legionella pneumophila serogroup 1 (Lp1) is responsible for more than 85% of cases of LD worldwide, while non-Lp1 infections occur more frequently in immunosuppressed patients [1]. Extrapulmonary infections, including arthritis, are scarce and not systematically related to pneumonia, suggesting a multi-faceted infectious process. Herein, we report a case of L. bozemanii monoarthritis in an immunosuppressed woman, following a fall on wet asphalt and intra-articular corticosteroid (CS) injections.\n\nCase presentation\nA 56-year-old woman was hospitalized in the rheumatology department for worsening pain and swelling of the left wrist over the 3 preceding days. Her medical history included type 1 diabete and anti-synthetase syndrome diagnosed 1 year previously and which was characterized by polyarthritis, dermatomyositis and interstitial lung disease, and treated by prednisone 10 mg/day, methotrexate (MTX) 20 mg/week, and tocilizumab 560 mg/month. During the 2 previous months, she suffered from stage-II synovitis of the left wrist predominant at radiocarpal and middle carpal joints, associated with flexor and extensor digitorum communis tenosynovitis; she received 2 intra-articular injections of triamcinolone 2 months and 3 days before admission.\n\nOn admission, the patient showed left wrist synovitis with no fever. Clinical examination found a wound of the 3rd proximal interphalangeal joint, related to an accidental fall on wet asphalt 4 days before. The blood count and C-reactive protein were normal. Chest X-ray showed no worsening of the interstitial lung disease. Blood samples were collected for culture. Over the following days, while she remained afebrile, local symptoms worsened, with onset of a painful epitrochlear lymphadenopathy. On day 4, a septic arthritis was suspected and aspiration of the left wrist fluid was performed; hemorrhagic fluid with a white blood cell count of 15.7 G/L and a neutrophil count of 8.0 G/L (51%) was found. One sample was sent to the microbiology laboratory; Gram stain revealed no microorganism. An intravenous anti-staphylococcal antibiotic therapy (oxacillin 12 g/day, gentamicin 240 mg/day) was initiated. On day 6, routine wrist fluid culture remained sterile, 16S rRNA [2] and Staphylococcus PCRs were negative, and blood cultures also remained sterile. On day 9, while the patient had improved, an inflammatory aspect of the back of the hand and severe pain persisted. The antibiotic spectrum was broadened to piperacillin-tazobactam 12 g/day and vancomycin 2 g/day on infectiologist advice. On day 14, the patient had not improved and she underwent emergency surgery that found phlegmon of the F2 and F5 sheaths, requiring drainage and arthroscopic joint lavage. Six samples were sent to the microbiology laboratory; after 14 days of culture (day 28) a single Lysinibacillus fusiformis colony was found in 1 sample, and rare Cutibacterium acnes colonies in a second sample, which were considered as contaminants. On day 29, the 16S rRNA PCRs were positive for Legionella spp. for 2 of the 4 sterile samples. The 23S–5S PCR performed on these samples identified L. bozemanii. The antibiotic regimen was modified to a 12-week course of oral levofloxacin 1 g/day and rifampin 1.2 g/day, and the symptoms quickly resolved. The immunosuppressive therapy by prednisone and MTX was continued Fig. 1.\nFig. 1 Timeline of interventions and outcomes\n\n\n\nRetrospectively, the joint fluid sampled on day 4 also tested positive for L. bozemanii by 23S–5S PCR. Five specimens (1 collected on day 4, and 4 on day 14) were plated onto BCYE, BMPA and MWY plates (Oxoid, Dardilly, France). Only 1 day-14 sample grew L. bozemanii after 9 days. A L. bozemanii seroconversion (< 1/16 before admission, 1/256 on day 53) was demonstrated by in-house serology.\n\nRegarding the source of infection, no clinical or radiological pneumonia was diagnosed before or during the course of the infection. L. bozemanii inoculation from asphalt at the time of her fall was strongly suspected. We hypothesized that the immunosuppressive treatment contributed to development of the infection and delayed diagnosis.\n\nDiscussion and conclusions\nWhen examining this case alongside those previously published and summarized in Table 1 (n = 9) [3–11], it is of note that Legionella arthritis was mostly identified incidentally by 16S rRNA PCR, which is consistent with the characteristics of the bacterium that does not usually grow on standard media. Interestingly, 2 clinical presentations can be distinguished. The first is monoarthritis (n = 7) that were all due to non-Lp1 strains and mainly reported in immunosuppressed patients (n = 6) with no history of pneumonia (n = 7); in 5 of the 7 cases, skin trauma close to the affected joint (n = 2) or an intra-articular injection or joint surgery (n = 3) was reported before arthritis. In contrast, cases of polyarthritis (n = 3) were all due to Lp1 and observed in patients with no immunosuppressive treatment who presented pneumonia at the time or before the diagnosis of arthritis. This dichotomous epidemiology suggests different physiopathological pathways leading to joint infection, which may result from both strain- and patient-related factors.\nTable 1 Demographic characteristics, clinical features, and microbiological diagnoses of the case reports of Legionella arthritis, including the current case\n\nCase\tGender\tAge (y)\tLocalization\tStrain\tMicrobiological diagnosis\tMedical history\tImmunosuppressive treatment\tSuspected origin of the infection\tPneumonia\t\nCurrent case\tFemale\t56\tLeft wrist\t\nL. bozemanii\n\t16S rRNA PCR, culture\tAnti-synthetase syndrome\tOral and intra-articular CS, MTX, tocilizumab\tWound after fall on a wet asphalt\tNo\t\nBanderet et al. 2017 [3]\tFemale\t90\tLeft wrist\t\nL. cincinnatiensis\n\t16S rRNA PCR, culture\tPresumed chondrocalcinosis, chronic kidney disease\tOral and intra- articular CS\tIntra-articular CS injection\tNo\t\nJust et al. 2012 [4]\tFemale\t71\tLeft knee\t\nL. bozemanii\n\t16S rRNA PCR, culture\tDermatomyositis\tOral CS, MTX\tSkin biopsy\tNo\t\nFernández-Cruz et al. 2011 [5]\tFemale\t83\tRight knee\t\nL. micdadei\n\t16S rRNA PCR, culture\tRheumatoid arthritis\tOral CS, MTX\tReplacement of prosthesis the year before\tNo\t\nFlendrie et al. 2011 [6]\tFemale\t58\tRight knee\t\nL. dumoffii\n\t16S rRNA PCR, culture\tSystemic erythematosus lupus-like disease\tOral and intra-articular CS, MTX\tIntra-articular injection 2 days before\tNo\t\nDugar et al. 2009 [7]\tMale\t56\tLeft foot\t\nL. longbeachae\n\tCulture\tRheumatoid arthritis, diabetes mellitus\tOral CS, MTX\tUnknown\tNo\t\nLinscott et al. 2004 [8]\tFemale\t80\tRight MCP joint\tL. pneumophila serogroup 4\tCulture on chocolate agar\tNo\tNo\tUnknown\tNo\t\nThurneysen and Boggian 2014 [9]\tMale\t70\tRight knee\n\nLeft ankle\n\n\tL. pneumophila serogroup 1\t16S rRNA PCR, culture\tSecondary thymoma- associated immunoglobulin deficiency\tNo\tUnknown\tYes, 5 months before\t\nNaito et al. 2007 [10]\tFemale\t80\tLeft and Right ankle\tL. pneumophila serogroup 1\tUrinary antigen, 16S rRNA PCR\tChronic kidney disease\tNo\tUnknown\tYes, LD 16 days before\t\nBemer et al. 2002 [11]\tMale\t51\tRight wrist and ankle, both knees\tL. pneumophila serogroup 1\tUrinary antigen, Culture on mycobacteria medium\tRecurrence of thymoma 1 year before\tNo\tUnknown\tYes, at the same time\t\nCS Corticosteroid, LD Legionnaires’ disease, MCP Metacarpophalangeal, MTX Methotrexate, rRNA PCR ribosomal ribonucleic acid polymerase chain reaction\n\n\n\nWhile more than 70 Legionella species have been isolated from freshwater and soil environments, less than half have been observed in clinical settings, and Lp1 is responsible for the vast majority of LD cases worldwide [1]. In contrast with pneumonia, non-Lp1 Legionella strains are predominant among the cases of monoarthritis reported in the literature (Table 1). This particular epidemiology is consistent with the environmental distribution of Legionella strains [12] and the direct mode of transmission from their natural niche; a similar epidemiology has been described for skin and soft tissue Legionella infections [13].\n\nHost response to Legionella infections involves both innate and adaptive immunity [14, 15] and immunosuppressive therapies such as systemic CS, cytotoxic chemotherapies, and biological therapies (i.e. tumor necrosis factor inhibitors) are risk factors for Legionella infections [15–17]. Post-inoculation arthritis were described in patients receiving CS with or without MTX (Table 1), suggesting that inoculated Legionella was not cleared at the first step of infection. Three cases received intra-articular CS that constitutes both a gateway for environmental germs and an additional local risk factor for infection. In the case described herein, the patient also received tocilizumab, an IL-6 receptor antagonist. A case of Lp1 pneumonia in a patient under tocilizimab has been described [18]. As described herein, the patient presented no fever as tocilizumab inhibits IL-6, an inflammation and fever mediator [19], and, by delaying the diagnosis, tocilizumab contributes to uncontrolled infections.\n\nAnother clinical feature of Legionella arthritis is polyarthritis occurring during the course or after pneumonia. Interestingly, the reported cases are all due to Lp1 strains that predominate in LD (Table 1) suggesting secondary joint infections after bacterial blood dissemination. Accordingly, cases of Lp1 bacteremia have been described [20–22], and Lindsay et al. reported that up to 80.5% of patients present an Lp1 blood positive PCR after LD onset [23]. Nevertheless, non-Lp1 bacteremias have also been described [24, 25] and no data comparing blood bacterial loads between Lp1 and non-Lp1 strains are available.\n\nIn conclusion, the clinical presentation of Legionella arthritis reveals the mode of infection and orientates the microbiological diagnosis towards either Lp1 or non-Lp1. In both contexts, 16S rRNA and Legionella specific PCRs are key factors for the diagnosis.\n\nAbbreviations\nCSCorticosteroid\n\nLDLegionnaires’ disease\n\nLp1Legionella pneumophila serogroup 1\n\nMCPMetacarpophalangeal\n\nMTXMethotrexate\n\nrRNA PCRRibosomal ribonucleic acid polymerase chain reaction\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nThe authors are grateful to Dr. P Robinson for his critical reading of the manuscript.\n\nAuthors’ contributions\nMI drafted the manuscript. LB made substantial contributions to the analysis and interpretation of the data. HL, AGR, CG participated to acquisition of data. SJ designed the study and reviewed the manuscript for intellectual content. GD designed the study, made substantial contributions to the analysis and interpretation of the data and drafted the manuscript. All authors read and approved the final manuscript.\n\nFunding\nNone.\n\nAvailability of data and materials\nNot applicable.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Cunha BA Burillo A Bouza E Legionnaires’ disease Lancet 2016 387 376 385 10.1016/S0140-6736(15)60078-2 26231463 \n2. 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Flendrie M Jeurissen M Franssen M Kwa D Klaassen C Vos F Septic arthritis caused by Legionella dumoffii in a patient with systemic lupus erythematosus-like disease J Clin Microbiol 2011 49 746 749 10.1128/JCM.00606-10 21106784 \n7. Dugar M Rankin WA Rowe E Smith MD “My foot hurts”: a flare of rheumatoid arthritis? Med J Aust 2009 190 392 393 10.5694/j.1326-5377.2009.tb02459.x 19351317 \n8. Linscott AJ Poulter MD Ward K Bruckner DA Legionella pneumophila Serogroup 4 isolated from joint tissue J Clin Microbiol 2004 42 1365 1366 10.1128/JCM.42.3.1365-1366.2004 15004121 \n9. Thurneysen C Boggian K Legionella pneumophila Serogroup 1 septic arthritis with probable endocarditis in an Immunodeficient patient J Clin Rheumatol 2014 20 297 298 10.1097/RHU.0000000000000128 25057741 \n10. Naito T Suda T Saga K Horii T Chida K Reactive Legionella pneumophila arthritis diagnosed by polymerase chain reaction Rheumatol Int 2007 27 415 416 10.1007/s00296-006-0223-3 17009015 \n11. Bemer P Leautez S Ninin E Jarraud S Raffi F Drugeon H Legionella pneumophila arthritis: use of medium specific for mycobacteria for isolation of L. pneumophila in culture of articular fluid specimens Clin Infect Dis 2002 35 e6 e7 10.1086/340713 12060893 \n12. Doleans A Aurell H Reyrolle M Lina G Freney J Vandenesch F Clinical and environmental distributions of Legionella strains in France are different J Clin Microbiol 2004 42 458 460 10.1128/JCM.42.1.458-460.2004 14715805 \n13. Padrnos LJ Blair JE Kusne S Dicaudo DJ Mikhael JR Cutaneous legionellosis: case report and review of the medical literature Transpl Infect Dis 2014 16 307 314 10.1111/tid.12201 24628820 \n14. Newton HJ Ang DKY Van Driel IR Hartland EL Molecular pathogenesis of infections caused by Legionella pneumophila Clin Microbiol Rev 2010 23 274 298 10.1128/CMR.00052-09 20375353 \n15. Lanternier F Ader F Pilmis B Catherinot E Jarraud S Lortholary O Legionnaire’s disease in compromised hosts Infect Dis Clin N Am 2017 31 123 135 10.1016/j.idc.2016.10.014 \n16. Carratala J Gudiol F Pallares R Dorca J Verdaguer R Ariza J Risk factors for nosocomial Legionella pneumophila pneumonia Am J Respir Crit Care Med 1994 149 625 629 10.1164/ajrccm.149.3.8118629 8118629 \n17. Lanternier F Tubach F Ravaud P Salmon D Dellamonica P Bretagne S Incidence and risk factors of Legionella pneumophila pneumonia during anti-tumor necrosis factor therapy: a prospective French study Chest 2013 144 990 998 10.1378/chest.12-2820 23744173 \n18. Arinuma Y Nogi S Ishikawa Y Nakayama H Hashimoto A Komiya A Fatal complication of Legionella pneumophila pneumonia in a Tocilizumab-treated rheumatoid arthritis patient Intern Med 2015 54 1125 1130 10.2169/internalmedicine.54.3103 25948362 \n19. Netea MG Kullberg BJ Van der Meer JWM Circulating Cytokines as Mediators of Fever Clin Infect Dis 2000 31 Supplement_5 S178 S184 10.1086/317513 11113021 \n20. Rihs JD Yu VL Zuravleff JJ Goetz A Muder RR Isolation of Legionella pneumophila from blood with the BACTEC system: a prospective study yielding positive results J Clin Microbiol 1985 22 422 424 4044800 \n21. Kaku N Yanagihara K Morinaga Y Sato T Nakashima M Sakai T Detection of Legionella pneumophila serogroup 1 in blood cultures from a patient treated with tumor necrosis factor-alpha inhibitor J Infect Chemother 2013 19 166 170 10.1007/s10156-012-0459-7 22911089 \n22. Lai CC Tan CK Chou CH Hsu HL Huang YT Liao CH Hospital-acquired pneumonia and bacteremia caused by Legionella pneumophila in an immunocompromised patient Infection 2010 38 135 137 10.1007/s15010-009-9253-1 20349106 \n23. Lindsay DSJ Abraham WH Findlay W Christie P Johnston F Edwards GFS Laboratory diagnosis of legionnaires’ disease due to Legionella pneumophila serogroup 1: comparison of phenotypic and genotypic methods J Med Microbiol 2004 53 183 187 10.1099/jmm.0.05464-0 14970242 \n24. Moriguchi S Abe M Kimura M Yoshino C Baba M Okada C The diagnosis of Legionella pneumophila Serogroup 5 Bacteremic pneumonia during severe neutropenia using loop-mediated isothermal amplification Intern Med 2017 57 1045 1048 10.2169/internalmedicine.9810-17 29269681 \n25. Cheung YF Leung MP Yuen KY Legionella pneumonia and bacteraemia in association with protein-losing enteropathy after Fontan operation J Inf Secur 2001 42 206 207\n\n",
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"keywords": "16S rRNA PCR; Arthritis; Corticosteroid; Extrapulmonary infections; Immunosuppression; Inoculation; Legionella bozemanii; Methotrexate; Tocilizumab",
"medline_ta": "BMC Infect Dis",
"mesh_terms": "D000058:Accidental Falls; D000284:Administration, Oral; D000305:Adrenal Cortex Hormones; D001170:Arthritis, Infectious; D005260:Female; D006801:Humans; D006838:Hydrocarbons; D016867:Immunocompromised Host; D007270:Injections, Intra-Articular; D016951:Legionellaceae; D007876:Legionellosis; D064704:Levofloxacin; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012336:RNA, Ribosomal, 16S; D012293:Rifampin; D016896:Treatment Outcome",
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"title": "The clinical presentation of Legionella arthritis reveals the mode of infection and the bacterial species: case report and literature review.",
"title_normalized": "the clinical presentation of legionella arthritis reveals the mode of infection and the bacterial species case report and literature review"
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"abstract": "Cerebral abscess due to Aspergillus species is a relatively uncommon presentation, even amongst immunocompromised patients. However it is increasingly being recognized as a complication of ibrutinib therapy in patients with chronic lymphocytic leukemia. We present a case of cerebral abscesses caused by Aspergillus felis in a patient receiving ibrutinib for chronic lymphocytic leukemia.",
"affiliations": "Department of Microbiology and Infectious Diseases, NSW Health Pathology-South West Sydney, Sydney, Australia.;Department of Microbiology and Infectious Diseases, NSW Health Pathology-South West Sydney, Sydney, Australia.;Department of Microbiology and Infectious Diseases, NSW Health Pathology-South West Sydney, Sydney, Australia.",
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"fulltext": "\n==== Front\nMed Mycol Case RepMed Mycol Case RepMedical Mycology Case Reports2211-7539Elsevier S2211-7539(18)30155-610.1016/j.mmcr.2019.02.005Case ReportCranial aspergillosis in a patient receiving ibrutinib for chronic lymphocytic leukemia Beresford Rohan rohan.beresford@gmail.comrohan.beresford@svha.org.aua∗Dolot Virginia aFoo Hong aba Department of Microbiology and Infectious Diseases, NSW Health Pathology-South West Sydney, Sydney, Australiab School of Medicine, Western Sydney University, Campbelltown, Australia∗ Corresponding author. rohan.beresford@gmail.comrohan.beresford@svha.org.au28 2 2019 6 2019 28 2 2019 24 27 29 20 12 2018 11 2 2019 25 2 2019 © 2019 The Authors. Published by Elsevier B.V. on behalf of International Society for Human and Animal Mycology.2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Cerebral abscess due to Aspergillus species is a relatively uncommon presentation, even amongst immunocompromised patients. However it is increasingly being recognized as a complication of ibrutinib therapy in patients with chronic lymphocytic leukemia. We present a case of cerebral abscesses caused by Aspergillus felis in a patient receiving ibrutinib for chronic lymphocytic leukemia.\n\nKeywords\nAspergillosisIbrutinibCerebral abscessChronic lymphocytic leukemia\n==== Body\n1 Introduction\nCentral nervous system (CNS) aspergillosis is an uncommon presentation, but has been seen in immunocompromised patients [1]. Ibrutinib is an inhibitor of Bruton's tyrosine kinase (BTK) increasingly being used in the management of chronic lymphocytic leukemia (CLL), a hematological malignancy which has generally been viewed as low risk for invasive fungal disease. As such, antifungal prophylaxis is not routinely recommended for CLL patients. There have been multiple reports of patients treated with ibrutinib, who have developed invasive fungal disease, with a noted predilection for the central nervous system [[3], [4], [5], [6], [7], [8]].\n\nWe present a case of cerebral aspergillosis in a patient with CLL receiving ibrutinib without other risk factors for invasive aspergillosis, and review the literature that suggest an association between ibrutninb therapy and an increased risk of invasive fungal disease, particularly affecting the central nervous system. Furthermore we discuss the isolation of a newly recognized species of Aspergillus section fumigati, Aspergillus felis, and the implications for treating this species, given its frequent association with high minimum inhibitory concentration (MIC) levels for triazoles.\n\n2 Case\nA 66 year old male presented to hospital with new onset confusion and expressive dysphasia over several days, on a background of CLL, and a previous excision of cutaneous melanoma one year previously with clear margins. His background history also included mild stable asthma, hypertension, and allergic rhinitis. His CLL treatment over several years had included: fludarabine, cyclophosphamide, bendamustine and rituximab. However, over the 12 months prior to presentation, he had been established on monthly intravenous immunoglobulin (IVIG) and ibrutinib. Of note, his lowest recorded neutrophil count in the previous 12 months was 1.5 × 109/L and he was not receiving concurrent corticosteroids or prophylactic antimicrobials.\n\nThe patient was afebrile on presentation, and apart from an expressive dysphasia, a neurology examination was unremarkable. Initial blood tests revealed a total white cell count of 4.7 × 109/L, with a neutrophil count of 2.6 × 109/L. A brain magnetic resonance imaging (MRI) scan with gadolinium enhancement demonstrated multiple rim-enhancing hemorrhagic lesions, the largest of which was located in the left parieto-temporal region (Fig. 1). A presumptive diagnosis of metastatic melanoma with hemorrhagic cerebral metastases was made and the patient was commenced on dexamethasone. He subsequently underwent craniotomy and excision of the left parieto-temporal lesion. Intra-operatively, the lesion was noted to have a thick fibrous capsule containing purulent material within, consistent with an abscess.Fig. 1 MRI scan T2 weighted (axial) with 14mm rim-enhancing left parieto-temporal lesion (arrow) and perilesional edema (arrowhead).\n\nFig. 1\n\nHistopathological examination of the tissue demonstrated gliosis and filamentous septate hyphae with acute angle branching (Fig. 2); with no evidence of malignant cells. Culture of the tissue demonstrated growth of white fungal colonies with blue-green reverse color. Microscopically, singly borne conidiophores with uniseriate phialides arising from the upper two thirds of the terminal vesicle were seen, consistent with Aspergillus fumigatus complex. A serum galactomannan (Platelia-Aspergillus Ag, Bio-Rad Laboratories, Hercules CA USA) was negative, as were fungal blood cultures. A computerised tomography (CT) scan of the chest and abdomen revealed a 5mm pulmonary nodule and widespread lymphadenopathy consistent with the diagnosis of CLL (which were unchanged from previous imaging). A trans-esophageal echocardiogram did not demonstrate any definite evidence of endocarditis.Fig. 2 Histopathology of left parieto-temporal lesion demonstrating septate fungal hyphae with acute angle branching on iron and hematoxylin (left) and Grocott's methenamine silver (right) stains.\n\nFig. 2\n\nThe patient was commenced on voriconazole with achievement of therapeutic drug levels, and the ibrutinib was ceased. He had a good clinical response to surgery and initiation of voriconazole and was discharged from hospital. His treatment course was complicated by the development of a photosensitivity rash, resulting in a switch from voriconazole to oral posaconazole. DNN sequence analysis of internal transcribed sequence 1, 5.8S and ITS2 regions was performed using published primers and standard sequencing methodologies, identified the fungus as a member of the Aspegillus felis complex within Aspegillus section Fumigati [9]. The sequence showed 100% identity (480 base pairs) to numerous reference strains in the Westerdijk Fungal Biodiversity Institute database including Aspegillus felis (CBS 130244), Aspergillus parafelis (CBS 140763) and Aspergillus pseudofelis (CBS 140763). Susceptibility testing by broth microdilution using the SensititreTM YeastONE YO10 plates (Thermo Fisher) revealed non-Wild-Type minimum inhibitory concentrations (MICs) for all tested triazoles (Table 1). In view of the marked clinical and radiological improvement on triazoles despite elevated MICs, and the lack of alternative oral antifungal options, the patient was maintained on posaconazole, which he continues to tolerate well. However, his CLL progressed after cessation of the ibrutinib, and he is currently being treated with rituximab. Given his ongoing immunosuppression he is expected to require indefinite antifungal therapy.Table 1 Antifungal susceptibility testing of Aspergillus felis isolate by broth microdilution.\n\nTable 1Antifungal\tMIC (ɥg/mL)\t\nAmphotericin B\t2\t\nAnidulafungin\t0.06\t\nItraconazole\t>16\t\nVoriconazole\t4\t\nPosaconazole\t1\t\nMIC, Minimum inhibitory concentration.\n\n\n\n3 Discussion\nWe present a case of a patient with CLL, without classic risk factors for invasive fungal disease, who develops cerebral aspergillosis whilst receiving ibrutinib. Patients at highest risk of developing invasive fungal disease include: those receiving intensive chemotherapy for acute myeloid leukemia or myelodysplastic syndromes; and those requiring corticosteroids for graft-versus-host-disease following allogeneic hematopoietic stem cell transplantation (AHSCT) or with prolonged neutropenia post-AHSCT. There are no current recommendations for routine antifungal prophylaxis in CLL patients, a group considered to be low risk for invasive fungal disease, or in patients receiving ibrutinib [2].\n\nIbrutinib is a newly approved treatment for CLL which selectively inhibits BTK, an enzyme that promotes survival and proliferation in normal B cells and CLL cells. Several reports have highlighted a possible link between ibrutinib therapy and the development of invasive fungal disease [3,4], with a distinct predilection for invasive cerebral disease [[6], [7], [8]]. Aspergillus species, Cryptococcus neoformans [7,8], and Pneumocystis jirovecii [7] causing invasive fungal disease have all been identified in patients on ibrutinib therapy. Onset of the invasive fungal infection can be seen early in ibrutinib therapy, without any other identifiable risk factor for fungal infection [7]. The mechanism by which BTK inhibition by ibrutinib results in a propensity for fungal disease is unclear. One proposed mechanism is the suppression of the activation and normal function of macrophages and neutrophils expressing BTK [6], thereby interfering with the host's primary lines of defense against fungal pathogens. Predilection for CNS involvement has been postulated to result from inhibition of CNS macrophages [6].\n\nAspergillus felis is a newly recognized member of Aspergillus section fumigati that has been isolated predominantly from cats, but also from dogs and humans [10]. Aspergillus felis differs morphologically from other Aspergillus section fumigati by its ability to grow at 45 °C; however it is only reliably identified by ITS sequencing. Notably this species may have high MICs to antifungal drugs, including triazoles, which was seen in our patient. This raises concerns that antifungal treatment may be more likely to fail in these patients, and therefore early identification of this organism may prompt avoidance of the triazole class until susceptibility is confirmed. In the case of our patient, by the time the Aspergillus identification and susceptibility was confirmed, he had clearly improved on triazole therapy.\n\nWith the increasing use of ibrutinib for CLL, it is important to be aware of a possible association with development of invasive fungal disease, particularly cerebral disease. Further study is required to determine if ibrutinib use warrants antifungal prophylaxis. Additionally, early identification of less commonly encountered Aspergillus species may be important in order to guide appropriate empiric antifungal therapy.\n\nConflict of interest\nNone of the authors have conflicts of interest to declare.\n\nAcknowledgements\nDr Lindsay Dunlop, Hematology Department, Liverpool Hospital, Sydney, Australia.\n\nAnatomical Pathology Department, Liverpool Hospital, Sydney, Australia.\n\nClinical Mycology Reference Laboratory, ICPMR – NSW Health Pathology, Westmead, Australia.\n==== Refs\nReferences\n1 Denning D.W. Invasive aspergillosis Clin. Infect. Dis. 26 1998 781 805 9564455 \n2 Fleming S. Yannakou C.K. Haeusler G.M. Consensus guidelines for antifungal prophylaxis in haematological malignancy and haemopoetic stem cell transplantation, 2014 Intern. Med. J. 44 2014 1 15 \n3 Ruchlemer R. Ami R.B. Lachish T. Ibrutinib for chronic lymphocytic leukemia New Eng. J. Med. Corresp. 374 2016 1592 1595 \n4 Arthurs B. Wunderle K. Hsu M. Invasive aspergillosis related to ibrutinib therapy for chronic lymphocytic leukaemia Respir. Med. Case Rep. 21 2017 27 29 28377877 \n5 Chamilos G. Lionakis M.S. Kontoyiannis D.P. Call for action: invasive fungal infections associated with ibrutinib and other small molecule inhibitors targeting immune signalling pathways Clin. Infect. Dis. 66 1 2018 140 148 29029010 \n6 Lionakis M. Dunleavy K. Roschewski M. Inhibition of B cell receptor signalling in primary CNS lymphoma Cancer Cell 31 6 2017 833 843 28552327 \n7 Ghez D. Calleja A. Protin C. Early-onset aspergillosis and other fungal infections in patients treated with ibrutinib Blood 131 17 2018 1955 1959 29437588 \n8 Messina J. Mariaz E.K. Spec A. Disseminated cryptococcosis with brain involvement in patients with chronic lymphoid malignancies on ibrutinib Open Forum Infect. Dis. 4 1 2017 ofw261 28480254 \n9 White T. Bruns T. Lee S. Taylow J.W. Amplification and direct sequencing of fungal ribosomal RNA genes for phylogenetics Gelfrand M. Innis D. Sninsky J. White T. PCR Protocols: a Guide to Methods and Applications 1990 Academic Press New York 315 322 \n10 Barr V.R. van Doorn Houbraken J. Aspergillus felis sp . Npov, an emerging agent of invasive aspergillosis in humans, cats, and dogs PLoS One 8 6 2013 e64871 23798996\n\n",
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"keywords": "Aspergillosis; Cerebral abscess; Chronic lymphocytic leukemia; Ibrutinib",
"medline_ta": "Med Mycol Case Rep",
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"title": "Cranial aspergillosis in a patient receiving ibrutinib for chronic lymphocytic leukemia.",
"title_normalized": "cranial aspergillosis in a patient receiving ibrutinib for chronic lymphocytic leukemia"
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"abstract": "We present a unique case of an open talar neck fracture with medial subtalar joint dislocation. This rare and traumatic injury was treated with immediate open reduction of the subtalar joint and open reduction internal fixation of the talar neck fracture. After a follow-up of 2.2 years, highlighted by numerous complications including posttraumatic arthritis, soft tissue abscess, and fibrotic adhesions, the patient recovered sufficiently to return full activity.",
"affiliations": "Podiatric Surgical Resident, Department of Podiatric Surgery, Beaumont Hospital Wayne, Wayne, MI. Electronic address: mpflippin@gmail.com.;Podiatric Surgical Resident, Department of Podiatric Surgery, Beaumont Hospital Wayne, Wayne, MI.",
"authors": "Flippin|Mitchell|M|;Fallat|Lawrence M|LM|",
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"mesh_terms": "D000058:Accidental Falls; D001863:Bone Screws; D004636:Emergency Service, Hospital; D005500:Follow-Up Studies; D005593:Fracture Fixation, Internal; D017102:Fracture Healing; D050723:Fractures, Bone; D005597:Fractures, Open; D006801:Humans; D015601:Injury Severity Score; D004204:Joint Dislocations; D008297:Male; D008875:Middle Aged; D017695:Soft Tissue Injuries; D013380:Subtalar Joint; D013628:Talus; D016896:Treatment Outcome",
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"title": "Open Talar Neck Fracture With Medial Subtalar Joint Dislocation: A Case Report.",
"title_normalized": "open talar neck fracture with medial subtalar joint dislocation a case report"
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"abstract": "Paracoccidioides brasiliensis is the cause of paracoccidioidomycosis, one of the most important systemic mycoses in Latin America. Human disease has been observed in a limited geographic and ecological niche, and it is attributed to exposure to the fungus in soil. Most primary infections are subclinical, as the infection is contained by the host mainly through cell-mediated immune response. However, as the fungus has the ability to survive in a dormant state for long periods, an impairment of the immune response may lead to reactivation and clinical disease. Surprisingly, paracoccidioidomycosis has rarely been reported in transplanted patients. The aim of this communication is to report a case occurring in a kidney recipient in an acute clinical form immediately after transplantation, and to review the available information on previously reported cases.",
"affiliations": "Infectious Diseases Department, Instituto de Nefrología/Nephrology, Buenos Aires, Buenos Aires, Argentina.;Infectious Diseases Department, Instituto de Nefrología/Nephrology, Buenos Aires, Buenos Aires, Argentina.;Parasitology Unit, Mycology (Unidad de Parasitologia Micología) Hospital JM Ramos Mejía, Buenos Aires, Argentina.;Infectious Diseases Department, Instituto de Nefrología/Nephrology, Buenos Aires, Buenos Aires, Argentina.;Parasitology Unit, Mycology (Unidad de Parasitologia Micología) Hospital JM Ramos Mejía, Buenos Aires, Argentina.;Infectious Diseases Department, Instituto de Nefrología/Nephrology, Buenos Aires, Buenos Aires, Argentina.;Kidney Transplant Unit, Department of Transplantation, Instituto de Nefrología/Nephrology, Buenos Aires, Buenos Aires, Argentina.;Kidney Transplant Unit, Department of Transplantation, Instituto de Nefrología/Nephrology, Buenos Aires, Buenos Aires, Argentina.",
"authors": "Radisic|Marcelo V|MV|http://orcid.org/0000-0002-7459-6156;Linares|Laura|L|;Afeltra|Javier|J|;Pujato|Natalia|N|;Vitale|Roxana G|RG|;Bravo|Martin|M|;Dotta|Ana C|AC|;Casadei|Domingo H|DH|",
"chemical_list": "D000935:Antifungal Agents; D007166:Immunosuppressive Agents; C068538:liposomal amphotericin B; D017964:Itraconazole; D014640:Vancomycin; D015378:Imipenem; D000666:Amphotericin B; D008775:Methylprednisolone",
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"issue": "19(2)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "endemic mycosis; kidney transplantation; liposomal amphotericin B; paracoccidioidomycosis; pulmonary disease",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000666:Amphotericin B; D000935:Antifungal Agents; D018893:Bronchoalveolar Lavage; D001992:Bronchoalveolar Lavage Fluid; D001999:Bronchoscopy; D005260:Female; D006084:Graft Rejection; D006801:Humans; D015378:Imipenem; D056724:Immunity, Humoral; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D017964:Itraconazole; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D007843:Latin America; D008172:Lung Diseases, Fungal; D008775:Methylprednisolone; D008875:Middle Aged; D010228:Paracoccidioides; D010229:Paracoccidioidomycosis; D010956:Plasmapheresis; D012121:Respiration, Artificial; D014057:Tomography, X-Ray Computed; D014640:Vancomycin",
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"pmid": "28039947",
"pubdate": "2017-04",
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"title": "Acute pulmonary involvement by paracoccidiodomycosis disease immediately after kidney transplantation: Case report and literature review.",
"title_normalized": "acute pulmonary involvement by paracoccidiodomycosis disease immediately after kidney transplantation case report and literature review"
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"abstract": "BACKGROUND\nLeukemic infiltration of the optic nerve is relatively rare. While previously described in acute leukemia, the infiltration in our case represents central nervous system (CNS) metastasis of Burkitt-type lymphoma that developed as a complication of solid-organ transplantation, resulting in a bilateral infiltrative optic neuropathy with sequential, bilateral central retinal artery occlusion (CRAO) and devastating vision loss.\n\n\nMETHODS\nThe medical record, serial ophthalmic examination findings, clinical course, and imaging including magnetic resonance imaging (MRI), fundus photographs, and fluorescein angiography of a single patient were retrospectively reviewed.\n\n\nRESULTS\nMRI demonstrated multifocal cortical and leptomeningeal CNS involvement, including the left optic nerve. Serial fundus examination/photography and fluorescein angiography showed that despite urgent whole-brain irradiation and systemic chemotherapy, CNS disease progressed to bilateral optic nerve infiltration and CRAO with no light perception vision in both eyes.\n\n\nCONCLUSIONS\nCRAO can occur as a devastating and irreversible complication of lymphoproliferative optic nerve infiltration.",
"affiliations": "Department of Ophthalmology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.;Department of Ophthalmology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.;Department of Radiology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.;Department of Ophthalmology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.;Department of Ophthalmology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.",
"authors": "DeSouza|Philip J|PJ|;Hooten|Claudia G|CG|;Lack|Christopher M|CM|;John|Vishak J|VJ|;Martin|Timothy J|TJ|",
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"issue": "3(3)",
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"keywords": "Burkitt lymphoma; Case report; Central retinal artery occlusion; Leukemic central nervous system infiltration; Optic nerve infiltration; Post-transplant lymphoproliferative disorder",
"medline_ta": "Ocul Oncol Pathol",
"mesh_terms": null,
"nlm_unique_id": "101656139",
"other_id": null,
"pages": "229-234",
"pmc": null,
"pmid": "29071274",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports",
"references": "3422790;22868923;11133721;10563423;17891208;19680271;12466183;2064557;16889577;15131694;4533925;23963042;6195573;24056821;3885451;12621474;23466659;21264909;21668784;25243420;26384356;15979320",
"title": "Bilateral Central Retinal Artery Occlusion Associated with Bilateral Lymphoproliferative Infiltrative Optic Neuropathy.",
"title_normalized": "bilateral central retinal artery occlusion associated with bilateral lymphoproliferative infiltrative optic neuropathy"
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"abstract": "Neuropathic pain occurrence is associated with some cytostatic and antibiotics use. Pharmacological therapy for the treatment of neuropathic pain is sometimes unsuccessful, and complementary methods like acupuncture are included. In this case report, a 14-year-old boy with cerebral tumour and neuropathic pain in his feet after chemotherapy and linezolid use is presented. A complete cessation of neuropathic pain symptoms like hyperalgesia and allodynia was accomplished after laser acupuncture application.",
"affiliations": "University of Osijek Medical School, Croatia; Children's Hospital Zagreb, Paediatric Pain Clinic, Croatia. Electronic address: diana.butkovic1@gmail.com.;University of Osijek Medical School, Croatia; Clinical Hospital Centre Osijek, Department for Pain Therapy, Croatia.",
"authors": "Butkovic|D|D|;Tot|O K|OK|",
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"issue": "35()",
"journal": "Complementary therapies in medicine",
"keywords": "Brain tumour; Laser acupuncture; Linezolid; Neuropathic pain; Paediatric",
"medline_ta": "Complement Ther Med",
"mesh_terms": "D015670:Acupuncture Therapy; D000293:Adolescent; D001932:Brain Neoplasms; D006801:Humans; D006930:Hyperalgesia; D007834:Lasers; D008297:Male; D009437:Neuralgia",
"nlm_unique_id": "9308777",
"other_id": null,
"pages": "53-56",
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"pmid": "29154067",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Laser acupuncture treatment of neuropathic pain in a boy with brain tumour.",
"title_normalized": "laser acupuncture treatment of neuropathic pain in a boy with brain tumour"
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"abstract": "To report a case of bilateral acute macular neuroretinopathy (AMN) associated with a COVID-19 infection.\nA 22-year-old female was referred for evaluation of bilateral scotomas concurrent with a mildly symptomatic COVID-19 infection. Exam showed normal visual acuity, bilateral reddish-brown petaloid retinal lesions which were hyporeflective on near infrared (NIR) optical coherence tomography (OCT), and had associated hypoperfusion of the deep vascular plexus on OCT-angiography (OCT-A) consistent with bilateral AMN. At follow-up, scotomas and retinal findings on near infrared imaging and spectral-domain optical coherence tomography had only slightly improved.\nCOVID-19 has been documented to be the etiology of a growing number of ocular manifestations including microvascular events. We report a case of bilateral acute macular neuroretinopathy in a patient with a recent diagnosis of COVID-19 infection that had persistent symptoms and findings at six month follow-up.",
"affiliations": "Louisiana State University Health Sciences Center, Department of Ophthalmology, 533 Bolivar St, Room 451B, New Orleans, LA, 70112, USA.;Louisiana State University Health Sciences Center, Department of Ophthalmology, 533 Bolivar St, Room 451B, New Orleans, LA, 70112, USA.",
"authors": "David|James A|JA|;Fivgas|George D|GD|",
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"doi": "10.1016/j.ajoc.2021.101232",
"fulltext": "\n==== Front\nAm J Ophthalmol Case Rep\nAm J Ophthalmol Case Rep\nAmerican Journal of Ophthalmology Case Reports\n2451-9936\nElsevier\n\nS2451-9936(21)00241-3\n10.1016/j.ajoc.2021.101232\n101232\nCase Report\nAcute macular neuroretinopathy associated with COVID-19 infection\nDavid James A. a\nFivgas George D. gfivga@lsuhsc.edu\nab∗\na Louisiana State University Health Sciences Center, Department of Ophthalmology, 533 Bolivar St, Room 451B, New Orleans, LA, 70112, USA\nb The Retina Center, 7777 Hennessy Blvd, Ste 3000, Baton Rouge, LA, 70808, USA\n∗ Corresponding author. Ophthalmology, Retina Division, The Retina Center, 7777 Hennessy Blvd, Ste 3000, Baton Rouge, LA, 70808, USA. gfivga@lsuhsc.edu\n10 11 2021\n12 2021\n10 11 2021\n24 10123231 1 2021\n30 7 2021\n8 11 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/).\nPurpose\n\nTo report a case of bilateral acute macular neuroretinopathy (AMN) associated with a COVID-19 infection.\n\nObservations\n\nA 22-year-old female was referred for evaluation of bilateral scotomas concurrent with a mildly symptomatic COVID-19 infection. Exam showed normal visual acuity, bilateral reddish-brown petaloid retinal lesions which were hyporeflective on near infrared (NIR) optical coherence tomography (OCT), and had associated hypoperfusion of the deep vascular plexus on OCT-angiography (OCT-A) consistent with bilateral AMN. At follow-up, scotomas and retinal findings on near infrared imaging and spectral-domain optical coherence tomography had only slightly improved.\n\nConclusions\n\nCOVID-19 has been documented to be the etiology of a growing number of ocular manifestations including microvascular events. We report a case of bilateral acute macular neuroretinopathy in a patient with a recent diagnosis of COVID-19 infection that had persistent symptoms and findings at six month follow-up.\n\nKeywords\n\nAcute macular neuroretinopathy\nCoronavirus\nCOVID\nCOVID-19\nSARS-CoV-2\n==== Body\npmc1 Introduction\n\nCOVID-19 (coronavirus disease of 2019) is caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that was first documented in Wuhan, China. This ribonucleic acid (RNA) virus has been known to cause a proinflammatory and hypercoagulable state that leads to multiple systemic complications including respiratory failure, myocardial infarction, deep venous thromboembolism (DVT), and cerebrovascular events with profound morbidity and mortality.1\n\nThe most commonly documented ocular complication of COVID-19 is conjunctivitis in up to one third of patients.2 However, there is a growing literature of retinal vascular manifestations potentially related to COVID-19 including isolated cotton wool spots and retinal microhemorrhages,3 retinal vein occlusions,4,5 as well as some cases of acute macular neuroretinopathy (AMN) and paracentral middle maculopathy (PAMM).6,7,8 Many of the reported AMN and PAMM findings associated with COVID-19 have had somewhat atypical presentations and findings including complicated underlying medical histories, advanced age, and atypical retinal findings including hemorrhages or subretinal fluid.\n\nHerein we report the case of a 22-year-old female with symptomatic scotomas and typical fundoscopic and supplementary imaging findings for bilateral AMN associated with an otherwise mild COVID-19 infection.\n\n2 Case report\n\nA 22-year-old female was referred for retina evaluation. The patient had a history of attention deficit disorder for which she took lisdexamfetamine dimesylate 70mg capsule daily. She was also on norgestimate 0.25mg and ethinyl estradiol 35mcg for oral contraception. There was no past ocular history. The patient endorsed subjective sinus headache between the eyes radiating to the right temple and bilateral scotomas she described as a “ring of black dots with a wave in the middle.” She was evaluated in the emergency room and was found to have mild lymphopenia (2.75, reference range 3.90–12.70 K/μL), normal comprehensive metabolic panel, trace occult blood on urinalysis, and a positive COVID-19 nasopharyngeal swab. Magnetic resonance venography of the brain was normal without thrombosis. Given no significant systemic findings, the patient and family were reassured and instructed to follow up with ophthalmology on an outpatient basis.\n\nTwenty days after onset of her visual symptoms, the patient presented to the retina service. The patient's headache had resolved but scotomas persisted. Ophthalmic examination revealed uncorrected visual acuity of 20/20 in both eyes and normal intraocular pressure. Anterior segment examination was unremarkable. Posterior segment examination showed multiple subtle reddish-brown petaloid lesions radiating from the fovea in both eyes (Fig. 1A and B) without ocular inflammation. Fundus autofluorescence was normal other than hyperfluorescent optic nerve drusen in the left eye. Intravenous fluorescein angiogram (IVFA) showed minimal petaloid hypofluorescence consistent with a filling defect more prominent in the right (Fig. 1C) than left (Fig. 1D) eye, corresponding with fundoscopic findings. Indocyanine green angiography was normal. Near infrared (NIR) imaging demonstrated prominent areas of petaloid hyporeflectivity (Fig. 2A and B) that corresponded to the lesions noted on funduscopic examination and IVFA. Individual spectral domain optical coherence tomography (SD-OCT) B-scans showed disruption of normal retinal banding patterns at the junction of the outer plexiform layer (OPL) and the outer nuclear layer (ONL) as well as attenuated reflectivity of the ellipsoid zone (EZ; Fig. 2C and D). The constellation of these findings correlated with a diagnosis of bilateral acute macular neuroretinopathy (AMN). Observation was recommended given no known treatment has been established for AMN. At five weeks and six months following initial evaluation, the patient's scotomas had slightly improved subjectively. Through six months, retinal findings became slightly less prominent although persistent on exam, NIR (Fig. 3A and B) and SD-OCT imaging (Fig. 3C and D). OCT-angiography (OCT-A) showed hypoperfusion more prominent at the level of the deep vascular complex (Fig. 3E and F) than the superficial vascular complex (3G-H).Fig. 1 Fundus photography (A, B) and intravenous fluorescein angiography (C, D) of the right and left eyes, respectively, at presentation. The color fundus photo demonstrates subtle petaloid red-brown lesions (solid white arrow) with their apices at the fovea (A, B). Corresponding areas of hypofluorescence (dotted white arrow) are noted on late phase images of fluorescein angiography of both eyes (C, D). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)\n\nFig. 1\n\nFig. 2 Near infrared images (A, B) and corresponding spectral domain optical coherence tomogram (SD-OCT) B-scan through the fovea (C, D) of the right and left eyes, respectively, at presentation. The petaloid lesions are well visualized as areas of decreased reflectivity surrounding the fovea on near infrared images (A, B). The SD-OCT scans show disruption at the junction of the outer plexiform layer and the outer nuclear layer (solid white arrow) and associated attenuation of ellipsoid zone reflectivity (dotted white arrow) of the right (C) and left (D) eyes.\n\nFig. 2\n\nFig. 3 Near infrared images (A, B) and corresponding spectral domain optical coherence tomogram (SD-OCT) B-scan through the fovea (C, D) of the right and left eyes at six months following presentation show persistence although slight improvement in the appearance of the retinal lesions. OCT-angiography shows much less prominent flow restriction in the superficial vascular complex (E, F) than in the deep vascular complex (G, H) corresponding with lesion seen on OCT (white arrows).\n\nFig. 3\n\n3 Discussion\n\nCOVID-19 is known to cause a hyperinflammatory and hypercoagulable state, with both a cytokine storm and thrombotic complications of the lungs, spleen, brain, gut, and periphery.1 Conjunctivitis was the first described ocular finding and those patients with more prominent ocular surface manifestations were found to have more aggressive systemic symptoms.2 It is now believed that COVID-19 can also directly affect the retina in humans, possibly through direct infection as well as secondarily through its thrombotic and inflammatory systemic effects. In a series of 14 autopsies of patients whom were COVID-19 positive at time of death, three (21%) were found to have COVID-19 RNA in the retina.9 Therefore, investigations into ophthalmologic complications of COVID-19 in humans is of great interest, especially those complications associated with visual compromise.\n\nAcute macular neuroretinopathy (AMN) is a rare retinal disorder resulting from localized nonperfusion of the deep capillary plexus of the retina with resulting disruption of the OPL, ONL, and EZ and associated temporary or permanent visual changes. Most affected patients are young (mean age 29.5 years old), non-Hispanic Caucasians, and female. The typical subjective complaint is a visual scotoma although decreased visual acuity, subjective blurry vision, floaters and metamorphopsia may occur. Predisposing or possible inciting factors have included nonspecific viral illness or fever (48%), oral contraceptive use (36%), vasoconstrictor and sympathomimetic use (8%), or less common causes such as bodily trauma and systemic shock.10 One report documented lisdexamphetamine mesylate use as a trigger.11 On clinical exam of AMN, the most classic findings are reddish-brown or orange petaloid- or wedge-shaped lesions surrounding the fovea which are hyporeflective on NIR imaging and are bilateral in approximately half of patients. Corresponding abnormalities of the OPL, ONL, and EZ are often noted on SD-OCT. IVFA demonstrates abnormalities in only 26% of cases and indocyanine green angiography (ICGA) in 17% of patients, possibly limited by low resolution.10 On the other hand, OCT-angiography (OCT-A) has been instrumental in visualizing vascular filling defects localized to the deep retinal capillary plexus.12\n\nA similar, albeit distinct, pathologic finding termed paracentral acute middle maculopathy (PAMM) was described by Sarraf et al., in 2013. PAMM is thought to result from ischemia of intermediate capillary plexus resulting in a hyperreflective band on OCT at the level of the OPL and INL, which is more superficial than in AMN.13 PAMM occurs in patients with a mean age of 49–53 years of age, there is no gender predilection, and visual acuity may be slightly worse than in AMN. In addition, the funduscopic findings are deep, smooth gray lesions rather than reddish-brown. Retinal vascular events such as arterial or venous occlusions can involve all three retinal capillary plexuses or cause isolated PAMM lesions, therefore PAMM lesions may sometimes be indicative of a more global retinal ischemic event.14\n\nThere are a few reported cases of possible AMN and PAMM in the setting of COVID-19, however these have all been confounded by complex underlying medical conditions, less classical NIR images, or concurrent atypical retinal findings such as hemorrhages or subretinal fluid. Gascon et al. described a case of possible combined AMN and PAMM findings in the left eye of a 53-year-old male with COVID19, however the patient also had multiple retinal hemorrhages, Roth spots, and subretinal fluid.6 Another case of AMN concurrent with COVID-19 infection was reported in a 35-year-old female with a scotoma and typical OCT findings, but the single AMN lesion was adjacent to a retinal hemorrhage. The patient also had other peripapillary hemorrhage and Roth spots in both eyes and had recently started chemotherapy for acute myeloid leukemia, a known risk factor for both retinal hemorrhages and possibly AMN.7 In the largest documented series of AMN cases of any cause, hemorrhages or macular edema were rare, found in only 3.2% of cases.10 This may lead one to question whether the aforementioned cases associated with COVID-19 were truly AMN or were due to more generalized ischemic retinal event. Finally, Virgo et al. reported a case of possible PAMM in a 37-year-old pregnant Caucasian female and a 32-year-old Caucasian male following COVID-19 infection, both with scotomas and OCT findings although the lesions were small and singular in each case.8\n\nThe case we report above is a more typical case of AMN in a patient with COVID-19. Our patient is an otherwise healthy, young, non-Hispanic Caucasian female, the most characteristic demographic for AMN. Her symptomatic scotomas and headache were noted to be present at the same time as her positive COVID-19 nasopharyngeal swab, so we believe her COVID-19 infection is likely the triggering etiology of AMN in her case. In addition, our patient's lesions were much more typical on examination and imaging than other reported cases of AMN or PAMM in COVID-19 disease, with reddish-brown petaloid appearance on funduscopy without hemorrhages or macular edema and with typical NIR, OCT, and OCT-A findings. We must concede that our patient did use oral contraceptives as well as lisdexamphetamine mesylate which are both reported risk factors for AMN. We believe that these medications likely augmented the hypercoagulable state caused by her COVID-19 infection, although COVID-19 ultimately was the principal cause for her retinal manifestations given timing of infection and ocular findings. In addition, it may be this combination of hypercoagulability secondary to medication use as well as COVID-19 infection that resulted in the large number of bilateral parafoveal lesions and scotomas in our patient. After observation at five week and six month follow-up, our patient had persistent manifestations from her AMN, albeit slightly improved.\n\nTo date, there is no clear treatment for AMN and even more limited data on outcomes of AMN secondary to COVID-19. Whereas intravitreal anti-VEGF injections for retinal vein occlusions (RVOs) may limit vascular nonperfusion and associated macular edema, the microvascular occlusion that occurs in AMN is much smaller in extent compared to an RVO. In a different case with AMN and PAMM lesions related to COVID-19, the small amount of subfoveal fluid resolved on its own within 15 days, lending support to observation for AMN including when associated with COVID-19.6 In a case of purported bilateral central retinal vein occlusion related to COVID-19, the authors proposed that early initiation of anticoagulation for DVT may have halted and reversed progression of ischemia.15 Fibrinolytic therapy is considered for COVID-19 related severe acute respiratory distress syndrome (ARDS), but the risk of major hemorrhagic events or hemorrhagic conversion of an unrecognized subacute stroke make this therapy less favorable.1 Therefore, there is much to be learned about potential interventions to prevent or limit the damage from AMN in COVID-19 cases. In addition, our case should raise the question of whether short term discontinuation of triggering variables such as oral contraceptions or stimulants including caffeine should be considered to prevent further ischemic compromise.\n\n4 Conclusions\n\nAcute macular neuroretinopathy is commonly associated with a flu-like viral illnesses that causes fever as well as multiple conditions that result in a hypercoagulable state. Our case reports adds to the literature that the hypercoagulable state associated with COVID-19 disease may cause retinal vascular complications such as AMN. Although conjunctivitis may be the most common ocular manifestation of COVID-19 disease, we recommend a thorough retinal evaluation including close examination of macular OCT for all patients with visual disturbances that occur surrounding the time of COVID-19 infection.\n\nIntellectual property\n\nWe confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property.\n\nResearch ethics\n\nWritten consent to publish potentially identifying information, such as details or the case and photographs, was obtained from the patient(s) or their legal guardian(s).\n\nContact with the editorial office\n\nThis author submitted this manuscript using his/her account in EVISE.\n\nWe understand that this Corresponding Author is the sole contact for the Editorial process (including EVISE and direct communications with the office). He/she is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs.\n\nWe confirm that the email address shown below is accessible by the Corresponding Author, is the address to which Corresponding Author's EVISE account is linked, and has been configured to accept email from the editorial office of American Journal of Ophthalmology Case Reports: gfivga@lsuhsc.edu\n\nPatient consent\n\nWritten consent to publish the case report was provided by the patient. This report does not contain any personal information that could identify the patient.\n\nFunding\n\nNo funding or grant support.\n\nAuthorship\n\nAll authors attest they meet the current ICMJE criteria for Authorship.\n\nDeclaration of competing interest\n\nThe authors have no financial or conflicting interests to disclose.\n\nAcknowledgements\n\nNone.\n==== Refs\nReferences\n\n1 Hanff T.C. Mohareb A.M. Giri J. Thrombosis in COVID-19 Am J Hematol 95 12 2020 Dec 1578 1589 32857878\n2 Wu P. Duan F. Luo C. Characteristics of ocular findings of patients with coronavirus disease 2019 (COVID-19) in Hubei Province, China JAMA Ophthalmol 138 5 2020 May 1 575 578 32232433\n3 Marinho P.M. Marcos A.A.A. Romano A.C. Retinal findings in patients with COVID-19 Lancet 395 10237 2020 May 23 1610 32405105\n4 Walinjkar J.A. Makhija S.C. Sharma H.R. Central retinal vein occlusion with COVID-19 infection as the presumptive etiology Indian J Ophthalmol 68 11 2020 Nov 2572 2574 33120696\n5 Ju Sheth Narayanan R. Goyal J. Goyal V. Retinal vein occlusion in COVID-19: a novel entity Indian J Ophthalmol 68 10 2020 Oct 2291 2293 32971697\n6 Gascon P. Briantais A. Bertrand E. Covid-19-Associated retinopathy: a case report Ocul Immunol Inflamm 28 8 2020 Nov 16 1293 1297 33021856\n7 Zamani G. Ataei Azimi S. Aminizadeh A. Acute macular neuroretinopathy in a patient with acute myeloid leukemia and deceased by COVID-19: a case report J Ophthalmic Inflamm Infect 10 1 2021 Jan 8 39 33415590\n8 Virgo J. Mohamed M. Paracentral acute middle maculopathy and acute macular neuroretinopathy following SARS-CoV-2 infection Eye (Lond). 34 12 2020 Dec 2352 2353 32620843\n9 Casagrande M. Fitzek A. Püschel K. Detection of SARS-CoV-2 in human retinal biopsies of deceased COVID-19 patients Ocul Immunol Inflamm 28 5 2020 Jul 3 721 725 32469258\n10 Bhavsar K.V. Lin S. Rahimy E. Acute macular neuroretinopathy: a comprehensive review of the literature Surv Ophthalmol 61 5 2016 Sep-Oct 538 565 26973287\n11 Munk M.R. Jampol L.M. Cunha Souza E. New associations of classic acute macular neuroretinopathy Br J Ophthalmol 100 3 2016 Mar 389 394 26294104\n12 Pecen P.E. Smith A.G. Ehlers J.P. Optical coherence tomography angiography of acute macular neuroretinopathy and paracentral acute middle maculopathy JAMA Ophthalmol 133 12 2015 Dec 1478 1480 26513596\n13 Moura-Coelho N. Gaspar T. Ferreira J.T. Paracentral acute middle maculopathy-review of the literature Graefes Arch Clin Exp Ophthalmol 258 12 2020 Dec 2583 2596 32661700\n14 Rahimy E. Kuehlewein L. Sadda S.R. Sarraf D. Paracentral acute middle maculopathy: what we knew then and what we know now Retina 35 10 2015 Oct 1921 1930 26360227\n15 Gaba W.H. Ahmed D. Al Nuaimi R.K. Bilateral central retinal vein occlusion in a 40-year-old man with severe coronavirus disease 2019 (COVID-19) Pneumonia Am J Case Rep 21 2020 Oct 29 e927691\n\n",
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"journal": "American journal of ophthalmology case reports",
"keywords": "Acute macular neuroretinopathy; COVID; COVID-19; Coronavirus; SARS-CoV-2",
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"title": "Acute macular neuroretinopathy associated with COVID-19 infection.",
"title_normalized": "acute macular neuroretinopathy associated with covid 19 infection"
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"abstract": "Cryptococcus neoformans is an opportunistic fungal pathogen and an important cause of morbidity and mortality in immunocompromised patients. We report a case of osteomyelitis caused by C. neoformans in a liver transplant recipient who presented with a headache and scalp lump after sustaining mild head trauma. There was no evidence of central nervous system involvement or dissemination. This is the first known case report of isolated cryptococcal osteomyelitis in a liver transplant recipient.",
"affiliations": "AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia.;AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia.;Department of Pathology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.;Department of Microbiology and Infectious Diseases, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia.;AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia.",
"authors": "Pudipeddi|Aviv V|AV|;Liu|Ken|K|;Watson|Geoffrey F|GF|;Davis|Rebecca J|RJ|;Strasser|Simone I|SI|",
"chemical_list": "D000935:Antifungal Agents; D007166:Immunosuppressive Agents",
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"keywords": "Cryptococcosis; fungal infection; immunosuppressed host; liver transplantation; opportunistic infection; osteomyelitis",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D000935:Antifungal Agents; D001706:Biopsy; D015209:Cholangitis, Sclerosing; D003399:Craniotomy; D003453:Cryptococcosis; D003455:Cryptococcus neoformans; D003646:Debridement; D006261:Headache; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D016031:Liver Transplantation; D008297:Male; D009894:Opportunistic Infections; D010019:Osteomyelitis; D012886:Skull; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014057:Tomography, X-Ray Computed",
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"references": null,
"title": "Cryptococcal osteomyelitis of the skull in a liver transplant patient.",
"title_normalized": "cryptococcal osteomyelitis of the skull in a liver transplant patient"
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"abstract": "BACKGROUND\nOutcomes remain poor for children after relapse of acute lymphoblastic leukemia (ALL), especially after early marrow relapse. Bortezomib is a proteasome inhibitor with in vitro synergy with corticosteroids and clinical activity in human lymphoid malignancies.\n\n\nMETHODS\nThis is a Phase I study of escalating doses bortezomib administered days 1, 4, 8, and 11, added to 4-drug induction chemotherapy with vincristine, dexamethasone, pegylated L-asparaginase, and doxorubicin (VXLD) in children with relapsed ALL.\n\n\nRESULTS\nTen patients were enrolled, five in first marrow relapse, and five in second relapse. Four patients were enrolled at dose level 1 (bortezomib 1 mg/m(2)). One patient was not evaluable for toxicity because of omitted dexamethasone doses. No dose-limiting toxicity (DLT) was observed. Six patients were enrolled at dose level 2 (bortezomib 1.3 mg/m(2)). One patient had dose-limiting hypophosphatemia and rhabdomyolysis after 1 dose of bortezomib, and died from a diffuse zygomyces infection on day 17. Five additional patients were enrolled with no subsequent DLTs. As planned, no further dose escalation was pursued. The regimen had predictable toxicity related to the chemotherapy drugs. Two patients had mild peripheral neuropathy (grades 1 and 2). Six of nine evaluable patients (67%) achieved a complete response (CR), and one had a bone marrow CR with persistent central nervous system leukemia.\n\n\nCONCLUSIONS\nThe combination of bortezomib (1.3 mg/m(2)) with VXLD is active with acceptable toxicity in pretreated pediatric patients with relapsed ALL. We are expanding the 1.3 mg/m(2) cohort for a phase II estimate of response. Study registered at ClinicalTrials.gov (http://clinicaltrials.gov/ct2/show/NCT00440726).",
"affiliations": "Pediatric Hematology and Oncology, Children's Hospitals and Clinics of Minnesota, St. Paul, Minnesota 55102, USA. yoav.messinger@childrensmn.org",
"authors": "Messinger|Yoav|Y|;Gaynon|Paul|P|;Raetz|Elizabeth|E|;Hutchinson|Raymond|R|;Dubois|Steven|S|;Glade-Bender|Julia|J|;Sposto|Richard|R|;van der Giessen|Jeannette|J|;Eckroth|Elena|E|;Bostrom|Bruce C|BC|",
"chemical_list": "D001897:Boronic Acids; D011480:Protease Inhibitors; D011719:Pyrazines; D014750:Vincristine; D000069286:Bortezomib; D003907:Dexamethasone; D004317:Doxorubicin; D001215:Asparaginase",
"country": "United States",
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"doi": "10.1002/pbc.22456",
"fulltext": null,
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"issn_linking": "1545-5009",
"issue": "55(2)",
"journal": "Pediatric blood & cancer",
"keywords": null,
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D001215:Asparaginase; D001897:Boronic Acids; D000069286:Bortezomib; D002648:Child; D002675:Child, Preschool; D003907:Dexamethasone; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin; D006801:Humans; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011480:Protease Inhibitors; D011719:Pyrazines; D016879:Salvage Therapy; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "101186624",
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"pages": "254-9",
"pmc": null,
"pmid": "20582937",
"pubdate": "2010-08",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article",
"references": null,
"title": "Phase I study of bortezomib combined with chemotherapy in children with relapsed childhood acute lymphoblastic leukemia (ALL): a report from the therapeutic advances in childhood leukemia (TACL) consortium.",
"title_normalized": "phase i study of bortezomib combined with chemotherapy in children with relapsed childhood acute lymphoblastic leukemia all a report from the therapeutic advances in childhood leukemia tacl consortium"
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"abstract": "OBJECTIVE\nThe concentration of capecitabine peaks at 1-2 hours after administration. We therefore assumed that proper timing of capecitabine administration and radiotherapy would maximize radiosensitization and influence survival among patients with locally advanced rectal cancer.\n\n\nMETHODS\nWe retrospectively reviewed 223 patients with locally advanced rectal cancer who underwent preoperative chemoradiation, followed by surgery from January 2002 to May 2006. All patients underwent pelvic radiotherapy (50 Gy/25 fractions) and received capecitabine twice daily at 12-hour intervals (1,650 mg/m2/day). Patients were divided into two groups according to the time interval between capecitabine intake and radiotherapy. Patients who took capecitabine 1 hour before radiotherapy were classified as Group A (n = 109); all others were classified as Group B (n = 114).\n\n\nRESULTS\nThe median follow-up period was 72 months (range, 7 to 149 months). Although Group A had a significantly higher rate of good responses (44% vs. 25%; p = 0.005), the 5-year local recurrence-free survival rates of 93% in Group A and 97% in Group B did not differ significantly (p = 0.519). The 5-year disease-free survival and overall survival rates were also comparable between the groups.\n\n\nCONCLUSIONS\nDespite the better pathological response in Group A, the time interval between capecitabine and radiotherapy administration did not have a significant effect on survivals. Further evaluations are needed to clarify the interaction of these treatment modalities.",
"affiliations": "Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Medical Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Radiation Oncology, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Korea.",
"authors": "Kim|Yeon Joo|YJ|;Kim|Jong Hoon|JH|;Yu|Chang Sik|CS|;Kim|Tae Won|TW|;Jang|Se Jin|SJ|;Choi|Eun Kyung|EK|;Kim|Jin Cheon|JC|;Choi|Wonsik|W|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.3857/roj.2017.00010",
"fulltext": "\n==== Front\nRadiat Oncol JRadiat Oncol JROJRadiation Oncology Journal2234-19002234-3164The Korean Society for Radiation Oncology 2871227310.3857/roj.2017.00010roj-2017-00010Original ArticleClinical InvestigationEffect of time interval between capecitabine intake and radiotherapy on local recurrence-free survival in preoperative chemoradiation for locally advanced rectal cancer Kim Yeon Joo MD1Kim Jong Hoon MDPhD1Yu Chang Sik MDPhD2Kim Tae Won MDPhD3Jang Se Jin MDPhD4Choi Eun Kyung MDPhD1Kim Jin Cheon MDPhD2Choi Wonsik MDPhD5\n1 Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea\n2 Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea\n3 Department of Medical Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea\n4 Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea\n5 Department of Radiation Oncology, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, KoreaCorrespondence: Jong Hoon Kim, MD, PhD, Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea. Tel: +82-2-3010-4434, Fax: +82-2-3010-6950, E-mail: jhkim2@amc.seoul.kr6 2017 30 6 2017 35 2 129 136 02 3 2017 20 3 2017 28 3 2017 Copyright © 2017. The Korean Society for Radiation Oncology2017This 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.Purpose\nThe concentration of capecitabine peaks at 1–2 hours after administration. We therefore assumed that proper timing of capecitabine administration and radiotherapy would maximize radiosensitization and influence survival among patients with locally advanced rectal cancer.\n\nMaterials and Methods\nWe retrospectively reviewed 223 patients with locally advanced rectal cancer who underwent preoperative chemoradiation, followed by surgery from January 2002 to May 2006. All patients underwent pelvic radiotherapy (50 Gy/25 fractions) and received capecitabine twice daily at 12-hour intervals (1,650 mg/m2/day). Patients were divided into two groups according to the time interval between capecitabine intake and radiotherapy. Patients who took capecitabine 1 hour before radiotherapy were classified as Group A (n = 109); all others were classified as Group B (n = 114).\n\nResults\nThe median follow-up period was 72 months (range, 7 to 149 months). Although Group A had a significantly higher rate of good responses (44% vs. 25%; p = 0.005), the 5-year local recurrence-free survival rates of 93% in Group A and 97% in Group B did not differ significantly (p = 0.519). The 5-year disease-free survival and overall survival rates were also comparable between the groups.\n\nconclusions\nDespite the better pathological response in Group A, the time interval between capecitabine and radiotherapy administration did not have a significant effect on survivals. Further evaluations are needed to clarify the interaction of these treatment modalities.\n\nCapecitabineChemoradiotherapyRectal neoplasmsSurvival analysis\n==== Body\nIntroduction\nTreatment for rectal cancer was associated with a high local failure rate before the introduction of radiotherapy (RT), chemotherapy, and total mesorectal excision (TME). However, considerable efforts to combine peri-operative RT with a 5-fluorouracil (5-FU)-based regimen have improved local control among patients with locally advanced rectal cancer, and further benefits were achieved with preoperative RT [1-4]. Notably, 5-FU has been used to treat a wide range of cancers during the past 40 years with the greatest effects against colorectal cancer, and the addition of oxaliplatin to 5-FU in adjuvant chemotherapy regimens has improved survival in colon cancer patients [5]. When the same approach was applied to the management of locally advanced rectal cancer in the German CAO/ARO/AIO-04 trial, the inclusion of oxaliplatin in preoperative chemoradiation (CRT) significantly improved the 3-year disease-free survival (DFS) [6]. However, the efficacy data from other randomized trials were inconclusive, and oxaliplatin has not yet been incorporated into standard regimens [7,8].\n\nCapecitabine is a recently developed oral prodrug of 5-FU. This prodrug is absorbed through the gastrointestinal tract mucosa and converted to 5'-deoxy-5-fluorocytidine by hepatic carboxylesterase and subsequently to 5'-deoxy-5-fluorouridine by cytidine deaminase in hepatic or tumor cells. Finally, 5-FU is released by the action of thymidine phosphorylase in a conversion that occurs preferentially in malignant cells [9-11]. This tumor-preferential activation could improve treatment efficacy and decrease systemic 5-FU exposure. In addition, oral capecitabine administration is more convenient than intravenous 5-FU administration. Encouragingly, a randomized phase-3 trial demonstrated that capecitabine was not inferior to and could therefore 5-FU [12].\n\nIntravenous 5-FU can be administered using two methods: (1) a short-course 5-FU infusion over 96 hours during the first and last weeks of a 5–6 week course of pelvic RT and (2) a protracted-course 5-FU infusion over 120 hours during weekdays or all 7 days per week. A previous study reported a significantly increased time to relapse and improved survival with protracted infusion in a postoperative CRT setting [13]. Theoretically, capecitabine can mimic the pharmacokinetics of continuous infusion 5-FU, which yielded superior outcomes when than bolus infusion.\n\nHowever, the concentrations of capecitabine and its metabolites peak at 1–2 hours after administration and decrease exponentially thereafter, with plasma half-lives of ≤1 hour [14,15]. Furthermore, capecitabine and its metabolites do not accumulate in plasma [16]. These findings suggest that the timing of RT and capecitabine administration should be calibrated to maximize the treatment effects of both modalities. A previous retrospective analysis at our center indicated better pathological responses among patients administered capecitabine 1 hour before RT [17]. In the present study, we evaluated whether the time interval between capecitabine administration and RT would also affect survival outcomes among patients with locally advanced rectal cancer.\n\nMaterials and Methods\nPatients with locally advanced rectal cancer who underwent preoperative CRT between January 2002 and May 2006 were retrospectively reviewed. Those who met the following criteria were included: (1) clinical stage T3 or T4 tumors or positive regional lymph nodes (LNs) without distant metastasis, (2) preoperative CRT regimens that included capecitabine, and (3) eventual surgical treatment. Patients were divided into two groups depending on the time interval between capecitabine intake and RT: Group A included patients who took capecitabine 1 hour before RT and Group B included those who took capecitabine ≥2 hours before RT. Of the 260 patients who received preoperative CRT between January 2002 and May 2006, 223 satisfied the inclusion criteria, and 109 and 114 were classified into Group A and Group B, respectively. This study was approved by the local Institutional Review Board, and the need for informed consent was waived.\n\nPretreatment evaluations included complete history taking, physical examination, complete blood count (CBC), serum biochemical tests, carcinoembryonic antigen (CEA) measurement, chest X-rays, colonofiberoscopy, abdominopelvic computed tomography (CT), endorectal ultrasound (EUS), whole-body bone scans (in cases with CEA levels >40 ng/mL), and chest CT (in cases with CEA levels >20 ng/mL). Clinical staging was according to abdominopelvic CT and EUS findings, according to the American Joint Committee on Cancer tumor-node-metastasis cancer staging system. Metastatic LNs were defined as those >5 mm in size. During preoperative CRT, patients underwent weekly CBC, biochemical tests and body weight measurement to monitor safety and compliances. Acute toxicities were evaluated using the National Cancer Institute Common Toxicity Criteria, version 4.0.\n\nPlanning CT images of patients in the prone position were obtained using a CT scanner with a 5-mm slice thickness. RT was delivered using three fields (posterior-anterior, two lateral fields) or four fields (anterior-posterior, posterior-anterior, two lateral fields) at an energy of 6 or 15 MV via a linear accelerator (Varian Clinac 1800; Varian Medical Systems, Palo Alto, CA, USA). The dose regimen was 46 Gy to the whole pelvis and a 4-Gy boost to the primary tumor, with a fraction size of 2 Gy. The clinical target volume (CTV) included the primary tumor, metastatic LN, perirectal fat tissue, and the internal iliac and presacral LNs. The bottom of L5 vertebra was defined as the superior CTV border, although this boundary was modulated to include gross tumors and LNs that extended beyond this limit in affected cases. The inferior border was 3 cm distal to the tumor. The planning target volume was defined as a 7-mm expansion of CTV in radial margins and 10mm expansion of CTV longitudinally.\n\nCapecitabine was administered twice daily at a total daily dose of 1,650 mg/2 beginning on day 1 of RT. From January 2002 to September 2004, patients were instructed to take capecitabine at 12-hour intervals approximately 30 minutes after breakfast and dinner. We obtained information about capecitabine intake times through telephone calls to the patients. Most patients had regular dining times and RT schedules. Beginning in October 2004, all patients were instructed to take capecitabine 1 hour before RT. Radiation oncologists educated patients regarding proper capecitabine intake during weekly monitoring, and radiation therapists also routinely confirmed capecitabine administration before every scheduled RT session.\n\nSurgical resection was performed 6–8 weeks after preoperative CRT, using standard TME and autonomic nerve preservation procedures. All surgeries were performed by qualified colorectal surgeons who had performed >100 TME procedures each year. Four weeks after surgery, adjuvant chemotherapy of 6 cycles of capecitabine was started. One cycle consisted of 2,500 mg/m2/day for 14 days, followed by a 7-day break. For pathological evaluations, primary tumors were sliced into 3-mm-thick sections that were stained with hematoxylin and eosin and subjected to microscopic examination. If tumor cells were not detected in the initial examination, thinner additional slices were taken from the residual tumor to ensure a thorough inspection. In addition, LNs were completely dissected from perirectal fat tissues and subjected to microscopic examination. Similar to our previous study, a complete response (CR) was defined as the absence of residual tumor. We also evaluated good responses which were defined as cases involving residual tumors <5 mm in size. However, the retrospective nature of this study precluded the use of Dworak’s classification of pathological response.\n\nThe primary end-point of the present study was 5-year local recurrence-free survival (LRFS). The secondary end-points were 5-year DFS, 5-year overall survival (OS), pathological response, and acute toxicity. Survival was calculated from the first day of preoperative CRT. Local recurrence was defined as an infield recurrence. The Kaplan-Meier method and log-rank test were used for survival analyzes. The Cox regression test was implemented in multivariate analyzes of significant factors affecting LRFS. Pearson chi-square test was used to compare pathological responses. A two-sided p-value of <0.05 was considered to indicate significance.\n\nResults\nThe patients’ characteristics are summarized in Table 1. Groups A and B were similar with respect to most variables, including the sphincter-saving rates (80% in both groups; p = 0.999). However, Group B included more T4N+ patients than Group A (5% vs. 21%; p = 0.001). Most patients tolerated the treatment regimen very well (Table 2). Only two patients in Group B required a radiation dose reduction, and four and seven patients in Groups A and B, respectively, required capecitabine dose reductions. The groups did not differ regarding compliance. The incidence of grade ≥3 acute toxicities was similar between the groups, with 23 and 17 patients in Groups A and B, respectively, being affected.\n\nThe median follow-up period was 72 months (range, 7 to 149 months). As shown in Fig. 1A, the groups did not differ significantly with respect to 5-year LRFS (A vs. B, 93% vs. 97%; p = 0.519), and they had nearly identical 5-year DFS and OS rates (Fig. 1B, 1C). We also compared survival after excluding cT4N+ patients, which comprised a higher proportion of Group B than that of Group A. Still, we observed no significant differences in survival (Fig. 2). Table 3 presents results from an analysis of several predictive factors for 5-year LRFS. The age, pathological ypN stage, and RM status were significant in a univariate analysis. However, none was significant in a multivariate analysis.\n\nIn this study, the main failure pattern was distant metastasis. Twelve patients experienced local recurrences, and 10 also developed distant metastases (Table 4). All but one patient with ypT1N0 disease exhibited poor pathological responses after preoperative CRT. The most prevalent local recurrent site was the regional LN (n = 5), followed by the pelvic wall (n = 4).\n\nAlthough Groups A and B did not differ regarding 5-year LRFS, Group A had a significantly better pathological response. The pathological T0 rates in Groups A and B were 25% and 9%, respectively (p = 0.009). Group A also had a significantly higher good response rate (A vs. B, 47% vs. 24%; p = 0.001). However, we observed no difference in ypN stage when only clinically node-positive patients were evaluated (A vs. B, 77% vs. 68%; p = 0.327). The improved ypT0 rate also led to a significantly better ypCR rate in Group A (A vs. B, 19% vs. 9%; p = 0.024).\n\nDiscussion and Conclusion\nMany attempts have been made to improve survival rates among patients with locally advanced rectal cancer by combining chemotherapy with RT, rather than administering preoperative RT alone. The largest trial, EORTC 22921, reported a significantly lower 5-year local recurrence rate following preoperative RT with concurrent and/or adjuvant chemotherapy than preoperative RT alone (8%–10% vs. 17%; p = 0.002) [2]. In that study, the pathological T0 rate was also increased in the preoperative CRT arm (14%) compared to the RT-alone arm (5%; p = 0.004). The French FFCD 9203 study also reported a lower 5-year local recurrence rate (8% vs. 17%; p < 0.0001) and better pathological CR rate (11% vs. 4%; p < 0.0001) with preoperative CRT than RT alone [1]. In addition, both studies failed to show significant differences in 5-year OS. Notably, the present study observed pathological CR rates of 19% in Group A and 9% in Group B. Maintaining a 1-hour time interval between capecitabine administration and RT appeared to maximize the radiosensitizing effect of capecitabine, thus yielding a better pathological response. However, we failed to demonstrate improvements in LRFS and OS. We assume that subsequent surgical resection offset the differences in local recurrence between the groups. The time interval between treatment modalities seemed to have no effect on distant metastasis or OS. The effect of a 1-hour interval was limited to the primary rectal tumor. It may attribute to the inaccuracy of clinical nodal staging. The accuracy in detecting metastatic LNs by 3-dimensional EUS, and CT in our center were 65% and 53%, respectively [18]. As result, the difference in response rates could have been reduced, and might have resulted in negative result.\n\nSimilar to our study, Bedi et al. [19] retrospectively investigated whether the timing of RT would affect the rates of pathological response and relapse in rectal cancer patients receiving capecitabine. A total of 111 patients treated with preoperative CRT were instructed to take capecitabine twice daily (early morning and night). Patients were divided into the AM group, including those who underwent RT before 12 PM (closer to the morning administration of capecitabine), and the PM group, including those who underwent RT after 12 PM (several hours after morning capecitabine administration). In that study, no significant differences were observed between the AM and PM groups regarding the ypCR rate and 2-year LRFS and DFS rates. However, Bedi et al. [19] noted some limitations, including the small sample size, potential variability in the time at which each patient took capecitabine (i.e., lack of documentation), and heterogeneity in the timing of RT within the AM and PM groups. We note that our study also had some limitations. This was a retrospective analysis of a small number of patients. We investigated all available prognostic factors, however, the possibility for unknown factors which could affect the outcomes still existed. Although the time interval between capecitabine intake and RT was an important factor in the present study, time interval investigation for patients who treated between January 2002 and September 2004 was performed through telephone call, and the results could be incorrect due to the wrong answers from the patients. In addition, the initial staging did not include pelvic MRI, leading to the possibility of inaccuracies, especially when discriminating between T3 and T4 tumors.\n\nAlthough we expected that the improved ypCR rate would lead to a higher sphincter-saving rate in Group A, this rate was 80% in both groups. We attribute this lack of difference to the low rate of patients with tumors ≤5 cm from the anal verge. Although our results should be validated by a prospective randomized trial, we cautiously suggest that 1-hour interval between capecitabine intake and RT could increase the sphincter-saving rate among patients with primary tumors near the anal verge. This practice might also improve the likelihood that patients with bulky tumors invading the mesorectal fascia will achieve a clear RM.\n\nThe present analysis did not demonstrate a significant effect of a 1-hour time interval between capecitabine administration and RT on survival among patients with locally advanced rectal cancer. However, those subjected to a 1-hour time interval exhibited better pathological responses. Further large prospective studies are warranted to clarify the interaction of capecitabine and RT.\n\nConflict of Interest\n\nNo potential conflict of interest relevant to this article was reported.\n\nFig. 1. Survivals of all patients including cT4N+ patients. (A) 5-year local recurrence-free survival (LRFS). (B) 5-year disease-free survival (DFS). (A) 5-year overall surivival (OS). Group A, patients who took capecitabine 1 hour before radiotherapy; Group B, patients who had 2 hours or more time interval between capecitabine intake and radiotherapy.\n\nFig. 2. Survivals of patients excluding cT4N+ patients. (A) 5-year local recurrence-free survival (LRFS). (B) 5-year disease-free survival (DFS). (C) 5-year overall surivival (OS). Group A, patients who took capecitabine 1 hour before radiotherapy; Group B, patients who had 2 hours or more time interval between capecitabine intake and radiotherapy.\n\nTable 1. Patient characteristics\n\n\tGroup A (n = 109)\tGroup B (n = 114)\tp-value\t\nAge (yr)\t52 (29–73)\t55 (30–76)\t0.54\t\nGender\t\t\t\t\n Male\t65 (60)\t78 (68)\t0.17\t\n Female\t44 (40)\t36 (32)\t\t\nHistologic differentiation\t\t\t\t\n Well\t17 (16)\t21 (18)\t0.34\t\n Moderately\t69 (63)\t73 (64)\t\t\n Poorly\t4 (4)\t8 (7)\t\t\n Others\t19 (17)\t12 (11)\t\t\nPreoperative clinical stage\t\t\t\t\n T3N0\t25 (23)\t17 (15)\t0.00\t\n T4N0\t0 (0)\t4 (3)\t\t\n T2N1\t1 (1)\t0 (0)\t\t\n T3N1-2\t77 (71)\t69 (61)\t\t\n T4N1-2\t6 (5)\t24 (21)\t\t\nInitial tumor size (cm)\t\t\t\t\n <4\t17 (16)\t28 (25)\t0.97\t\n 4–6\t67 (61)\t60 (52)\t\t\n >6\t25 (23)\t26 (23)\t\t\nInitial CEA (ng/mL)\t\t\t\t\n <20\t98 (90)\t103 (90)\t0.95\t\n ≥20\t11 (10)\t11 (10)\t\t\nLymphovascular invasion\t\t\t\t\n (-)\t103 (94)\t96 (84)\t0.01\t\n (+)\t6 (6)\t18 (16)\t\t\nSphincter preserving surgery\t\t\t\t\n Yes\t87 (80)\t91 (80)\t1.00\t\n No\t22 (20)\t23 (20)\t\t\nAdjuvant chemotherapy\t\t\t\t\n Yes\t102 (94)\t107 (94)\t0.93\t\n No\t7 (6)\t7 (6)\t\t\nValues are presented as median (range) or number (%).\n\nGroup A, patients who took capecitabine 1 hour before radiotherapy; Group B, patients who had 2 hours or more time interval between capecitabine intake and radiotherapy; CEA, carcinoembryonic antigen.\n\nTable 2. Compliance and ≥grade 3 acute toxicities\n\n\tGroup A (n = 109)\tGroup B (n = 114)\t\nCompliance\t\t\t\n Radiation dose reduction\t0 (0)\t2 (2)\t\n Capecitabine dose reduction\t4 (4)\t7 (6)\t\n≥Grade 3 acute toxicities\t\t\t\n Dermatitis\t0 (0)\t2 (2)\t\n Proctitis\t1 (1)\t0 (0)\t\n Hand-foot syndrome\t1 (1)\t1 (1)\t\n Leukopenia\t2 (2)\t2 (2)\t\n Anemia\t5 (5)\t2 (2)\t\n Thrombocytopenia\t0 (0)\t1 (1)\t\n Ileus\t7 (6)\t7 (6)\t\n Fistula\t5 (5)\t1 (1)\t\n Pelvic abscess\t2 (2)\t1 (1)\t\nValues are presented as number (%).\n\nGroup A, patients who took capecitabine 1 hour before radiotherapy; Group B, patients who had 2 hours or more time interval between capecitabine intake and radiotherapy.\n\nTable 3. Predictive factors for 5-year LRFS\n\nTarget volume\tUnivariate\tMultivariate\t\n5-yr LRFS (%)\tp-value\tHR (95% CI)\tp-value\t\nAge (yr)\t\t\t\t\t\n <55\t92.2\t0.02\tReference\t0.86\t\n ≥55\t98.1\t\t0.81 (0.07–9.09)\t\t\nGender\t\t\t\t\t\n Male\t96.1\t0.13\t-\t-\t\n Female\t93.4\t\t\t\t\nDifferentiation\t\t\t\t\t\n Well\t94.4\t0.83\t-\t-\t\n Moderate\t94.7\t\t\t\t\n Poor\t100\t\t\t\t\n Others\t96.2\t\t\t\t\nInitial tumor size (cm)\t\t\t\t\t\n <4\t97.1\t0.45\t-\t-\t\n 4–6\t96.0\t\t\t\t\n >6\t90.8\t\t\t\t\nInitial CEA (ng/mL)\t\t\t\t\t\n <20\t96.1\t0.15\t-\t-\t\n ≥20\t85.7\t\t\t\t\nLymphovascular invasion\t\t\t\t\t\n (-)\t95.6\t0.10\t-\t-\t\n (+)\t90.5\t\t\t\t\ncT stage\t\t\t\t\t\n 2\t100\t0.81\t-\t-\t\n 3\t94.3\t\t\t\t\n 4\t94.7\t\t\t\t\ncN stage\t\t\t\t\t\n 0\t92.9\t0.61\t-\t-\t\n 1\t95.6\t\t\t\t\n 2\t100\t\t\t\t\nResponse\t\t\t\t\t\n Good response\t94.8\t0.94\t-\t-\t\n Others\t95.0\t\t\t\t\nypT stage\t\t\t\t\t\n 0\t100\t0.41\t-\t-\t\n 1\t87.5\t\t\t\t\n 2\t96.6\t\t\t\t\n 3\t92.9\t\t\t\t\n 4\t100\t\t\t\t\nypN stage\t\t\t\t\t\n 0\t97.4\t0.05\tReference\t0.22\t\n 1\t87.6\t\t2.60 (0.57–11.86)\t\t\n 2\t90.9\t\t-\t\t\nyp stage\t\t\t\t\t\n ypCR\t100\t0.41\t-\t-\t\n non-ypCR\t94.2\t\t\t\t\nResection margin\t\t\t\t\t\n R0\t95.5\t0.04\tReference\t0.58\t\n R1\t66.7\t\t2.33 (0.12–45.78)\t\t\n R2\t100\t\t\t\t\nAdjuvant chemotherapy\t\t\t\t\t\n Yes\t95.2\t0.72\t-\t-\t\n No\t92.9\t\t\t\t\nLRFS, local recurrence-free survival; HR, hazard ratio; CI, confidence interval; CEA, carcinoembryonic antigen; CR, complete response\n\nTable 4. Patients with local recurrence\n\nPatient no.\tAge (yr)\tGender\tClinical stage\tGroup\tOperation\typ stage\tMargin\tLocal recurrence site\tLRFS (mo)\tDistant metastasis site\t\n1\t38\tF\tT3N1\tA\tLAR\tT3N1\t-\tRight bladder dome\t15\tLung\t\n2\t47\tF\tT3N1\tB\tLAR\tT3N0\t-\tLeft pelvic side wall\t34\tLung\t\n3\t42\tF\tT4N1\tB\tLAR\tT3N0\t-\tRight common/internal iliac LN\t69\tPancreas\t\n4\t57\tM\tT3N1\tA\tLAR\tT3N1\t+\tLeft obturator LN\t21\tLung\t\n5\t33\tF\tT3N0\tA\tAPR\tT3N1\t-\tLeft pelvic side wall\t53\t-\t\n6\t53\tM\tT3N0\tA\tLAR\tT2N0\t-\tAnastomosis site\t26\tParacaval LN\t\n7\t53\tM\tT3N1\tA\tAPR\tT3N0\t-\tPresacral area\t38\tLung\t\n8\t54\tF\tT3N0\tB\tAPR\tT2N0\t-\tBoth common iliac/Lt internal iliac LN\t86\t-\t\n9\t59\tF\tT3N0\tB\tLAR\tT3N1\t-\tPresacral/Rt common iliac LN\t25\tLung\t\n10\t45\tM\tT3N1\tB\tAPR\tT3N1\t-\tRight pelvic side wall\t15\tPeritoneal seeding\t\n11\t54\tF\tT3N1\tA\tLAR\tT2N2\t-\tCommon iliac LN\t9\tLung\t\n12\t34\tF\tT3N1\tA\tLAR\tT1N0\t-\tRight pelvic side wall\t24\tLung\t\nGroup A, patients who took capecitabine 1 hour before radiotherapy; Group B, patients who had 2 hours or more time interval between capecitabine intake and radiotherapy; LRFS, local recurrence free survival; LAR, low anterior resection; APR, abdominoperineal resection; LN, lymph node.\n==== Refs\nReferences\n1 Gerard JP Conroy T Bonnetain F Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203 J Clin Oncol 2006 24 4620 5 17008704 \n2 Bosset JF Collette L Calais G Chemotherapy with preoperative radiotherapy in rectal cancer N Engl J Med 2006 355 1114 23 16971718 \n3 Braendengen M Tveit KM Berglund A Randomized phase III study comparing preoperative radiotherapy with chemoradiotherapy in nonresectable rectal cancer J Clin Oncol 2008 26 3687 94 18669453 \n4 Sauer R Liersch T Merkel S Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years J Clin Oncol 2012 30 1926 33 22529255 \n5 Andre T Boni C Navarro M Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial J Clin Oncol 2009 27 3109 16 19451431 \n6 Rodel C Graeven U Fietkau R Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial Lancet Oncol 2015 16 979 89 26189067 \n7 Gerard JP Azria D Gourgou-Bourgade S Comparison of two neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer: results of the phase III trial ACCORD 12/0405-Prodige 2 J Clin Oncol 2010 28 1638 44 20194850 \n8 Aschele C Cionini L Lonardi S Primary tumor response to preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer: pathologic results of the STAR01 randomized phase III trial J Clin Oncol 2011 29 2773 80 21606427 \n9 Miwa M Ura M Nishida M Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue Eur J Cancer 1998 34 1274 81 9849491 \n10 Ishikawa T Utoh M Sawada N Tumor selective delivery of 5-fluorouracil by capecitabine, a new oral fluoropyrimidine carbamate, in human cancer xenografts Biochem Pharmacol 1998 55 1091 7 9605432 \n11 Saif MW Targeting cancers in the gastrointestinal tract: role of capecitabine Onco Targets Ther 2009 2 29 41 20616892 \n12 Hofheinz RD Wenz F Post S Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial Lancet Oncol 2012 13 579 88 22503032 \n13 O'Connell MJ Martenson JA Wieand HS Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery N Engl J Med 1994 331 502 7 8041415 \n14 Reigner B Blesch K Weidekamm E Clinical pharmacokinetics of capecitabine Clin Pharmacokinet 2001 40 85 104 11286326 \n15 Cassidy J Dirix L Bissett D A Phase I study of capecitabine in combination with oral leucovorin in patients with intractable solid tumors Clin Cancer Res. 1998 4 2755 61 9829739 \n16 Mackean M Planting A Twelves C Phase I and pharmacologic study of intermittent twice-daily oral therapy with capecitabine in patients with advanced and/or metastatic cancer J Clin Oncol 1998 16 2977 85 9738566 \n17 Yu CS Kim TW Kim JH Optimal time interval between capecitabine intake and radiotherapy in preoperative chemoradiation for locally advanced rectal cancer Int J Radiat Oncol Biol Phys 2007 67 1020 6 17197127 \n18 Kim JC Kim HC Yu CS Efficacy of 3-dimensional endorectal ultrasonography compared with conventional ultrasonography and computed tomography in preoperative rectal cancer staging Am J Surg 2006 192 89 97 16769283 \n19 Bedi M Das P Skibber JM Capecitabine and timing of radiotherapy during preoperative chemoradiation for rectal cancer Gastrointest Cancer Res 2007 1 44 8 19262718\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2234-1900",
"issue": "35(2)",
"journal": "Radiation oncology journal",
"keywords": "Capecitabine; Chemoradiotherapy; Rectal neoplasms; Survival analysis",
"medline_ta": "Radiat Oncol J",
"mesh_terms": null,
"nlm_unique_id": "101577577",
"other_id": null,
"pages": "129-136",
"pmc": null,
"pmid": "28712273",
"pubdate": "2017-06",
"publication_types": "D016428:Journal Article",
"references": "17008704;22529255;9605432;20616892;16971718;19262718;19451431;9738566;11286326;9849491;18669453;17197127;26189067;21606427;9829739;8041415;16769283;22503032;20194850",
"title": "Effect of time interval between capecitabine intake and radiotherapy on local recurrence-free survival in preoperative chemoradiation for locally advanced rectal cancer.",
"title_normalized": "effect of time interval between capecitabine intake and radiotherapy on local recurrence free survival in preoperative chemoradiation for locally advanced rectal cancer"
} | [
{
"companynumb": "KR-ROCHE-1969951",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": "3",
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{
"abstract": "The Botswana Tsepamo study reported neural tube defects (NTDs) in 4 of 426 (0.94%) infants of women receiving preconception dolutegravir (DTG) antiretroviral therapy (ART) vs 14 of 11 300 (0.12%) receiving preconception non-DTG ART. Data are needed to investigate this potential safety signal. Clinicians, patients, and pharmaceutical companies can report adverse drug reactions (ADRs) to pharmacovigilance databases. Data from ADRs reported to various pharmacovigilance databases were searched for NTDs.\n\n\n\nFour pharmacovigilance databases (World Health Organization [WHO] VigiAccess; United Kingdom Medicines Health Regulatory Authority [UK MHRA]; European Medicines Agency [EMA] EudraVigilance; US Food and Drug Administration Adverse Event Reporting System [FAERS]) with online data availability were analyzed for NTD reports for 4 integrase inhibitors (DTG, raltegravir, elvitegravir, bictegravir), 2 protease inhibitors (darunavir, atazanavir), and 2 nonnucleoside reverse transcriptase inhibitors (nevirapine, efavirenz). Reports in the system organ class \"congenital or familial disorders\" were searched for NTDs.\n\n\n\nNTDs have been reported among infants born from women taking a wide range of antiretrovirals in 4 pharmacovigilance databases (WHO VigiAccess, 116 reactions; UK MHRA, 8 cases; EMA EudraVigilance, 20 cases; FAERS, 44 cases). Six NTDs were identified for DTG across the pharmacovigilance databases. Cases were very hard to interpret, given the lack of clear denominators.\n\n\n\nPharmacovigilance databases have many limitations, most importantly lack of a clear denominator for patients exposed to the drug of interest and duplicate cases that are difficult to identify. Given widespread use of new antiretroviral drugs worldwide and anticipated use of new drugs, prospective follow-up of pregnant women and birth surveillance studies such as Tsepamo are critically needed.",
"affiliations": "London School of Hygiene and Tropical Medicine, London.;London School of Hygiene and Tropical Medicine, London.;Chelsea and Westminster Hospital National Health Service Foundation Trust, London.;Human Immunodeficiency Virus i-Base, London.;Cardiff and Vale University Health Board, United Kingdom.;Tours University Hospital, France.;Elizabeth Glaser Paediatric AIDS Foundation, Washington, District of Columbia.;Liverpool School of Tropical Medicine, United Kingdom.",
"authors": "van De Ven|Nikolien S|NS|;Pozniak|Anton L|AL|;Levi|Jacob A|JA|;Clayden|Polly|P|;Garratt|Anna|A|;Redd|Christopher|C|;Mofenson|Lynne M|LM|;Hill|Andrew|A|",
"chemical_list": "D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; C562325:dolutegravir",
"country": "United States",
"delete": false,
"doi": "10.1093/cid/ciz684",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-4838",
"issue": "70(12)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": " dolutegravir; HIV; neural tube defects; pharmacovigilance; pregnancy outcomes",
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D001902:Botswana; D016208:Databases, Factual; D005260:Female; D015658:HIV Infections; D006575:Heterocyclic Compounds, 3-Ring; D006801:Humans; D010078:Oxazines; D060735:Pharmacovigilance; D010879:Piperazines; D011247:Pregnancy; D011446:Prospective Studies; D011728:Pyridones; D006113:United Kingdom",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "2599-2606",
"pmc": null,
"pmid": "31595301",
"pubdate": "2020-06-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Analysis of Pharmacovigilance Databases for Dolutegravir Safety in Pregnancy.",
"title_normalized": "analysis of pharmacovigilance databases for dolutegravir safety in pregnancy"
} | [
{
"companynumb": "GB-MYLANLABS-2020M1099233",
"fulfillexpeditecriteria": "1",
"occurcountry": "BW",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOLUTEGRAVIR"
},
"drugadditional": null,
... |
{
"abstract": "We report a case of acute respiratory insufficiency due to peripartum cardiomyopathy after Caesarean section in a term pregnancy with twins. The patient was a 30-year-old woman with a spontaneous twin pregnancy at 32 weeks of gestation who was admitted to our obstetrics department with preterm premature rupture of membranes. After 48 hours, the tocolysis was stopped and an uneventful Caesarean was performed under general anesthesia. As the patient was waking up, her SPO2 decreased to 32%, and she became cyanotic and tachypneic. Auscultation revealed rales in her lower lung lobes bilaterally. Her oxygen saturation did not increase in the hours that followed, and her cyanosis persisted, so we decided to admit her to the Intensive Care Unit. She was mechanically ventilated. Her chest X-ray showed an enlarged cardiac silhouette and pulmonary infiltrates in the lower lobes. On the second postoperative day, transthoracic echocardiography was performed and revealed an EF of 45%, mild left ventricular systolic dysfunction and moderate mitral valve failure. Lisinopryl and furosemide were started. On postoperative day four, her symptoms and radiological signs had resolved. She was weaned from mechanical ventilation and discharged from the obstetric ward on postoperative day seven.",
"affiliations": "Departments of Anesthesiology and Reanimation, Duzce School of Medicine, Duzce University, Duzce, Turkey.;Departments of Anesthesiology and Reanimation, Duzce School of Medicine, Duzce University, Duzce, Turkey.;Departments of Anesthesiology and Reanimation, Duzce School of Medicine, Duzce University, Duzce, Turkey.;Departments of Obstetrics and Gynecology, Duzce School of Medicine, Duzce University, Duzce, Turkey.;Departments of Anesthesiology and Reanimation, Duzce School of Medicine, Duzce University, Duzce, Turkey.",
"authors": "Demiraran|Yavuz|Y|;Iskender|Abdulkadir|A|;Ersoy|Ozlem|O|;Albayrak|Mustafa|M|;Kaynak|Gursel|G|",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.5152/eajm.2010.40",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1308-8734",
"issue": "42(3)",
"journal": "The Eurasian journal of medicine",
"keywords": "Peripartum cardiomyopathy; Pulmonary edema",
"medline_ta": "Eurasian J Med",
"mesh_terms": null,
"nlm_unique_id": "101557701",
"other_id": null,
"pages": "148-50",
"pmc": null,
"pmid": "25610146",
"pubdate": "2010-12",
"publication_types": "D002363:Case Reports",
"references": "19137251;10935677;9023057;10454675;10432149;2935758;10703781;19128569;4255967;9305313",
"title": "Acute respiratory insufficiency due to peripartum cardiomyopathy after caesarean section in a term pregnancy with twins.",
"title_normalized": "acute respiratory insufficiency due to peripartum cardiomyopathy after caesarean section in a term pregnancy with twins"
} | [
{
"companynumb": "TR-BAYER-2015-014232",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BETAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "Solifenacin is a muscarinic receptor antagonist that has been used to treat overactive bladder since 2004. It has a great affinity for the detrusor M3 receptor, which must be stimulated for bladder muscle contraction, and demonstrates the most selective profile to the bladder of the muscarinic receptor subtypes. It is thought that urinary antimuscarinic agents, due to their passage to the central nervous system and lipophilic properties, may cause central nervous system symptoms in some rare cases. A case report of a 42-year-old male patient who had an acute psychotic attack as a result of solifenacin treatment for overactive bladder is presented in this article.",
"affiliations": "Psychiatry, Istanbul Erenkoy Mental and Nervous Diseases Training and Research Hospital, Istanbul, Turkey.;Psychiatry, Istanbul Erenkoy Mental and Nervous Diseases Training and Research Hospital, Istanbul, Turkey.;Urology, Kocaeli University, School of Medicine, Kocaeli, Turkey.",
"authors": "Kirsavoglu|Betul|B|;Odabasi|Ozan|O|0000-0001-7460-3072;Avci|Ibrahim Erkut|IE|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/gpsych-2021-100586",
"fulltext": "\n==== Front\nGen Psychiatr\nGen Psychiatr\ngpsych\ngpsych\nGeneral Psychiatry\n2517-729X\nBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR\n\ngpsych-2021-100586\n10.1136/gpsych-2021-100586\nCase Report\n1506\nSolifenacin-induced acute psychosis: a case report\nKirsavoglu Betul 1*\nhttp://orcid.org/0000-0001-7460-3072\nOdabasi Ozan 1\nAvci Ibrahim Erkut 2\n1 Psychiatry, Istanbul Erenkoy Mental and Nervous Diseases Training and Research Hospital, Istanbul, Turkey\n2 Urology, Kocaeli University, School of Medicine, Kocaeli, Turkey\nCorrespondence to Betul Kirsavoglu; betulkirsavoglu@hotmail.com\n2021\n12 10 2021\n34 5 e10058604 6 2021\n21 9 2021\n© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.\n\nSolifenacin is a muscarinic receptor antagonist that has been used to treat overactive bladder since 2004. It has a great affinity for the detrusor M3 receptor, which must be stimulated for bladder muscle contraction, and demonstrates the most selective profile to the bladder of the muscarinic receptor subtypes. It is thought that urinary antimuscarinic agents, due to their passage to the central nervous system and lipophilic properties, may cause central nervous system symptoms in some rare cases. A case report of a 42-year-old male patient who had an acute psychotic attack as a result of solifenacin treatment for overactive bladder is presented in this article.\n\npsychotic disorders\ncentral nervous system\nspecial-featureunlocked\n==== Body\npmcIntroduction\n\nOveractive bladder (OAB) is defined as urinary urgency, usually accompanied by increased daytime frequency and/or nocturia, with urinary incontinence (OAB-wet) or without (OAB-dry), in the absence of urinary tract infection or another detectable disease.1 In a population-based survey of 16 776 men and women aged >40 years conducted in six countries, the prevalence of OAB in Europe was estimated to be 15.6% in men and 17.4% in women, with an overall prevalence of 16.6%.2 Antimuscarinic medications are currently the mainstay of treatment for OAB. They differ in their pharmacological profiles, including muscarinic receptor affinity and other modes of action, and also differ in their pharmacokinetic properties, such as lipid solubility and half-life. Systemic adverse effects are common in treatments due to the extensive involvement of muscarinic receptors in the autonomic nervous system and the passage of some agents to the central nervous system. Five muscarinic receptor subtypes (M1 to M5) have been identified, with M2 and M3 being the most prevalent in the detrusor. Although M2 is one of the most expressed subtypes, the M3 subtype is more functionally significant in bladder contractions.3 4 Solifenacin demonstrated a highly bladder-selective profile in preclinical studies when compared with other antimuscarinic agents.5 Common side effects of solifenacin that lead to discontinuation of treatment have been reported as dry mouth, blurred vision, constipation and headache. In one study, it was stated that headache, confusion, cognitive impairment, disorientation, agitation, dysarthria and changes in consciousness might be observed due to the high penetration of solifenacin, which is not a P-glycoprotein substrate. Such agents can increase the dopamine level in the synaptic gap.6\n\nIn the literature, although there was no case of psychotic disorder due to solifenacin use, it was reported that a man in his 80s was prescribed solifenacin for the diagnosis of OAB whose clinical manifestation that began with anxiety progressed to delirium. The delirium manifestation improved with the discontinuation of the treatment.7 This article presents a case report of a 42-year-old male patient who had an acute psychotic attack due to solifenacin treatment for OAB.\n\nCase history\n\nA 42-year-old married man, a high school graduate, working in the private sector, belonging to middle upper socioeconomic status and living with his family presented at the psychiatry emergency department with his relatives because of psychiatric complaints. The patient himself and his family had no known history of psychiatric illness. In addition, the patient had no other known medical disease. He was recently diagnosed with OAB due to lower urinary tract symptoms, with predominant storage symptoms such as urinary urgency, increased urinary frequency, pass urine that is difficult to defer and involuntary loss of urine. Fifteen days ago, he was initiated on solifenacin at a dose of 5 mg/day by the urologist. He was advised to apply for a follow-up examination 4 weeks after he started taking medication. Because symptoms persisted despite taking the prescribed dose, on the fifth day of his treatment, the patient doubled his daily dose without consulting his doctor. Although his psychiatric complaints started right after he increased the medicine dosage, he continued to use the medicine at a dose of 10 mg/day.\n\nInitially, there were complaints of restlessness, irritability and sleep disturbance, along with excessive suspiciousness. A few days later, these complaints were accompanied by self-talking, leaving home without informing anyone, and severe, tenaciously held, systematised paranoid thoughts that his wife would hurt him and his family was pursuing him. The family discontinued solifenacin treatment given that the patient could not cooperate in applying to the hospital and getting psychiatric help.\n\nApproximately 7 days after the treatment was discontinued, the patient presented to the psychiatry emergency service with his relatives of his own will. In his mental state examination and his anamnesis, his level of consciousness and awareness were intact, his mood and affect were irritable and his thought content included paranoid thoughts about his colleagues. There were no hallucinations. Goal orientation, abstract thinking, attention, memory functions and test judgement were intact; the insight about the current situation and the recommended treatment was partial. There was no active homicidal or suicidal thinking. According to a history obtained from the patient’s family, his condition was closely observed by family members throughout 1 week. His thought that he would be harmed if he left home decreased over time. The neurological examination, blood tests, cranial CT and diffusion MRI of the patient consulted in the neurology department revealed no abnormalities. The urology department was consulted about the patient’s current condition and how to proceed with the treatment in future. They were advised to wait until the patient’s psychiatric symptoms subsided, after which he would be re-evaluated to determine the right treatment and that it would be more appropriate to follow up without using anticholinergic drugs during this time.\n\nThe patient did not have active homicidal or suicidal ideation. He refused to be treated in an inpatient psychiatric clinic. Consequently, he was discharged after obtaining both his consent and the consent of his family members, and communicating with them about the need for oral medication (outpatient) and follow-up. Olanzapine 10 mg/day treatment was initiated. After the second week of the treatment, the patient’s delusions completely regressed, his mood changed in the direction of euthymia and he gained a complete insight about his disease and treatment. In the following course, the dose of olanzapine was reduced to 5 mg/day due to sedation side effects. As no psychotic findings were noted during the follow-up period, the treatment was continued with olanzapine at a dose of 5 mg/day.\n\nDiscussion\n\nAnticholinergic agents can increase the dopamine level in the synaptic gap, and confusion, cognitive impairment, disorientation, agitation, dysarthria and changes in consciousness may accompany the typical psychotic symptoms in psychotic disorders associated with anticholinergic drug use.8 They also act as potent indirect dopamine agonists by blocking the presynaptic uptake of dopamine and causing its release from presynaptic terminals.9 Adverse effects associated with the use of antimuscarinic drugs relate to the central nervous system which are frequently mentioned in the literature. In a meta-analysis published in 2011, these side effects were listed as dizziness, sleepiness, vertigo, insomnia, restlessness, weakness, confusion and cognitive dysfunction. The most common side effects were stated as dizziness and sleepiness.10 The presence of the receptors on the drugs used in the treatment of OAB affects the central nervous system; the presence of factors that affect the deterioration of the blood–brain barrier, especially in older adults, leads to variability in terms of side effects with pharmacodynamic and pharmacokinetic differences.11\n\nIn a comparison of studies performed with different antimuscarinic agents, no significant difference was found in terms of central side effects, and it was stated that anticholinergic side effects may be observed due to the high rate of oral oxybutynin treatment crossing the blood–brain barrier.12 A single dose of solifenacin, oxybutynin and placebo was investigated in another randomised, double-blind study that investigated attention, information processing, processing memory, episodic memory and mood changes; oxybutynin was shown to cause impairment in various cognitive areas.13 This study also noted that cognitive impairment related to antimuscarinic use may increase with age, accumulation of anticholinergic effects of other drugs used, Parkinson’s disease, cerebrovascular diseases, multiple sclerosis and schizophrenia.\n\nWhen evaluated together with the literature, in our case, the discontinuation of solifenacin treatment the regression of symptoms in the second week after the initiation of antipsychotic treatment, the absence of organicity that may cause psychosis and the lack of need for high antipsychotic doses in outpatient clinic visits suggest that the psychotic attack was associated with solifenacin.\n\nSolifenacin is a frequently used agent in the treatment of OAB. Although it is known that it may have central nervous system and psychiatric side effects with its introduction to the market in 2004, data on this subject are limited. To our knowledge, this is the first case of psychosis associated with solifenacin reported in our country. Although psychosis is very rare with solifenacin treatment, it should be kept in mind that if an acute psychotic attack occurs while under solifenacin treatment, the disorder may be related to this treatment. In addition to the necessity of selecting agents with known lower central effects for treatment, it would be highly beneficial to inform patients about acute psychiatric conditions that may occur due to this treatment and how to manage these conditions.\n\nI would like to express my special gratitude and thanks to my colleague Dr Ezgi Yilmaz for imparting her knowledge and providing the necessary information regarding this case report.\n\nBetul Kirsavoglu obtained a bachelor's degree from Faculty of Medicine, Hacettepe University, Turkey, in 2014, and a master's degree on adult psychiatry area at Istanbul Erenkoy Mental Health Research and Training Hospital in Turkey in 2020. Currently, she is working as a medical specialist for psychiatry at Giresun Bulancak State Hospital in Turkey. In addition, she is also an active member for Turkish Psychiatry Association, European Federation of Psychiatry Trainees and Viktor Frankl Institute USA Faculty. Bipolar disorder, neuropsychiatry, psychosis, trauma, psychological resilience, post-traumatic growth, logotherapy and supportive psychotherapy are the main areas that she is working on. Her main research interests include investigation of psychological resilience, post-traumatic growth, caregiver burden and related factors in patients with bipolar disorder and their caregivers.\n\nEthics statements\n\nPatient consent for publication\n\nNot applicable.\n\nContributors: BK evaluated the patient in the psychiatry emergency department, collected data, did a literature search and took the lead in writing the manuscript. OO prepared the manuscript draft with data analysis and interpretation. IEA evaluated the patient in terms of urological complaints and made contribution to writing and revising the draft. All authors provided critical feedback and helped shape the manuscript. All authors approved the final form. BK is responsible for the overall content 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\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n\n1 Haylen BT, de Ridder D, Freeman RM, et al . An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic floor dysfunction. Neurourol Urodyn 2010;29 :4–20. 10.1002/nau.20798 19941278\n2 Zecca C, Riccitelli GC, Disanto G, et al . Urinary incontinence in multiple sclerosis: prevalence, severity and impact on patients' quality of life. Eur J Neurol 2016;23 :1228–34. 10.1111/ene.13010 27120000\n3 Matsui M, Motomura D, Karasawa H, et al . Multiple functional defects in peripheral autonomic organs in mice lacking muscarinic acetylcholine receptor gene for the M3 subtype. Proc Natl Acad Sci U S A 2000;97 :9579–84. 10.1073/pnas.97.17.9579 10944224\n4 Chess-Williams R, Chapple CR, Yamanishi T, et al . The minor population of M3-receptors mediate contraction of human detrusor muscle in vitro. J Auton Pharmacol 2001;21 :243–8. 10.1046/j.1365-2680.2001.00231.x 12123469\n5 Ohtake A, Sato S, Sasamata M, et al . The forefront for novel therapeutic agents based on the pathophysiology of lower urinary tract dysfunction: ameliorative effect of solifenacin succinate (Vesicare), a bladder-selective antimuscarinic agent, on overactive bladder symptoms, especially urgency episodes. J Pharmacol Sci 2010;112 :135–41. 10.1254/jphs.09R13FM 20134114\n6 Moriya H, Takagi Y, Nakanishi T, et al . Affinity profiles of various muscarinic antagonists for cloned human muscarinic acetylcholine receptor (mAChR) subtypes and mAChRs in rat heart and submandibular gland. Life Sci 1999;64 :2351–8. 10.1016/S0024-3205(99)00188-5 10374898\n7 Štuhec M. Solifenacin-induced delirium and hallucinations. Gen Hosp Psychiatry 2013;35 :682.e3–682.e4. 10.1016/j.genhosppsych.2013.06.002\n8 Gulsun M, Pinar M, Sabanci U. Psychotic disorder induced by oxybutynin. Clin Drug Investig 2006;26 :603–6. 10.2165/00044011-200626100-00007\n9 Bezchlibnyk-Butler KZ, Remington GJ. Antiparkinsonian drugs in the treatment of neuroleptic-induced extrapyramidal symptoms. Can J Psychiatry 1994;39 :74–84. 10.1177/070674379403900203 7908605\n10 Paquette A, Gou P, Tannenbaum C. Systematic review and meta-analysis: do clinical trials testing antimuscarinic agents for overactive bladder adequately measure central nervous system adverse events? J Am Geriatr Soc 2011;59 :1332–9. 10.1111/j.1532-5415.2011.03473.x 21718264\n11 Abrams P, Andersson K-E. Muscarinic receptor antagonists for overactive bladder. BJU Int 2007;100 :987–1006. 10.1111/j.1464-410X.2007.07205.x 17922784\n12 Chancellor M, Boone T. Anticholinergics for overactive bladder therapy: central nervous system effects. CNS Neurosci Ther 2012;18 :167–74. 10.1111/j.1755-5949.2011.00248.x 22070184\n13 Wesnes KA, Edgar C, Tretter RN, et al . Exploratory pilot study assessing the risk of cognitive impairment or sedation in the elderly following single doses of solifenacin 10 Mg. Expert Opin Drug Saf 2009;8 :615–26. 10.1517/14740330903260790 19747069\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2517-729X",
"issue": "34(5)",
"journal": "General psychiatry",
"keywords": "central nervous system; psychotic disorders",
"medline_ta": "Gen Psychiatr",
"mesh_terms": null,
"nlm_unique_id": "101735271",
"other_id": null,
"pages": "e100586",
"pmc": null,
"pmid": "34723090",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "17922784;23866158;10374898;7908605;17163294;22070184;10944224;12123469;19747069;27120000;20134114;21718264;19941278",
"title": "Solifenacin-induced acute psychosis: a case report.",
"title_normalized": "solifenacin induced acute psychosis a case report"
} | [
{
"companynumb": "TR-ASTELLAS-2021US042788",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SOLIFENACIN"
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"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe purpose of this study was to determine if pain level was associated with demographic or surgery-specific characteristics among patients recovering from ambulatory surgery; and to assess the relationship between pain level and nausea over the 7-day postoperative period, controlling for demographic and surgery-related covariates.\n\n\nMETHODS\nThis longitudinal study assessed the pain and nausea of 248 eligible patients during the day of surgery (DOS) and the 7 days following ambulatory surgery. Postoperative data were assessed using standardized questions about severity of pain and nausea symptoms. Participants who had a cumulative pain score of ≥24 over the 8-day period were categorized as having high pain. Repeated-measures analysis of variance was used to assess differences in nausea by pain group over time, controlling for demographic, surgical variables, and antiemetic and analgesic use.\n\n\nRESULTS\nThere were significant differences between 2 pain groups in age, surgical procedure, cumulative morphine equivalent dose, and use of antiemetics postdischarge. The longitudinal analysis demonstrated that patients in the high-pain group reported a greater degree of nausea on DOS and on each of the first 5 days postsurgery, controlling for differences in age, sex, education, use of antiemetics presurgery and postsurgery, use of acetaminophen postsurgery, daily morphine equivalent dose, and surgical procedure.\n\n\nCONCLUSIONS\nYounger patients and those receiving orthopedic procedures may be at greatest risk for postoperative pain. Patients with high pain reported a significantly greater degree of nausea on DOS through the first 5 days postdischarge. As the majority of surgeries are now conducted in the ambulatory setting, it is imperative that we determine pain management regimens and patient education practices that will allow for a more comfortable recovery for our patients.",
"affiliations": "*College of Nursing, University of Kentucky, Lexington, KY †University of California ‡Department of Anesthesia and Perioperative Care, University of California, San Francisco General Hospital ¶Associate Adjunct Professor, Department of Epidemiology & Biostatistics, University of California, San Francisco, CA §Department of Anesthesiology and Critical Care Medicine, University Hospital Carl Gustav Carus Dresden at the TU Dresden, Fetscherstr, Dresden ∥Medical College of Georgia, Augusta, GA.",
"authors": "Odom-Forren|Jan|J|;Rayens|Mary K|MK|;Gokun|Yevgeniya|Y|;Jalota|Leena|L|;Radke|Oliver|O|;Hooper|Vallire|V|;Wiggins|Amanda T|AT|;Apfel|Christian C|CC|",
"chemical_list": "D000701:Analgesics, Opioid; D009020:Morphine",
"country": "United States",
"delete": false,
"doi": "10.1097/AJP.0000000000000170",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0749-8047",
"issue": "31(10)",
"journal": "The Clinical journal of pain",
"keywords": null,
"medline_ta": "Clin J Pain",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000556:Ambulatory Surgical Procedures; D000701:Analgesics, Opioid; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D009020:Morphine; D010147:Pain Measurement; D010149:Pain, Postoperative; D020250:Postoperative Nausea and Vomiting; D055815:Young Adult",
"nlm_unique_id": "8507389",
"other_id": null,
"pages": "845-51",
"pmc": null,
"pmid": "25370136",
"pubdate": "2015-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "The Relationship of Pain and Nausea in Postoperative Patients for 1 Week After Ambulatory Surgery.",
"title_normalized": "the relationship of pain and nausea in postoperative patients for 1 week after ambulatory surgery"
} | [
{
"companynumb": "US-JNJFOC-20150913200",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "HYDROCODONE"
},
"drugadditional": null,
... |
{
"abstract": "Systematic data on the ability of pegfilgrastim to mobilize stem cells after chemotherapy are scarce. We evaluated the efficacy of a single 6 mg dose of pegfilgrastim for mobilizing peripheral blood stem cells (PBSC) in aggressive lymphoma patients. Between July 2004 and October 2005, 17 aggressive non-Hodgkin's lymphoma and 11 poor-risk Hodgkin's lymphoma were treated with cycles containing cisplatin-aracytin. At the end of chemotherapy, the patients received 6 mg of pegfilgrastim. Duration of grade 4 neutropenia, adverse events, time to neutrophil recovery, peak and harvest of CD34+ cells were recorded. Twenty-seven out of 28 patients harvested a median of 17.3 x 10(6)/CD34+ cells (range 2.5-28.9) after a median of 9 days (range 8-12 days), with a single apheresis procedure in 25 cases. All patients had grade 3-4 neutropenia, median duration 3 days. The only adverse event was mild bone pain. To date, 13 patients have been autografted with a median of 15.4 x 10(6) CD34+ pegfilgrastim-mobilized cells per kg (range 2.5-28.9) with rapid and sustained engraftment. Mobilization, harvesting and autografting of pegfilgrastim-mobilized PBC can be successfully achieved in pretreated patients with aggressive lymphoma.",
"affiliations": "Divisione di Ematologia, Niguarda Ca' Granda Hospital, Milan, Italy.",
"authors": "Nosari|A|A|;Cairoli|R|R|;Ciapanna|D|D|;Gargantini|L|L|;Intropido|L|L|;Baraté|C|C|;Scarpati|B|B|;Santoleri|L|L|;Nador|G|G|;Pezzetti|L|L|;Morra|E|E|",
"chemical_list": "D018952:Antigens, CD34; D000964:Antimetabolites, Antineoplastic; D011994:Recombinant Proteins; D003561:Cytarabine; D016179:Granulocyte Colony-Stimulating Factor; C455861:pegfilgrastim; D011092:Polyethylene Glycols; D000069585:Filgrastim; D002945:Cisplatin",
"country": "England",
"delete": false,
"doi": "10.1038/sj.bmt.1705459",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-3369",
"issue": "38(6)",
"journal": "Bone marrow transplantation",
"keywords": null,
"medline_ta": "Bone Marrow Transplant",
"mesh_terms": "D000328:Adult; D000368:Aged; D018952:Antigens, CD34; D000964:Antimetabolites, Antineoplastic; D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D003561:Cytarabine; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor; D019650:Hematopoietic Stem Cell Mobilization; D006689:Hodgkin Disease; D006801:Humans; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008875:Middle Aged; D009503:Neutropenia; D010146:Pain; D036102:Peripheral Blood Stem Cell Transplantation; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D014182:Transplantation, Autologous",
"nlm_unique_id": "8702459",
"other_id": null,
"pages": "413-6",
"pmc": null,
"pmid": "16878144",
"pubdate": "2006-09",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Efficacy of single dose pegfilgrastim in enhancing the mobilization of CD34+ peripheral blood stem cells in aggressive lymphoma patients treated with cisplatin-aracytin-containing regimens.",
"title_normalized": "efficacy of single dose pegfilgrastim in enhancing the mobilization of cd34 peripheral blood stem cells in aggressive lymphoma patients treated with cisplatin aracytin containing regimens"
} | [
{
"companynumb": "IT-AMGEN-ITASP2020128082",
"fulfillexpeditecriteria": "2",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nDabigatran is a novel target specific oral anticoagulant for stroke prevention in non valvular atrial fibrillation. Little is still known about its real-world effectiveness and safety in the italian population. Aim of our study was to evaluate the efficacy and safety of dabigatran in a large single-center cohort of \"real-life\" italian population with non-valvular AF and to compare the results with those obtained from the RE-LY trial and the Medicare study.\n\n\nMETHODS\nWe studied a prospective cohort of 2108 patients (1119 male; mean age 69.4 ± 9.4 years) who started the oral anticoagulant treatment with dabigatran 110 mg twice-daily (DAB 110; N = 1075; 51%) or 150 mg twice-daily (DAB 150; N = 1033; 49%). Follow-up data were obtained trough outpatients visits each 3-6 months for assessing the clinical status, adherence to treatment, occurrence of side effects and major cardiovascular complications.\n\n\nRESULTS\nIn DAB 150 group the mean age was 64.9 ± 8.8 years, 56.8% of patients was male. CHA2DS2Vasc Score was ≥ 3 in 94.3% and HAS-BLED was ≥ 3 in 59.7%. In DAB 110 group (N = 1075) the mean age was 73.9 ± 7.5 years; 49.5% of patients was male. CHA2DS2Vasc Score was ≥ 3 in 73.4% and HAS-BLED was ≥ 3 in 87.4% of DAB 110 patients. One patient taking Dabigatran 110 mg bid had ischemic stroke without significantly neurological sequelae. In both groups, no patient experienced hemorrhagic stroke during the follow-up period. 147 patients (6.9%) of MonaldiCare population reported adverse effects from treatment with dabigatran, of whom 121 patients (5.7%) discontinued therapy. We reported one case of subarachnoid hemorrhage (0.05%) in a patient with high thrombo-embolic and high hemorrhagic risk score who was taking dabigatran 150 mg bid and one case (0.05%) of bladder bleeding in a patient who was taking dabigatran 110 mg bid. No major gastrointestinal bleeding was observed in the MonaldiCare population.\n\n\nCONCLUSIONS\nMonaldiCare registry showed a safety profile of both dosages of dabigatran regarding major of fatal bleeding in a \"real life\" single center italian population at high thromboembolic and hemorrhagic risk. The majority of MonaldiCare patients tolerated dabigatran treatment without significant side effects. The efficacy of dabigatran was demonstrated by very low prevalence of ictus/TIA, also when patients underwent electrical AF cardioversion independently of the transesophageal examination.",
"affiliations": "Department of Cardio-Thoracic and Respiratory Sciences, Second University of Naples, Monaldi Hospital, Naples, Italy. v.p.russo@libero.it.",
"authors": "Russo|V|V|;Bianchi|V|V|;Cavallaro|C|C|;Vecchione|F|F|;De Vivo|S|S|;Santangelo|L|L|;Sarubbi|B|B|;Calabrò|P|P|;Nigro|G|G|;D'Onofrio|A|A|",
"chemical_list": "D000991:Antithrombins; D000069604:Dabigatran",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1128-3602",
"issue": "19(20)",
"journal": "European review for medical and pharmacological sciences",
"keywords": null,
"medline_ta": "Eur Rev Med Pharmacol Sci",
"mesh_terms": "D000368:Aged; D000991:Antithrombins; D001281:Atrial Fibrillation; D015331:Cohort Studies; D000069604:Dabigatran; D004415:Dyspepsia; D005260:Female; D005500:Follow-Up Studies; D006470:Hemorrhage; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D011159:Population Surveillance; D015995:Prevalence; D011446:Prospective Studies; D012042:Registries; D012307:Risk Factors; D020521:Stroke; D013923:Thromboembolism; D016896:Treatment Outcome",
"nlm_unique_id": "9717360",
"other_id": null,
"pages": "3961-7",
"pmc": null,
"pmid": "26531286",
"pubdate": "2015-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Efficacy and safety of dabigatran in a \"real-life\" population at high thromboembolic and hemorrhagic risk: data from MonaldiCare registry.",
"title_normalized": "efficacy and safety of dabigatran in a real life population at high thromboembolic and hemorrhagic risk data from monaldicare registry"
} | [
{
"companynumb": "IT-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2015-BI-62659BI",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "We present two rare cases of mixed large cell neuroendocrine carcinoma and squamous cell carcinoma of the colon. A literature search revealed only three published cases with similar histology but none of these reports provided profound molecular and mutational analyses. Our two cases exhibited a distinct, colon-like immunophenotype with strong nuclear CDX2 and β-catenin expression in more than 90% of the tumour cells of both components. We analysed the two carcinomas regarding microsatellite stability, RAS, BRAF and PD-L1 status. In addition, next-generation panel sequencing with Ion AmpliSeq™ Cancer Hotspot Panel v2 was performed. This approach revealed mutations in FBXW7, CTNNB1 and PIK3CA in the first case and FBXW7 and RB1 mutations in the second case. We looked for similar mutational patterns in three publicly available colorectal adenocarcinoma data sets, as well as in collections of colorectal mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) and colorectal neuroendocrine carcinomas. This approach indicated that the FBXW7 point mutation, without being accompanied by classical adenoma-carcinoma sequence mutations, such as APC, KRAS and TP53, likely occurs at a relatively high frequency in mixed neuroendocrine and squamous cell carcinoma and therefore may be characteristic for this rare tumour type. FBXW7 codifies the substrate recognition element of an ubiquitin ligase, and inactivating FBXW7 mutations lead to an exceptional accumulation of its target β-catenin which results in overactivation of the Wnt-signalling pathway. In line with previously described hypotheses of de-differentiation of colon cells by enhanced Wnt-signalling, our data indicate a crucial role for mutant FBXW7 in the unusual morphological switch that determines these rare neoplasms. Therefore, mixed large cell neuroendocrine and a squamous cell carcinoma can be considered as a distinct carcinoma entity in the colon, defined by morphology, immunophenotype and distinct molecular genetic alteration(s).",
"affiliations": "Institute of Pathology, Medical Faculty, Ludwig-Maximilians-Universität München, Munich, Germany.;Institute of Pathology, Medical Faculty, Ludwig-Maximilians-Universität München, Munich, Germany.;Institute of Pathology, Medical Faculty, Ludwig-Maximilians-Universität München, Munich, Germany.;Institute of Pathology, Medical Faculty, Ludwig-Maximilians-Universität München, Munich, Germany.;Practice of Pathology, Munich, Germany.;Medizinische Klinik und Poliklinik 4, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany.;Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany.;Institute of Pathology, Medical Faculty, Ludwig-Maximilians-Universität München, Munich, Germany.;Institute of Pathology, Medical Faculty, Ludwig-Maximilians-Universität München, Munich, Germany.",
"authors": "Woischke|Christine|C|0000-0003-1804-5904;Jung|Peter|P|;Jung|Andreas|A|;Kumbrink|Jörg|J|;Eisenlohr|Sibylle|S|;Auernhammer|Christoph Josef|CJ|;Vieth|Michael|M|;Kirchner|Thomas|T|;Neumann|Jens|J|",
"chemical_list": "D014408:Biomarkers, Tumor; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human",
"country": "England",
"delete": false,
"doi": "10.1002/cjp2.183",
"fulltext": "\n==== Front\nJ Pathol Clin Res\nJ Pathol Clin Res\n10.1002/(ISSN)2056-4538\nCJP2\nThe Journal of Pathology: Clinical Research\n2056-4538 John Wiley & Sons, Inc. Hoboken, USA \n\n33197299\n10.1002/cjp2.183\nCJP2183\nOriginal Article\nOriginal Articles\nMixed large cell neuroendocrine carcinoma and squamous cell carcinoma of the colon: detailed molecular characterisation of two cases indicates a distinct colorectal cancer entity\nDistinct mixed colorectal carcinoma entityC Woischke et alWoischke Christine https://orcid.org/0000-0003-1804-5904\n1\n Jung Peter \n1\n\n2\n\n3\n Jung Andreas \n1\n\n2\n\n3\n Kumbrink Jörg \n1\n\n2\n Eisenlohr Sibylle \n4\n Auernhammer Christoph Josef \n5\n\n6\n Vieth Michael \n7\n Kirchner Thomas \n1\n\n2\n\n3\n Neumann Jens \n1\n\n2\n\n3\njens.neumann@med.uni-muenchen.de \n1 \nInstitute of Pathology, Medical Faculty\nLudwig‐Maximilians‐Universität München\nMunich\nGermany\n\n\n2 \nGerman Cancer Consortium (DKTK), partner site\nMunich\nGermany\n\n\n3 \nGerman Cancer Research Center (DKFZ)\nHeidelberg\nGermany\n\n\n4 \nPractice of Pathology\nMunich\nGermany\n\n\n5 \nMedizinische Klinik und Poliklinik 4\nKlinikum der Universität München, Ludwig‐Maximilians‐Universität München\nMunich\nGermany\n\n\n6 \nInterdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET‐KUM)\nKlinikum der Universität München (KUM), Ludwig‐Maximilians‐University\nMunich\nGermany\n\n\n7 \nInstitute of Pathology\nKlinikum Bayreuth\nBayreuth\nGermany\n\n* \nCorrespondence: Jens Neumann, Institute of Pathology, Medical Faculty, Ludwig‐Maximilians‐Universität München, Thalkirchner Straße 36, 80337 Munich, Germany. E‐mail: jens.neumann@med.uni-muenchen.de\n\n16 11 2020 \n1 2021 \n7 1 10.1002/cjp2.v7.175 85\n06 7 2020 12 9 2020 19 9 2020 © 2020 The Authors. The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland & John Wiley & Sons, Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Abstract\nWe present two rare cases of mixed large cell neuroendocrine carcinoma and squamous cell carcinoma of the colon. A literature search revealed only three published cases with similar histology but none of these reports provided profound molecular and mutational analyses. Our two cases exhibited a distinct, colon‐like immunophenotype with strong nuclear CDX2 and β‐catenin expression in more than 90% of the tumour cells of both components. We analysed the two carcinomas regarding microsatellite stability, RAS, BRAF and PD‐L1 status. In addition, next‐generation panel sequencing with Ion AmpliSeq™ Cancer Hotspot Panel v2 was performed. This approach revealed mutations in FBXW7, CTNNB1 and PIK3CA in the first case and FBXW7 and RB1 mutations in the second case. We looked for similar mutational patterns in three publicly available colorectal adenocarcinoma data sets, as well as in collections of colorectal mixed neuroendocrine‐non‐neuroendocrine neoplasms (MiNENs) and colorectal neuroendocrine carcinomas. This approach indicated that the FBXW7 point mutation, without being accompanied by classical adenoma–carcinoma sequence mutations, such as APC, KRAS and TP53, likely occurs at a relatively high frequency in mixed neuroendocrine and squamous cell carcinoma and therefore may be characteristic for this rare tumour type. FBXW7 codifies the substrate recognition element of an ubiquitin ligase, and inactivating FBXW7 mutations lead to an exceptional accumulation of its target β‐catenin which results in overactivation of the Wnt‐signalling pathway. In line with previously described hypotheses of de‐differentiation of colon cells by enhanced Wnt‐signalling, our data indicate a crucial role for mutant FBXW7 in the unusual morphological switch that determines these rare neoplasms. Therefore, mixed large cell neuroendocrine and a squamous cell carcinoma can be considered as a distinct carcinoma entity in the colon, defined by morphology, immunophenotype and distinct molecular genetic alteration(s).\n\nneuroendocrine carcinomasquamous cell carcinomamutationsdistinct entityFBXW7colorectal cancer source-schema-version-number2.0cover-dateJanuary 2021details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.5 mode:remove_FC converted:15.12.2020No conflicts of interest were declared.\n==== Body\nIntroduction\nNeuroendocrine carcinomas of the colorectum are rare and highly aggressive tumours with poor clinical outcome. Their incidence is 0.1–0.6% [1, 2]. The percentage of pure squamous cell carcinoma among all colorectal carcinomas is even lower [3, 4]. Here we present two cases of mixed large cell neuroendocrine carcinoma and squamous cell carcinoma in the colon. Previously, only three cases with an identical histology were described in the caecum, rectum and the descending colon [5, 6, 7], but extensive immunohistochemical and molecular profiling was not performed. This is the first report of this rare type of carcinoma that also defines its typical molecular genetic features. Combined neuroendocrine and squamous cell carcinomas also occur in organs with original squamous epithelium, such as the maxillary sinus or the oesophagus [8, 9]. Such neoplasms biologically present tumour development via stages of increasing atypia. On the contrary, mixed neuroendocrine and squamous cell carcinomas in the colon represent a different kind of tumour emergence. In our opinion, these rare carcinomas might be the outcome of progressive malignant transformation of mixed neuroendocrine‐non‐neuroendocrine neoplasms (MiNENs), formerly termed mixed adenoneuroendocrine carcinomas (MANECs) [10]. In accordance with this hypothesis, single cases with an additional squamous carcinoma component are known among high‐grade MiNENs in the colorectum [11]. Alongside accurate morphological evaluation, molecular classification of colorectal cancers with high grade morphology, via immunohistochemistry of mismatch repair proteins and mutational analyses of BRAF and other genes, has proven essential to provide best guidance for patient treatment and therapeutic outcome. Hence, we carefully analysed the present lesions morphologically and immunohistochemically. In order to better understand the pathophysiological mechanisms underlying these rare neoplasms, we additionally applied next‐generation sequencing and compared the mutational results to data sets of classical colorectal adenocarcinoma as well as MiNEN and neuroendocrine carcinomas of the colorectum. Based on next‐generation panel sequencing data and immunohistochemical analyses, our data indicate that mixed neuroendocrine and squamous cell carcinoma may be a distinct new colon cancer entity.\n\nMaterials and methods\nTumour specimens, histology and immunohistochemistry\nThis study was conducted according to the recommendations of the ethics committee of the Medical Faculty of the Ludwig‐Maximilians‐University Munich, Germany and the standards set in the declaration of Helsinki 1975. Archival tissue from two formalin‐fixed and paraffin‐embedded (FFPE) cases of colorectal combined large cell neuroendocrine carcinoma and squamous cell carcinoma were accessed from the Institute of Pathology in Bayreuth as well as from a practice of pathology in Munich. The neoplasms were resected in 2014 (first case) and 2017 (second case). Sections of 5 μm were cut, deparaffinised and stained with H&E for histological preparation. For immunohistochemistry, sections were incubated with prediluted mouse anti‐β‐catenin (14, ready to use, Ventana), rabbit mouse anti‐CK5/6 (D5/16B4, ready to use, Ventana), mouse anti‐MSH‐2 (G219‐1129, ready to use, Ventana), rabbit anti‐MSH‐6 (SP93, ready to use, Ventana), mouse anti‐PMS‐2 (A16‐4, ready to use, Ventana), rabbit anti‐PDL‐1 (SP263, ready to use, Ventana), mouse anti‐CD56 (123C3, ready to use, Ventana), rabbit anti‐synaptophysin (MRQ‐40, ready to use, Ventana), mouse anti‐chromogranin A (LK2H10, ready to use, Ventana), mouse anti‐neuron‐specific enolase (NSE; BBS/NC/VI‐H14, 1:200, Dako, Santa Clara, CA, USA), rabbit anti‐CDX2 (EPR2764y, 1:50, Medac; Bio‐Genex), mouse anti‐MLH‐1 (ES05, 1:100, Leica, Wetzlar, Germany), rabbit anti‐NUT (C52B1, 1:75, Cell Signaling), mouse anti‐p63 (BC4A4, 1:100, Zytomed; Biocare Medical, Pacheco, CA, USA), mouse anti‐p40 (BC28, 1:100, Zytomed, Berlin, Germany), mouse anti‐TTF‐1 (8G7G3/1, 1:200, Agilent, Santa Clara, CA, USA), or mouse anti‐Ki67 antibody (MIB‐1, 1:150, Dako). For staining, a Ventana Benchmark XT autostainer was used. Detection was performed with either ultraView Universal DAB detection kits or optiView DAB IHC detection kits (Ventana Medical Systems, Tuscon, AZ, USA).\n\n\nDNA extraction and pyrosequencing\nTo identify tumour areas, we used sections stained with H&E, which were subsequently used as templates to isolate areas of the combined large cell neuroendocrine and squamous cell carcinoma under microscopic control from deparaffinised serial sections using sterile scalpel blades. Neuroendocrine and squamous components were not micro‐dissected separately. Tumour DNA was extracted with QIAamp DNA Micro Kits and GeneRead DNA FFPE Kits (Qiagen, Hilden, Germany) for consecutive analyses of KRAS, NRAS and BRAF V600E gene mutations as well as panel sequencing, respectively. The mutational status of KRAS exon 2–4, NRAS exon 2–4 and BRAF V600E was analysed by pyrosequencing on a PyroMark Q24 Advanced instrument (Qiagen), as previously described [12].\n\nPanel sequencing\nThe Ion AmpliSeq Cancer Hotspot Panel v2, covering the mutation hotspots of 50 oncogenes and tumour suppressor genes (Life Technologies, Calsbad, CA, USA), was used for next‐generation panel sequencing following the manufacturer's protocol. 10 ng of Qubit quantified DNA was used for library generation with Ion AmpliSeq Library Kits and Ion Xpress Barcode Adapters (Thermo Fisher, Calsbad, CA, USA). After emulsion PCR and bead purification, multiplexed libraries were then loaded onto 318 chips, and sequenced on an Ion Personal Genome Machine (all Thermo Fisher). For data analysis, sequence reads were mapped to human reference genome hg19 and filtered for non‐synonymous variants using Ion reporter software v5.0 (Thermo Fisher). Annotations, information on pathogenesis and population allele frequencies were retrieved from Ensembl VEP (www.ensembl.org/Homo_sapiens/Tools/VEP).\n\nResults\nCase presentations\nCase 1\nClinical data and pathological findings\nA 51 year old male patient with known ulcerative colitis presented with rectal bleeding and diarrhoea, leading to the diagnosis of a tumour in the sigmoid colon followed by complete surgical resection. The 8 cm large, ulcerated tumour caused luminal stenosis and infiltration of the entire wall into the surrounding adipose tissue. Histology revealed lymphangiosis carcinomatosa, venous invasion and three lymph node metastases. Resection margins were free of tumour cells. Samples showed no signs of ulcerative colitis.\n\nThe carcinoma showed a solid growth pattern without gland formation or mucin production. In central areas, the tumour cells exhibited distinct squamous differentiation, whereas large tumour cells in the marginal zone exhibited no specific differentiation. Profound atypia, high rates of apoptosis, and numerous atypical mitoses, with Ki‐67 labelling index up to 90%, were present. Immunohistochemistry revealed strong nuclear expression of CDX2 and β‐catenin in over 90% of tumour cells. Cells with squamous differentiation were positive for cytokeratin 5/6 and p63, whereas the large tumour cells without specific differentiation showed strong positivity for synaptophysin and neuron specific enolase (NSE). Morphological and immunhistochemical findings are shown in Figure 1 and supplementary material, Figure S1. All tumour cells were negative for CD56, chromogranin A, p40 and TTF‐1. To distinguish the lesion from NUT (nuclear protein in testis) midline carcinoma (NMC), we performed NUT immunohistochemistry, which was negative. Immunohistochemistry for hMLH1, hMSH2, hMSH6 and hPMS2 showed nuclear expression in all tumour cells, characterising the neoplasm as a microsatellite stable tumour. In summary, a mixed large cell neuroendocrine and squamous cell carcinoma of the sigmoid colon, pT3, pN1a (3/17), V1, L1, Pn0 was diagnosed.\n\nFigure 1 Morphological and immunohistochemical characteristics of the first case of colorectal combined large cell neuroendocrine carcinoma and squamous cell carcinoma pictured in overview (A) and close‐up view (B–H). Examples of neuroendocrine differentiation are shown by immunostaining for synaptophysin (accentuated in marginal areas; C). Tumour cells exhibit strong expression of β‐catenin (D). The squamous component is marked with a dotted line and foci of keratinisation are highlighted by arrows (E). The neoplasm shows intense staining of CDX2 (F). Examples of squamous differentiation as well as proliferation are shown by immunostaining for CK5/6 (accentuated in central areas; G) and Ki67 (H), respectively.\n\nWithin the following months of disease, distant metastasis to the liver and the abdominal wall occurred (pM1c [HEP, OTH]) resulting in a final UICC‐stage IVC. Therapy with three courses of panitumumab plus FOLFOX 6, two courses of cisplatin and etoposide and later four courses of bevacizumab and FOLFOXIRI was performed.\n\nMolecular pathology\nBecause of insufficient therapeutic response, immunohistochemistry for PDL1 and molecular genetic analysis were carried out. PDL1 expression was not detectable in carcinoma cells or in the surrounding stroma. No mutations were present in exons 2, 3 and 4 of the KRAS and NRAS genes and in exon 15 of the BRAF gene. Next‐generation sequencing analysis surveying hotspot regions of 50 oncogenes and tumour suppressor genes detected CTNNB1 (c.110C>G, p.Ser37Cys), PIK3CA (c.1173A>G, p.Ile391Met) and FBXW7 (c.1393C>T, p.Arg465Cys) mutations.\n\nFollow up\nThe tumour progressed rapidly under bevacizumab plus FOLFOXIRI therapy. Chemotherapy was changed to paclitaxel, carboplatin and palliative care. The patient died 1 year after initial diagnosis of the tumour.\n\nCase 2\nClinical data and pathological findings\nA 46 year old female patient without relevant pre‐existing conditions underwent colonoscopy due to diarrhoea with admixed blood. A tumour in the sigmoid colon was found and complete surgical resection performed. The resection specimen showed a 2.5 cm ulcerated tumour. Histology revealed a high‐grade carcinoma with solid growth devoid of glandular differentiation. The transmural infiltration involved the serosa. Five regional lymph node metastases were detected. Lymphangiosis carcinomatosa and venous invasion were present. Resection margins were free of tumour cells. PET‐CT scanning showed diffuse liver metastases.\n\nThe histology of the carcinoma exhibited clusters of squamous tumour cells showing immunohistochemical expression of cytokeratin 5/6, but not p63 or p40. A second tumour component showed solid and trabecular growth of large carcinoma cells with strong immunohistochemical expression of synaptophysin and CD56, but negativity for chromogranin A and NSE. All tumour cells exhibited strong cytoplasmic expression of nuclear β‐catenin and CDX2. The mitotic rate was high and the Ki‐67 proliferation index was 80% of tumour cells (Figure 2). No TTF‐1 and NUT expression was detectable by immunohistochemistry. Analysis of hMLH1, hMSH2, hMSH6 and hPMS2 showed nuclear expression in tumour cells. In summary, a mixed large cell neuroendocrine and squamous cell carcinoma of the sigmoid colon devoid of microsatellite instability was diagnosed. The following staging was reported: pT4a, pN2a (5/19), cM1a (HEP), L1, V1, Pn0, R0, UICC‐stage IVA.\n\nFigure 2 Morphological and immunohistochemical characteristics of the second case of colorectal combined large cell neuroendocrine carcinoma and squamous cell carcinoma pictured in overview (A) and close‐up view (B–H). Examples of neuroendocrine differentiation are shown by immunostaining for synaptophysin (accentuated in marginal areas; C). Tumour cells exhibit strong expression of β‐catenin (D). The squamous component is again marked with dotted lines (E). The overview shows intense staining of CDX2 in tumor and remaining normal colon mucosa (F; asterisk). Examples of squamous differentiation as well as proliferation are shown by immunostaining for CK5/6 (accentuated in central areas; G) and Ki67 (H), respectively.\n\nMolecular pathology\nNext‐generation sequencing analysis revealed a FBXW7 (c.1393C>T, p.Arg465Cys) point mutation, as was also true for the first analysed case. In addition, a RB1 (c.2284C>T, p.Gln762Ter) mutation was found. In contrast to the first case, no CTNNB1 and PIK3CA mutations were detected.\n\nFollow up\nIn accordance with standard guidelines and results from the NORDIC NEC study [13], therapy with five cycles of cisplatin and etoposide followed. Follow‐up PET‐CT scanning showed complete remission of liver metastasis. Three years later one new liver metastasis with strong immunohistochemical expression of NSE was successfully ablated by local brachytherapy.\n\nData set analyses\nGenomic data analysis on three publicly available colorectal adenocarcinoma cohort data sets was performed, employing the cBioPortal as a cancer genomics tool. The TCGA Nature 2012 Study, the updated TCGA Pan Cancer Atlas Study on CRC, and the MSKCC 2018 Cancer Cell Study for metastatic colorectal cancer [14, 15, 16, 17, 18] were screened for other cases with FBXW7, CTNNB, PIK3CA and RB1 mutations. Our search revealed 5–8% CTNNB1 mutations, 13–17% FBXW7 mutations, 20–28% PIK3CA mutations and 3–5% RB1 mutations, respectively. As expected, the classical adenoma–carcinoma sequence mutations, such as APC, KRAS and TP53, outnumber those findings by far (Table 1). In addition, we screened for significant co‐occurrences or mutual exclusivities between FBXW7, CTNNB1, PIK3CA and RB1 mutations in all three data sets, which mostly consist of classic adenocarcinoma cases, in order to explore possible mutational correlations that could potentially also occur in the scarce mixed neoplasms described here. Here again we included most common classical adenoma–carcinoma sequence mutations, such as APC, KRAS and TP53, for comparison. Referring to these, we detected significant co‐occurrence of APC and KRAS and APC and TP53 in two of three data sets. In addition, mutations in the genes coding for APC and CTNNB1 as well as TP53 and PIK3CA related to the classical adenoma–carcinoma sequence were found to be mutually exclusive. Importantly, significant co‐occurrence of FBXW7 and PIK3CA as well as FBXW7 and RB1 mutations, as was found in the scarce neoplasm type described here, was identified in two of the three data sets (Table 2). This points to functional importance of these two mutational interactions also in classical adenocarcinomas. To define similarities and differences between classical colorectal adenocarcinomas, mixed large cell neuroendocrine and squamous cell carcinomas of the colorectum, colorectal MANECs and pure colorectal neuroendocrine carcinomas, we compared frequencies of genetic alterations between those entities (Table 3). In the two cases of mixed large cell neuroendocrine and squamous cell carcinoma described here, and in contrast to MiNENs and classic adenocarcinomas, we noted the absence of APC, KRAS and TP53 mutations, as well as the occurrence of mutations in the FBXW7 gene in both tumours. The frequency of mutations in FBXW7 in particular was markedly lower (16–25%) in classic adenocarcinomas and MiNENs (Table 3), although we cannot exclude the existence of FBXW7 wild‐type, mixed neuroendocrine and squamous cell carcinoma cases from our case report on only two individuals affected by this very rare tumour type. Given that tissue images of colorectal carcinoma cases with FBWX7 mutation were available via cBioPortal within the TCGA Nature 2012 study, these were screened for unusual morphology, such as squamous or neuroendocrine differentiation. However, only two of the reviewed 35 cases showed a tendency toward neuroendocrine differentiation, and none of those had relevant morphological features which would have pointed towards squamous differentiation. Hence, other factors, such as the cell of tumour origin or epigenetic peculiarities might also be needed which, presumably in collaboration with mutant FBXW7, contribute to the occurrence of this very rare, mixed colorectal cancer entity.\n\nTable 1 Gene alteration frequencies in colorectal adenocarcinoma data sets.\n\nGenes\tTCGA Nature 2012 Study\tTCGA Pan Cancer Atlas Study\tMSKCC 2018 Cancer Cell Study\t\n\nAPC\n\t76\t75\t76\t\n\nCTNNB1\n\t5\t7\t8\t\n\nFBXW7\n\t17\t17\t13\t\n\nKRAS\n\t42\t42\t45\t\n\nPIK3CA\n\t20\t28\t20\t\n\nTP53\n\t53\t60\t73\t\n\nRB1\n\t3\t5\t3\t\nValues indicate the frequency of gene alterations (in percent) in three different data sets according to The Cancer Genome Atlas Program 2012 (TCGA, [16]), TCGA Pan Cancer Atlas Study [17] and Memorial Sloan Kettering Cancer Center Study (MSKCC, [18]). Classical adenoma–carcinoma sequence mutations, such as APC, KRAS and TP53, are highlighted in orange.\n\nTable 2 Co‐occurrences and mutual exclusivities of mutated genes in colorectal adenocarcinoma data sets.\n\n\tSignificant co‐occurrence\tSignificant mutual exclusivity\t\nMutated genes\tTCGA Nature 2012 Study\tTCGA Pan Cancer Atlas Study\tMSKCC 2018 Cancer Cell Study\tTCGA Nature 2012 Study\tTCGA Pan Cancer Atlas Study\tMSKCC 2018 Cancer Cell Study\t\n\nAPC and CTNNB1\n\t0\t0\t0\t0\t1 (0.014)\t1 (<0.001)\t\n\nAPC and KRAS\n\t0\t1 (<0.001)\t1 (0.014)\t0\t0\t0\t\n\nAPC and PIK3CA\n\t0\t0\t1 (0.019)\t0\t0\t0\t\n\nAPC and TP53\n\t0\t1 (<0.001)\t1 (0.022)\t0\t0\t0\t\n\nCTNNB1 and FBXW7\n\t0\t1 (<0.001)\t0\t0\t0\t0\t\n\nCTNNB1 and PIK3CA\n\t0\t1 (<0.001)\t0\t0\t0\t0\t\n\nCTNNB1 and RB1\n\t0\t1 (<0.001)\t0\t0\t0\t0\t\n\nFBXW7 and KRAS\n\t0\t0\t1 (0.001)\t0\t0\t0\t\n\nFBXW7 and PIK3CA\n\t0\t1 (0.012)\t1 (<0.001)\t0\t0\t0\t\n\nFBXW7 and TP53\n\t0\t0\t0\t0\t0\t1 (0.013)\t\n\nFBXW7 and RB1\n\t0\t1 (0.014)\t1 (0.001)\t0\t0\t0\t\n\nKRAS and PIK3CA\n\t1 (<0.001)\t1 (<0.001)\t1 (<0.001)\t0\t0\t0\t\n\nKRAS and TP53\n\t0\t0\t0\t0\t0\t1 (<0.001)\t\n\nPIK3CA and TP53\n\t0\t0\t0\t0\t1 (<0.001)\t1 (<0.001)\t\nValues indicate the existence (1) or non‐existence (0) of significant co‐occurrence, or significant mutual exclusivity between the listed mutated genes in three different data sets according to The Cancer Genome Atlas Program 2012 (TCGA, [16]), TCGA Pan Cancer Atlas Study [17] and Memorial Sloan Kettering Cancer Center Study (MSKCC, [18]). No significant finding is shown in red, significant correlation in one data set is marked in orange and significant findings in two or more data sets are highlighted in green. P values are indicated in parenthesis.\n\nTable 3 Mutations in colorectal neoplasms.\n\nEntity\tAC\tMiNEN\tMiNEN\tNEC\tNEC\tCombined large cell neuroendocrine carcinoma and squamous cell carcinoma\t\nSource\tTCGA, 2012\tWoischke et al, 2017\tJesinghaus et al, 2017\tWoischke et al, 2017\tJesinghaus et al, 2017\tPresent study\t\nNumber of cases\t269\t6\t19\t4\t8\t2\t\nMutations\t\t\t\t\t\t\t\nAKT1\t0\t0\t\t25\t\t0\t\nAPC\t61\t83\t16\t75\t63\t0\t\nATM\t4\t0\t14\t50\t\t0\t\nBRAF\t8\t16\t37\t25\t25\t0\t\nCTNNB1\t1\t\t\t\t\t(1 out of 2 cases)\t\nEGFR\t2\t16\t\t25\t\t0\t\nERBB4\t0\t0\t\t25\t\t0\t\nFBXW7\t12\t16\t16\t25\t\t(2 out of 2 cases)\t\nFGFR2\t0\t0\t\t25\t\t0\t\nFLT3\t5\t0\t\t25\t\t0\t\nGNAS\t0\t0\t\t25\t\t0\t\nHRAS\t0\t0\t\t25\t\t0\t\nIDH1\t0\t16\t\t0\t\t0\t\nIDH2\t1\t0\t\t25\t\t0\t\nJAK2\t1\t0\t\t25\t\t0\t\nKDR\t0\t16\t\t25\t\t0\t\nKRAS\t35\t83\t21\t100\t25\t0\t\nMET\t0\t33\t\t50\t\t0\t\nNOTCH1\t0\t33\t\t25\t\t0\t\nPIK3CA\t16\t50\t5\t25\t\t(1 out of 2 cases)\t\nPTEN\t5\t0\t11\t0\t\t0\t\nPTPN11\t1\t0\t\t25\t\t0\t\nRB1\t1\t16\t\t50\t\t(1 out of 2 cases)\t\nRET\t0\t33\t\t0\t\t0\t\nSMAD4\t10\t0\t5\t25\t\t0\t\nSMO\t0\t0\t\t25\t\t0\t\nTP53\t45\t100\t47\t75\t63\t0\t\nVHL\t0\t16\t\t25\t\t0\t\nFrequencies of genetic alterations (in percent) of colorectal adenocarcinomas (AC), MiNENs, neuroendocrine carcinomas (NEC) in three studies (The Cancer Genome Atlas Program 2012 (TCGA, [16]), Jesinghaus et al [48] and Woischke et al [47]) in comparison with the genetic alterations of the two cases of mixed large cell neuroendocrine carcinoma and squamous cell carcinoma. Regarding TCGA cases, only putative driver mutations are included. Frequencies are highlighted by a coloured scale ranging from 0% (yellow) to 100%, or out of two for the category of mixed large cell neuroendocrine carcinoma and squamous cell carcinoma (green).\n\nDiscussion\nIn this study, we analysed two mixed large cell neuroendocrine and squamous cell carcinomas of the colorectum by next‐generation sequencing and compared the results with data from three publicly available colorectal adenocarcinoma data sets, as well as from cohorts of colorectal MiNENs and colorectal neuroendocrine carcinomas. This approach revealed a shared FBXW7 mutation and a lack of classical adenoma–carcinoma sequence mutations in both of our cases. This is in contrast to classic adenocarcinomas and MiNENs and therefore represents a molecular signature, which, together with the unique morphological features, may distinguish mixed neuroendocrine carcinoma and squamous carcinoma of the colorectum from other colorectal cancer types. Neuroendocrine carcinomas of colorectal origin represent very rare but highly aggressive tumours with a poor prognosis [1, 2]. Nevertheless, pure squamous cell carcinomas have been reported at an even lower incidence [3, 4, 19]. Since the first pure squamous cell carcinoma in the colorectum was reported by Schmidtmann in 1919 [20], profound literature research provided only 75 more cases to date, stating this neoplasm as extremely rare, with frequencies of 0.1–0.25% of all colorectal carcinomas [3, 4, 19]. Possible causes for this squamous colonic carcinoma are chronic inflammation in the context of ulcerative colitis, schistosomiasis, human papillomavirus infection, abdominal sinus or fistula, or pelvic radiation [4, 21]. Associations between neuroendocrine carcinomas or MiNEN of the colon and ulcerative colitis, as seen in case 1, are sporadically reported [22, 23]. The combination of the two neoplasm types in the colorectal region is highly exceptional and so far very little is known about the underlying mutational landscape of such combined carcinomas. In accordance with the new World Health Organization Classification from 2019, mixed large cell neuroendocrine carcinoma and squamous cell carcinoma in the colorectum is subsumed under the category of MiNENs, formerly named MANECs, in which each component accounts for ≥30% of the neoplasm [24]. Although three case reports of mixed neuroendocrine carcinoma and squamous cell carcinoma of the colorectum in literature do exist [5, 6, 7], only one of those has been assessed for microsatellite stability. In addition, one study examined the mutational status of KRAS and BRAF [5]. However, none of these cases has been analysed regarding its underlying genetic background via next‐generation sequencing. Thus, we performed for the first time next‐generation sequencing‐based multigene panel analysis of mixed large cell neuroendocrine carcinoma and squamous cell carcinoma of the colon.\n\nOur two cases contain several remarkable similarities. One is the striking morphology, showing squamous carcinoma cells in central areas and poorly differentiated large cell neuroendocrine carcinoma in marginal areas, each component accounting for >30% of the tumour. The squamous cell differentiation was demonstrated not only by morphological features, such as intercellular bridges and focal keratinisation, but also by immunohistochemical expression of cytokeratin 5/6 and/or p63, with p63 being positive only in case 1. Cytokeratin 5/6 shows a sensitivity of 84% and a specificity of 79% in the diagnosis of squamous cell carcinoma, and p63 exhibits similar diagnostic performance, with a sensitivity of 81–84% and specificity of 85% [25, 26]. Neuroendocrine differentiation was confirmed by strong immunohistochemical positivity for synaptophysin, which has been approved as the best single marker for neuroendocrine tumours [27]. In accordance with one previous study, we found remarkably strong nuclear expression of CDX2 and β‐catenin in over 90% of tumour cells of both carcinoma cases as well as in both components (neuroendocrine and squamous) of the tumours [7]. The high nuclear abundance of β‐catenin detected here in large cell neuroendocrine carcinomas is very exceptional, but has been reported previously [11]. Besides clinical and morphological aspects, the strong nuclear CDX2 expression detected in the vast majority of carcinoma cells indicates the colon as the primary origin of the lesion, since CDX2 is known as a reliable marker for cancers of intestinal origin [28]. Despite the young age of the patients, both carcinomas were microsatellite stable (MSS), excluding Lynch syndrome.\n\nIn one of the cases, we identified a CTNNB1 mutation, which is a key factor in the Wnt signalling pathway and well described in the development of colorectal carcinomas [29, 30]. In one of our cases, there was a mutation in the tumour suppressor gene RB1, which are present in 5.8% of all colorectal cancers (14, 15). To date, no statistically significant impact of RB1 gene mutations on patient prognosis in colorectal cancer has been shown [31]. In addition to CTNNB1 and RB1, a PIK3CA mutation was found in one of the two neoplasms. Mutations in PIK3CA can be detected in various cancer types and have been associated with more aggressive metastatic behaviour in colorectal cancer [32]. However the PIK3CA (c.1173A>G, p.Ile391Met) mutation found here was a variant of uncertain significance (VUS) at the time of diagnosis but is now considered benign [33]. Through analyses of PIK3CA mutations in three colorectal carcinoma data sets we detected a significant co‐occurrence of PIK3CA and KRAS, which supports previous findings on that correlation [34].\n\nThe most important common feature of the two cases is the FBXW7 point mutation c.1393C>T(p.Arg465Cys). The FBXW7 gene codes for the substrate recognition component of a SCF (SKP1‐CUL1‐F‐box protein) E3 ubiquitin–protein ligase complex, which functions as an ubiquitin ligase marking several dominant oncogenic proteins, including c‐myc, cyclin E, notch and β‐catenin for ubiquitin mediated proteasomal degradation [35, 36]. Loss of function FBXW7 mutations, like the R465C gene variant described here, occur in approximately 11% of colorectal cancers [37]. Mono‐allelic missense alterations, which affect crucial arginine residues, have been reported to be the most common mutant genotypes, even though bi‐allelic inactivation mutations occur [38]. In 2017, Korphaisarn et al showed data suggesting a greater emphasis of FBXW7 missense mutation in comparison to other gene aberrations for patient outcome, linking these mutations, like those found in the above presented two cases, with a strong negative prognostic association [39]. Additional to its role as a key player in maintaining the balance between stem cell resting state and self‐regeneration [40], FBXW7 is a known regulator of Wnt/β‐catenin signalling in pancreatic cancer [41]. Although the latter has not yet been shown in colorectal cancer cells, the concept of FBXW7 controlling Wnt/β‐catenin signalling in colorectal cancer seems plausible, as a correlation between FBXW7 status and Wnt/β‐catenin signalling has been demonstrated in various cancer types [41, 42, 43]. Therefore, we suppose that the detected FBXW7 mutation resulted in malfunctioning of β‐catenin depletion with subsequent β‐catenin accumulation in the nucleus, leading to extreme overactivation of Wnt‐signalling. Due to this excessive activation of the Wnt/β‐catenin pathway, tumour cells in the colon may gain a pronounced plasticity, which may cause the critical switch towards this special combined morphology. Consistent with this hypothesis, de‐differentiation of colon cells by soluble Wnt‐ligand was recently shown by others [44]. Furthermore studies indicated the induction of squamous transdifferentiation through activation of β‐catenin signalling in various tissues [45]. Additionally, this hypothesis is supported by the findings of Davis et al, who showed reinforced Wnt‐signalling through FBXW7 propeller tip mutation and hence a driven tumorigenesis in mouse models [46]. Notably, the R465 gene variant found in our two cases also represents a propeller tip mutation.\n\nOf note, Wnt activating mutations in FBXW7 and CTNNB1 are not restricted to the rare colorectal cancer type identified here, but also occur in classical adenocarcinoma. However, it is widely accepted that the intestinal epithelial cell subtype of cancer origin has a major influence on ultimate tumour characteristics. In neuroendocrine tumours, these cells are most likely represented by neural crest‐derived, precursor (entero)endocrine cells [47]. Different subtypes of these secretory precursor cells localise close to the crypt base, show mixed expression of secretory and bona‐fide intestinal stem cell markers, and possess a high degree of plasticity when confronted by regenerative signals, such as pathway Wnt activation [48, 49]. Importantly, a study by Wang et al revealed that aberrant Wnt activation at an early stage of neurogenin three‐dependent enteroendocrine cell differentiation induces small intestinal adenomas positive for serotonin expression in mice [50]. Given the low frequency of enteroendocrine cells (1–2%), and the short lifespan of their early precursors, this might explain the rare occurrence of neuroendocrine tumours, and the mixed neuroendocrine and squamous cell carcinomas described here, in colorectal cancer patients. Future studies on animal models should clarify if the propeller mutation in FBXW7 alone or in combination with alterations in RB1 or CTNNB1, when occurring in distinct (neuro)endocrine precursor cells of the adult colon, gives rise to the mixed cancer type characterised in our study.\n\nIn summary, these data seem to be a first important hint for the tumorigenesis of the mixed neuroendocrine and squamous carcinoma subtype. The underlying FBXW7 mutation might be the connecting element and the trigger for the crucial morphological switch, via overactivation of the canonical Wnt/β‐catenin signalling pathway. Its special relevance is also highlighted by the fact that it appears to reveal co‐occurrence with two mutations, specifically RB1 and PIK3CA, which were also detected in the presented cases. Other genes related to neuroendocrine differentiation, like ASCL1, may also play a role in the development of the neuroendocrine component, especially since ASCL1 is involved in the Notch‐Hes1 axis, which is analogous to the Wnt‐beta catenin signalling pathway, altered by the FBXW7 mutation [51, 52, 53]. Our findings may expedite the understanding of combined tumour development in the colon and in addition help establish awareness for such rare neoplasms, although continuing research, especially with regard to divergent differentiation of neuroendocrine‐ and squamous‐related genes, is necessary to fully decode the development of this combined neoplasm.\n\nIn the past, we and others provided evidence that MiNEN do have a monoclonal origin and are not stochastically neighbouring tumours [54, 55]. Furthermore, we found key mutations such as KRAS, TP53 and APC in both tumour components of MiNEN, which indicated a tumour progression similar to the well‐known classical adenoma–carcinoma sequence of colorectal adenocarcinomas [54]. We assume that the large cell neuroendocrine carcinoma, after originating from an adenoma or an adenocarcinoma, developed squamous structures via transdifferentiating processes and hence resulted in a combined large cell neuroendocrine carcinoma and squamous cell carcinoma, in which the original glandular component vanished or was no longer detectable. Interestingly, the initial colon biopsy of the first case showed parts of an ulcerated carcinoma in addition to colon mucosa with distinct serrated morphology, which supports this hypothesis. A different option in the development of the combined morphology, such as chemotherapy‐induced transdifferentiation, as reported in lung cancer, has to be considered as well [56]. However, in our cases chemotherapy took place after the microscopic characterisation of the resected specimen was completed and thus a chemotherapy‐induced switch resulting in the combined morphology seems unlikely.\n\nIn conclusion, a mixed large cell neuroendocrine carcinoma and squamous cell carcinoma of the colon can occur, even if it is extremely rare. Furthermore, we provide the histological and genetic evidence for a primary origin of this combined carcinoma in the colon and our data indicate that tumour development might occur via FBXW7 mutation‐triggered tumorigenesis, and very intensive Wnt‐signalling pathway enhancement. In combination with the absence of classical mutations of the adenoma–carcinoma sequence, as well as the notable morphology, this could be a first hint toward a distinct entity and novel subtype of colorectal carcinoma.\n\nAuthor contributions statement\nCW conceived and carried out experiments, drafted the article and contributed substantially to conception and design of the study and interpretation of data. TK and JN contributed substantially to conception of the study and interpretation of data and revised the article critically for important intellectual content. PJ, AJ, JK, SE, CJA and MV carried out experiments, analysed data and revised the article critically. All authors were involved in writing the paper and had final approval of the submitted and published versions.\n\nSupporting information\n\nFigure S1. Morphological characteristics from case 1 in close‐up view\n\nClick here for additional data file.\n\n Acknowledgement\nWe thank G Charell and J Kövi for excellent technical assistance. Open access funding enabled and organized by Projekt DEAL.\n==== Refs\nReferences\n1 \n\nBernick \nPE \n, \nKlimstra \nDS \n, \nShia \nJ \n, et al\nNeuroendocrine carcinomas of the colon and rectum\n. Dis Colon Rectum \n2004 ; 47: \n163 –169\n.15043285 \n2 \n\nLai \nCC \n, \nWang \nCW \n, \nChang \nC \n, et al\nNeuroendocrine carcinomas of the colon and rectum: result of a 15‐year experience\n. J Soc Colon Rectal Surgeon (Taiwan) \n2008 ; 19: \n87 –95\n.\n3 \n\nFrizelle \nFA \n, \nHobday \nKS \n, \nBatts \nKP \n, et al\nAdenosquamous and squamous carcinoma of the colon and upper rectum: a clinical and histopathologic study\n. 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"fulltext_license": "CC BY-NC",
"issn_linking": "2056-4538",
"issue": "7(1)",
"journal": "The journal of pathology. Clinical research",
"keywords": "FBXW7; colorectal cancer; distinct entity; mutations; neuroendocrine carcinoma; squamous cell carcinoma",
"medline_ta": "J Pathol Clin Res",
"mesh_terms": "D014408:Biomarkers, Tumor; D018287:Carcinoma, Large Cell; D018278:Carcinoma, Neuroendocrine; D002294:Carcinoma, Squamous Cell; D003110:Colonic Neoplasms; D000073979:F-Box-WD Repeat-Containing Protein 7; D017809:Fatal Outcome; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D018193:Neoplasms, Complex and Mixed; D010641:Phenotype; D016896:Treatment Outcome",
"nlm_unique_id": "101658534",
"other_id": null,
"pages": "75-85",
"pmc": null,
"pmid": "33197299",
"pubdate": "2021-01",
"publication_types": "D002363:Case Reports; D013485:Research Support, Non-U.S. Gov't",
"references": "27543871;17081971;22967994;23676439;28059096;27485116;26912724;19379690;22588877;26602384;26979497;17592150;27325016;26212098;22052063;23000963;21088235;22323043;31279236;24327102;24885062;27586204;12359204;25314076;15043285;28938699;11773619;30098710;21274559;31443481;29361862;30085060;28424412;11289278;22810696;22293787;25465645;3278968;16119980;29625048;24240071;23550210;32440349;30999935;22157894;29316426;24817981;27358379;11764070;18451101;15498494;26755357;21107086",
"title": "Mixed large cell neuroendocrine carcinoma and squamous cell carcinoma of the colon: detailed molecular characterisation of two cases indicates a distinct colorectal cancer entity.",
"title_normalized": "mixed large cell neuroendocrine carcinoma and squamous cell carcinoma of the colon detailed molecular characterisation of two cases indicates a distinct colorectal cancer entity"
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"abstract": "Malignant ovarian germ cell tumors are rare tumors, affecting young women with a generally favorable prognosis. The French reference network for Rare Malignant Gynecological Tumors (TMRG) aims to improve their management. The purpose of this study is to report clinicopathological features and long-term outcomes, to explore prognostic parameters and to help in considering adjuvant strategy for stage I patients.\n\n\n\nData from patients with MOGCT registered among 13 of the largest centers of the TMRG network were analyzed. We report clinicopathological features, estimated 5-year event-free survival (5y-EFS) and 5-year overall survival (5y-OS) of MOGCT patients.\n\n\n\nWe collected data from 147 patients including 101 (68.7%) FIGO stage I patients. Histology identifies 40 dysgerminomas, 52 immature teratomas, 32 yolk sac tumors, 2 choriocarcinomas and 21 mixed tumors. Surgery was performed in 140 (95.2%) patients and 106 (72.1%) received first line chemotherapy. Twenty-two stage I patients did not receive chemotherapy. Relapse occurred in 24 patients: 13 were exclusively treated with upfront surgery and 11 received surgery and chemotherapy. 5y-EFS was 82% and 5y-OS was 92.4%. Stage I patients who underwent surgery alone had an estimated 5y-EFS of 54.6% and patients receiving adjuvant chemotherapy 94.4% (P < .001). However, no impact on estimated 5y-OS was observed: 96.3% versus 97.8% respectively (P = .62). FIGO stage, complete primary surgery and post-operative alpha fetoprotein level significantly correlated with survival.\n\n\n\nAdjuvant chemotherapy does not seem to improve survival in stage I patients. Active surveillance can be proposed for selected patients with a complete surgical staging.",
"affiliations": "Medical Oncology Department, Centre Hospitaliser Yves Le Foll, Saint Brieuc, France.;Medical Oncology Department, Institut Bergonié, Bordeaux, France.;Medical Oncology Department, CARIO, Plérin, France.;Medical Oncology Department, Centre Eugène Marquis, Rennes, France.;Medical Oncology Department, Sorbonne University, APHP, Paris, France.;Medical Oncology Department, Hôpital Cochin, APHP, Paris, France.;Medical Oncology Department, Institut Gustave Roussy, Villejuif, France.;Surgical Oncology Department, Institut Claudius Regaud, Toulouse, France.;Medical Oncology Department, Hôpital Européen Georges Pompidou, APHP, Paris, France.;Medical Oncology Department, Centre Eugène Marquis, Rennes, France.;Medical Oncology Department, Centre Hospitalier Universitaire Bretonneau, Tours, France.;Medical Oncology Department, Centre Léon Bérard, Lyon, France.;Medical Oncology Department, Institut de Cancérologie de l'Ouest, Angers, France.;Gynecology Department, Centre Hospitalier Universitaire, Rennes, France.;Medical Oncology Department, Centre Hospitalier Régional Universitaire, Besançon, France.;Medical Oncology Department, Institut de Cancérologie de l'Ouest, Nantes, France.;Diaconnesses Hospital Group, Paris, France.;Gynecology Department, CHU de Poitiers, Poitiers, France.;Medical Oncology Department, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.;Medical Oncology Department, Centre François Baclesse, Caen, France.;Medical Oncology Department, Centre Henri-Becquerel, Rouen, France.;Medical Oncology Department, Centre Jean Perrin, Clermont-Ferrand, France.;Medical Oncology Department, Centre Georges François Leclerc, Dijon, France.;Medical Oncology Department, Centre Oscar Lambret, Lille, France.;Medical Oncology Department, CHU Dupuytren, Limoges, France.;Medical Oncology Department, Institut Paoli Calmettes, Marseille, France.;Medical Oncology Department, Institut régional du Cancer Montpellier, Montpellier, France.;Medical Oncology Department, Institut de Cancérologie de Lorraine - Alexis Vautrin, Vandoeuvre-Les-Nancy, France.;Medical Oncology Department, Hôpital Privé du Confluent, Nantes, France.;Medical Oncology Department, Hôpital Européen Georges Pompidou, APHP, Paris, France.;Medical Oncology Department, Centre Léon Bérard, Lyon, France.;Medical Oncology Department, Centre Eugène Marquis, Rennes, France. Electronic address: thibault.delamotterouge@rennes.unicancer.fr.",
"authors": "Derquin|F|F|;Floquet|A|A|;Hardy-Bessard|A C|AC|;Edeline|J|J|;Lotz|J P|JP|;Alexandre|J|J|;Pautier|P|P|;Angeles|M A|MA|;Delanoy|N|N|;Lefeuvre-Plesse|C|C|;Cancel|M|M|;Treilleux|I|I|;Augereau|P|P|;Lavoue|V|V|;Kalbacher|E|E|;Berton Rigaud|D|D|;Selle|F|F|;Nadeau|C|C|;Gantzer|J|J|;Joly|F|F|;Guillemet|C|C|;Pomel|C|C|;Favier|L|L|;Abdeddaim|C|C|;Venat-Bouvet|L|L|;Provansal|M|M|;Fabbro|M|M|;Kaminsky|M C|MC|;Lortholary|A|A|;Lecuru|F|F|;Coquard|I Ray|IR|;de La Motte Rouge|T|T|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ygyno.2020.06.491",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0090-8258",
"issue": "158(3)",
"journal": "Gynecologic oncology",
"keywords": "Prognostic factors; Rare malignant ovarian tumors; Stage I; TMRG",
"medline_ta": "Gynecol Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D002822:Choriocarcinoma; D004407:Dysgerminoma; D018240:Endodermal Sinus Tumor; D005260:Female; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D009373:Neoplasms, Germ Cell and Embryonal; D010051:Ovarian Neoplasms; D011379:Prognosis; D012189:Retrospective Studies; D013724:Teratoma; D057832:Watchful Waiting; D055815:Young Adult",
"nlm_unique_id": "0365304",
"other_id": null,
"pages": "666-672",
"pmc": null,
"pmid": "32624235",
"pubdate": "2020-09",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Need for risk-adapted therapy for malignant ovarian germ cell tumors: A large multicenter analysis of germ cell tumors' patients from French TMRG network.",
"title_normalized": "need for risk adapted therapy for malignant ovarian germ cell tumors a large multicenter analysis of germ cell tumors patients from french tmrg network"
} | [
{
"companynumb": "FR-TEVA-2020-FR-1837380",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BLEOMYCIN SULFATE"
},
"drugadditional": null,
... |
{
"abstract": "Cardiotoxicity (CDT) is the main adverse effect related to trastuzumab (TTZ). The role of the right ventricle (RV) in this context is not clear. We aimed to evaluate the longitudinal changes in RV function during TTZ therapy and to determine RV function changes associated with subclinical CDT. Breast cancer patients underwent echocardiograms at the beginning of TTZ treatment (Exam 1) and every 3 months during the first year (Exams 2, 3, and 4). Subclinical CDT was defined as ≥ 12% relative reduction of left ventricle global longitudinal strain (LV GLS). Twenty-five women (52.1 ± 13.1 y-o) were included. We found a decrease in LV ejection fraction between the first and fourth exams (Ex1: 64.1% ± 4.9 vs Ex4: 60.9% ± 4.9, p = 0.003) and the LV GLS gradually decreased during follow-up (Ex1: - 20.6% ± 2.0; Ex2: - 19.4% ± 2.1; Ex3: - 19.2% ± 1.8; Ex4: - 19.0% ± 2.1, all p < 0.05). RV GLS changed from baseline to 3 month and to 6 month (Ex1: - 23.9% ± 1.6; Ex2: - 22.5% ± 2.1; Ex3: - 22.5% ± 2.3, all p < 0.05), and the RV Fractional Area Change was lower in the third exam (Ex1: 44.3% ± 6.6 vs Ex3: 39.9% ± 6.0, p = 0.004). We found subclinical CDT in 13 patients (52%); worsening in RV parameters did not differ between those with and without subclinical CDT. In this sample, the RV function decreased during TTZ therapy and the decrease was not associated to the observed LV cardiotoxicity.",
"affiliations": "Cardiology Division, Hospital de Clínicas de Porto Alegre (HCPA), Rua Ramiro Barcelos, 2350, Room 2061, Porto Alegre, RS, 90035-903, Brazil. gmazzutti@hcpa.edu.br.;Post-Graduate Program in Cardiology and Cardiovascular Sciences, Medical School, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.;Medical School, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.;Cardiology Division, Hospital de Clínicas de Porto Alegre (HCPA), Rua Ramiro Barcelos, 2350, Room 2061, Porto Alegre, RS, 90035-903, Brazil.;Cardiology Division, Hospital de Clínicas de Porto Alegre (HCPA), Rua Ramiro Barcelos, 2350, Room 2061, Porto Alegre, RS, 90035-903, Brazil.;Cardiology Division, Hospital de Clínicas de Porto Alegre (HCPA), Rua Ramiro Barcelos, 2350, Room 2061, Porto Alegre, RS, 90035-903, Brazil.",
"authors": "Mazzutti|Géris|G|http://orcid.org/0000-0002-9521-5017;Pivatto Júnior|Fernando|F|;Costa|Guilherme Oliveira Magalhães|GOM|;Foppa|Murilo|M|;Biolo|Andreia|A|;Santos|Angela Barreto Santiago|ABS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s10554-021-02470-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1569-5794",
"issue": null,
"journal": "The international journal of cardiovascular imaging",
"keywords": "Breast cancer; Cardiotoxicity; Myocardial strain; Right ventricular; Trastuzumab",
"medline_ta": "Int J Cardiovasc Imaging",
"mesh_terms": null,
"nlm_unique_id": "100969716",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34783929",
"pubdate": "2021-11-16",
"publication_types": "D016428:Journal Article",
"references": "27253694;32893704;23158536;16236737;28191909;22736713;22744937;27713603;24090744;33220426;34709307;28381081;32620556;26339242;30811091;24703918;28497844;27344413;18378625;31165940",
"title": "Right ventricular function during trastuzumab therapy for breast cancer.",
"title_normalized": "right ventricular function during trastuzumab therapy for breast cancer"
} | [
{
"companynumb": "BR-ROCHE-2962819",
"fulfillexpeditecriteria": "1",
"occurcountry": null,
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRASTUZUMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "The development of acute abdominal pain in a laboring parturient after a previous cesarean delivery is of concern and may be the result of a potentially life-threatening condition such as uterine rupture. We present a case of a parturient with type II diabetes mellitus, who had undergone 2 previous cesarean deliveries and now presented in labor with increasing abdominal pain. An emergency cesarean delivery was performed for probable uterine rupture. Intraoperatively, the patient was noted to be severely hypocarbic with significant metabolic acidosis, and the diagnosis of diabetic ketoacidosis was established.",
"affiliations": "From the Department of Anesthesiology, Geisinger Medical Center, Danville, Pennsylvania.",
"authors": "Cardonell|Bradford L|BL|;Marks|Barry A|BA|;Entrup|Michael H|MH|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000000290",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2325-7237",
"issue": "6(8)",
"journal": "A & A case reports",
"keywords": null,
"medline_ta": "A A Case Rep",
"mesh_terms": "D015746:Abdominal Pain; D002585:Cesarean Section; D003924:Diabetes Mellitus, Type 2; D016883:Diabetic Ketoacidosis; D005260:Female; D006801:Humans; D011247:Pregnancy; D014597:Uterine Rupture; D055815:Young Adult",
"nlm_unique_id": "101637720",
"other_id": null,
"pages": "228-9",
"pmc": null,
"pmid": "26825994",
"pubdate": "2016-04-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Normoglycemic Diabetic Ketoacidosis in a Pregnant Patient with Type II Diabetes Mellitus Presenting for Emergent Cesarean Delivery.",
"title_normalized": "normoglycemic diabetic ketoacidosis in a pregnant patient with type ii diabetes mellitus presenting for emergent cesarean delivery"
} | [
{
"companynumb": "US-JNJFOC-20160528728",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nPsoriasis affects a considerable proportion of women in their reproductive years. Limited published data exist about the possible negative impact of the disease itself in the prognosis of pregnancy. On this background, the emergence of newer biologic agents for psoriasis treatment - such as ustekinumab - raises safety issues concerning the exposure to the drug during pregnancy. To our knowledge this is the first report in the literature describing a pregnancy outcome under ustekinumab treatment.\n\n\nMETHODS\nWe report a 35-year-old female psoriasis patient who was under treatment with ustekinumab for a year when she inadvertedly became pregnant. The drug was discontinued immediately and the patient did not opt for termination. During the 12th week of gestation she experienced a spontaneous abortion.\n\n\nCONCLUSIONS\nAlthough the patient's profile fulfilled 2 general risk factors for spontaneous abortion - she was a smoker and this was her third pregnancy - one could not underestimate the possible role of the drug and of psoriasis per se in this adverse pregnancy outcome. Pregnancy registries and large prospective studies are needed in order to determine whether poorer pregnancies outcomes in psoriatic women are due to the disease itself, associated comorbidities or side-effects of new therapies such as ustekinumab.",
"affiliations": "First Department of Dermatology-Venereology, Aristotle University Medical School, Thessaloniki, Greece.",
"authors": "Fotiadou|Christina|C|;Lazaridou|Elizabeth|E|;Sotiriou|Eleni|E|;Ioannides|Demetrios|D|",
"chemical_list": null,
"country": "Poland",
"delete": false,
"doi": "10.3315/jdcr.2012.1116",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1898-7249",
"issue": "6(4)",
"journal": "Journal of dermatological case reports",
"keywords": "abortion; biologic agents; pregnancy outcomes; psoriasis; ustekinumab",
"medline_ta": "J Dermatol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101493700",
"other_id": null,
"pages": "105-7",
"pmc": null,
"pmid": "23329988",
"pubdate": "2012-12-31",
"publication_types": "D002363:Case Reports",
"references": "20970879;17191045;21108670;18486739;20540088;12730473;12850341;19437229;3393170;21362710;20545678;18441722;16129937",
"title": "Spontaneous abortion during ustekinumab therapy.",
"title_normalized": "spontaneous abortion during ustekinumab therapy"
} | [
{
"companynumb": "GR-JNJFOC-20130112802",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "USTEKINUMAB"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nSecondary plasma cell leukemia (sPCL) patients typically are either refractory to conventional therapies or have short remissions to drug regimens used in multiple myeloma (MM), which highlights sPCL's aggressive nature and association with advanced stage disease. t(11,14) is correlated with increased BCL-2 expression, which makes it a cytogenic marker of interest for use of the BCL-2 inhibitor venetoclax. Little data of venetoclax's use has been published in plasma cell leukemia. We present a case of a refractory/relapsed sPCL patient displaying t(11,14) who achieved a very good partial response (VGPR) from venetoclax therapy in combination with dexamethasone and bortezomib.\n\n\nMETHODS\nOur case describes a 67-year-old male initially diagnosed with IgG kappa MM in 2013, which transformed into non-secretory secondary plasma cell leukemia. Over a two-year period, despite responses to various therapies, the patient continued to experience relapses and exhausted options of novel agents seen in MM treatment. The patient was started on venetoclax in combination with bortezomib and oral dexamethasone.\nDue to the patient's disease transformation into a non-secretory form of sPCL, PET/CT scans were relied upon to monitor disease progression. The PET/CT scan after three months of venetoclax combination treatment showed a very good partial response to therapy, with near resolution of metabolically active osseous disease.\n\n\nCONCLUSIONS\nThe success of venetoclax-based therapy in achieving a very good partial response suggests its utility in relapsed/refractory sPCL patients, who have exhausted various combinations of drug regimens used in treatment of MM and have historically poor survival outcomes.",
"affiliations": "Hematology/Oncology Pharmacy Division, University of Washington Medicine, Seattle, WA, USA.;Hematology/Oncology Pharmacy Division, Levine Cancer Institute, Charlotte, NC, USA.;Plasma Cell Disorders, Levine Cancer Institute, Charlotte, NC, USA.",
"authors": "Kupsh|Allison|A|https://orcid.org/0000-0001-6120-614X;Arnall|Justin|J|;Voorhees|Peter|P|",
"chemical_list": "D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D013449:Sulfonamides; D000069286:Bortezomib; D003907:Dexamethasone; C579720:venetoclax",
"country": "England",
"delete": false,
"doi": "10.1177/1078155219895072",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "26(5)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Multiple myeloma; secondary plasma cell leukemia; venetoclax",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069286:Bortezomib; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003907:Dexamethasone; D006801:Humans; D007952:Leukemia, Plasma Cell; D008297:Male; D000072078:Positron Emission Tomography Computed Tomography; D012008:Recurrence; D013449:Sulfonamides; D016896:Treatment Outcome",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "1274-1278",
"pmc": null,
"pmid": "31865846",
"pubdate": "2020-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A successful case of venetoclax-based therapy in relapsed/refractory secondary plasma cell leukemia.",
"title_normalized": "a successful case of venetoclax based therapy in relapsed refractory secondary plasma cell leukemia"
} | [
{
"companynumb": "US-AMGEN-USASP2020117287",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARFILZOMIB"
},
"drugadditional": "3",
... |
{
"abstract": "Ectopic ACTH syndrome (EAS) accounts for 10-20% of endogenous Cushing's syndrome (CS). Hardly any cases of adrenal medullary hyperplasia have been reported to ectopically secrete adrenocorticotropic hormone (ACTH). Here we describe a series of three patients with hypercortisolism secondary to ectopic production of ACTH from adrenal medulla. Cushingoid features were absent in case 1 but evident in the other two cases. Marked hypokalemia was found in all three patients, but hyperglycemia and osteoporosis were present only in case 2. All three patients showed significantly elevated serum cortisol and 24-h urinary cortisol levels. The ACTH levels ranged from 19.8 to 103.0pmol/L, favoring ACTH-dependent Cushing's syndrome. Results of bilateral inferior petrosal sinus sampling (BIPSS) for case 1 and case 3 confirmed ectopic origin of ACTH. The extremely high level of ACTH and failure to suppress cortisol with high dose dexamethasone suppression test (HDDST) suggested EAS for patient 2. However, image studies failed to identify the source of ACTH secretion. Bilateral adrenalectomy was performed for rapid control of hypercortisolism. After surgery, cushingoid features gradually disappeared for case 2 and case 3. Blood pressure, blood glucose and potassium levels returned to normal ranges without medication for case 2. The level of serum potassium also normalized without any supplementation for case 1 and case 3. The ACTH levels of all three patients significantly decreased 3-6 months after surgery. Histopathology revealed bilateral adrenal medullary hyperplasia and immunostaining showed positive ACTH staining located in adrenal medulla cells. In summary, our case series reveals the adrenal medulla to be a site of ectopic ACTH secretion. Adrenal medulla-originated EAS makes the differential diagnosis of ACTH-dependent Cushing's syndrome much more difficult. Control of the hypercortisolism is mandatory for such patients.",
"affiliations": "Department of Endocrinology, Chinese PLA General Hospital, Beijing, China.;Department of Pathology, Chinese PLA General Hospital, Beijing, China.;Department of Endocrinology, Chinese PLA General Hospital, Beijing, China.;Department of Endocrinology, Chinese PLA General Hospital, Beijing, China.;Department of Endocrinology, Chinese PLA General Hospital, Beijing, China.;Department of Endocrinology, Chinese PLA General Hospital, Beijing, China.;Department of Endocrinology, Chinese PLA General Hospital, Beijing, China.;Department of Endocrinology, Chinese PLA General Hospital, Beijing, China.;Department of Endocrinology, Chinese PLA General Hospital, Beijing, China.",
"authors": "Cheng|Yu|Y|;Li|Jie|J|;Dou|Jingtao|J|;Ba|Jianming|J|;Du|Jin|J|;Zhang|Saichun|S|;Mu|Yiming|Y|;Lv|Zhaohui|Z|;Gu|Weijun|W|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fendo.2021.687809",
"fulltext": "\n==== Front\nFront Endocrinol (Lausanne)\nFront Endocrinol (Lausanne)\nFront. Endocrinol.\nFrontiers in Endocrinology\n1664-2392\nFrontiers Media S.A.\n\n10.3389/fendo.2021.687809\nEndocrinology\nCase Report\nCase Report: Three Rare Cases of Ectopic ACTH Syndrome Caused by Adrenal Medullary Hyperplasia\nCheng Yu 1 †\nLi Jie 2 †\n\nDou Jingtao 1\n\nBa Jianming 1\nDu Jin 1\nZhang Saichun 1\nMu Yiming 1 *\n\nLv Zhaohui 1 *\n\nGu Weijun 1 *\n1 Department of Endocrinology, Chinese PLA General Hospital, Beijing, China\n2 Department of Pathology, Chinese PLA General Hospital, Beijing, China\nEdited by: Barbara Altieri, University Hospital of Wuerzburg, Germany\n\nReviewed by: Marcio Machado, University of São Paulo, Brazil; Carl Christofer Juhlin, Karolinska Institutet (KI), Sweden\n\n*Correspondence: Yiming Mu, muyiming@301hospital.com.cn; Zhaohui Lv, metabolism301@126.com; Weijun Gu, guweijun301@163.com\n†These authors have contributed equally to this work\n\nThis article was submitted to Cancer Endocrinology, a section of the journal Frontiers in Endocrinology\n\n01 7 2021\n2021\n12 68780930 3 2021\n07 6 2021\nCopyright © 2021 Cheng, Li, Dou, Ba, Du, Zhang, Mu, Lv and Gu\n2021\nCheng, Li, Dou, Ba, Du, Zhang, Mu, Lv and Gu\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.\nEctopic ACTH syndrome (EAS) accounts for 10–20% of endogenous Cushing’s syndrome (CS). Hardly any cases of adrenal medullary hyperplasia have been reported to ectopically secrete adrenocorticotropic hormone (ACTH). Here we describe a series of three patients with hypercortisolism secondary to ectopic production of ACTH from adrenal medulla. Cushingoid features were absent in case 1 but evident in the other two cases. Marked hypokalemia was found in all three patients, but hyperglycemia and osteoporosis were present only in case 2. All three patients showed significantly elevated serum cortisol and 24-h urinary cortisol levels. The ACTH levels ranged from 19.8 to 103.0pmol/L, favoring ACTH-dependent Cushing’s syndrome. Results of bilateral inferior petrosal sinus sampling (BIPSS) for case 1 and case 3 confirmed ectopic origin of ACTH. The extremely high level of ACTH and failure to suppress cortisol with high dose dexamethasone suppression test (HDDST) suggested EAS for patient 2. However, image studies failed to identify the source of ACTH secretion. Bilateral adrenalectomy was performed for rapid control of hypercortisolism. After surgery, cushingoid features gradually disappeared for case 2 and case 3. Blood pressure, blood glucose and potassium levels returned to normal ranges without medication for case 2. The level of serum potassium also normalized without any supplementation for case 1 and case 3. The ACTH levels of all three patients significantly decreased 3-6 months after surgery. Histopathology revealed bilateral adrenal medullary hyperplasia and immunostaining showed positive ACTH staining located in adrenal medulla cells. In summary, our case series reveals the adrenal medulla to be a site of ectopic ACTH secretion. Adrenal medulla-originated EAS makes the differential diagnosis of ACTH-dependent Cushing’s syndrome much more difficult. Control of the hypercortisolism is mandatory for such patients.\n\nACTH-dependent Cushing’s syndrome\nectopic ACTH syndrome\nadrenal medullary hyperplasia\nimmunohistochemical staining\nbilateral adrenalectomy\n==== Body\nIntroduction\n\nAdrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome can be classified as either Cushing’s disease or ectopic ACTH syndrome (EAS). It is estimated that EAS is responsible for 10–20% of all cases of Cushing’s syndrome. The frequencies of tumors associated with EAS vary among series (1). In the 1970s, EAS were mainly represented by small-cell lung carcinomas (SCLCs). But the most prevalent tumor of EAS has recently shifted from SCLCs to neuroendocrine tumors (NETs), and particularly bronchial carcinoids in the recent literature (2–4). Other origins of tumors responsible for EAS are the thymus (5), pancreas, and thyroid. Pheochromocytoma also has been reported to have ectopic ACTH secretion and accounts for approximately 5% of EAS cases (6). Adrenal medullary hyperplasia, characterized by an increased medullary cell mass, is even more rare for excess catecholamine production (7, 8). Hardly any case of adrenal medullary hyperplasia was previously reported to ectopically secrete ACTH according to our systematic search of publications. Here, we reported three cases of EAS associated with adrenal medullary hyperplasia in our center.\n\nCase Description\n\nCase series results are summarized in Tables 1 and 2 and are individually described here.\n\nTable 1 Summary of Characteristics and Laboratory Findings at Presentation.\n\n\tCase 1\tCase 2\tCase 3\tNormal Range\t\nAge at diagnosis\t23y\t28y\t31y\t\t\n Sex\tFemale\tMale\tMale\t\n BMI\t20.8\t28.0\t31.6\t<28kg/m2\t\n HbA1c\t5.7\t5.6\t5.4\t<6.5%\t\nGlucose after 75g OGTT\t\t\t\t\t\n 0min\t3.9\t8.65\t4.8\t3.4-6.1mmol/L\t\n 60min\t6.95\t16.48\t8.34\t<11.1mmol/L\t\n 120min\t7.06\t17.12\t7.26\t≥7.8mmol/L\t\nBlood pressure\t130/80\t150/100\t130/90\t<140/90mmHg\t\n Z score\t-1.3\t-4.0\t0.2\t>-1\t\n L1-L4 spine\t\nSerum potassium\t2.56\t1.29\t2.66\t3.5-4.5mmol/L\t\nSerum cortisol\t\t\t\t\t\n 0AM\t1007.19\t3048.0\t785.28\t0-165.7nmol/L\t\n 8AM\t1229.25\t3577.9\t1080.58\t198.7-797.5nmol/L\t\n 4PM\t1152.32\t3394.7\t164.21\t85.3-459.6nmol/L\t\nUrine free cortisol\t6674.8\t47862\t6358.8\t98.0-500.1nmol/24h\t\n Serum ACTH\t\t\t\t\t\n 0AM\t13.3\t88.8\t38.4\t\t\n 8AM\t19.8\t103.0\t42.0\t<10.12pmol/L\t\n 4PM\t23.5\t62.6\t66.4\t\t\nLDDST\t\t\t\t\t\n Serum cortisol\t1997.19\t\t850.21\t<50nmol/L\t\n Serum ACTH\t24.4\t_\t28.4\t\t\n Urine free cortisol\t7499.5\t\t6419.9\t<98.0nmol/24h\t\nHDDST\t\t\t\t\t\n Serum cortisol\t1673.45 (136%)\t3789.9 (106%)\t1793.09 (166%)\t<50%\t\n Serum ACTH\t22.6\t100.0\t15.7\t\t\n Urine free cortisol\t4243.3 (63%)\t50800 (106%)\t5697.0 (90%)\t<50%\t\nDDAVP\t\t\t\t\t\n ACTH max/ACTH basal\t7.11\t_\t5.77\t\t\nBIPSS\t\t\t\t\t\n Central/peripheral ACTH at basal\t0.93\t_\t1.02\t\t\n Central/peripheral ACTH after DDAVP stimulation\t1.5\t_\t0.67\t\t\n\nTable 2 Assessment Before and After Bilateral Adrenalectomy.\n\n\tCase 1\tCase 2\tCase 3\t\nSerum ACTH\n(pmol/L)\tBefore 3m 12m\tBefore 3m 12m\tBefore 3m 12m\t\n 0AM\t13.3 1.77 -\t88.8 1.1 1.1\t38.4 3.53 7.3\t\n 8AM\t19.8 11.9 -\t103.0 4.06 54.2\t42.0 7.33 86.1\t\n 4PM\t23.5 10.1 -\t62.6 4.00 12.6\t66.4 6.64 49.3\t\nSerum Cortisol\n(nmol/L)\tBefore 3m 12m\tBefore 3m 12m\tBefore 3m 12m\t\n 0AM\t1007.19 197.34 -\t3048.0 134.65 40.50\t785.28 121.81 <25.7\t\n 8AM\t1229.25 304.11 -\t3577.9 <25.7 31.37\t1080.58 342.89 231.36\t\n 4PM\t1152.32 123.76 -\t3394.7 130.54 85.81\t164.21 <25.7 <25.7\t\n\nCase 1\n\nA 23-year-old woman was admitted to our department presented with a one-month history of general fatigue, acne and hirsutism. Blood pressure was 130/80 mmHg. Her weight was 55 kg, and height was 162.5 cm (Body mass index 20.8Kg/m2). She had no typical symptoms of Cushing’s syndrome such as moon face, central obesity, supraclavicular fat accumulation, or buffalo hump. Stria was also invisible. Hypokalemia was evident, which could not be normalized with oral and intravenous potassium supplementation until spironolactone (60mg tid) was added. The level of HbA1c was 5.4%, and blood glucose levels were within normal range after a 75-g oral glucose tolerance test (OGTT). Dual-energy X-ray absorptiometry (DXA) bone densitometry suggested osteopenia with a Z-score of -1.3 at L1-L4 spine. Biochemical workup ( Table 1 ) revealed loss of circadian rhythm, elevated 24-h urinary cortisol levels and failure to suppress cortisol with classical low dose dexamethasone suppression test (LDDST). Plasma ACTH level was elevated to 19.8 pmol/L, favoring ACTH-dependent Cushing’s syndrome. Desmopressin stimulation resulted in ACTH increase by about 700%. But cortisol was not suppressed after high dose dexamethasone intake. Magnetic resonance imaging (MRI) showed normal pituitary gland ( Supplementary Figure 1A ). So next, bilateral inferior petrosal sinus sampling (BIPSS) was performed and showed a central-to-peripheral ACTH gradient < 2 at baseline and < 3 after desmopressin stimulation. Finally, diagnosis of EAS was considered. The lesion was not localized by CT scans. Further evaluation with 68Ga-DOTATATE PET/CT and 18F-PET/CT still failed to identify the source of ACTH secretion. Only bilateral adrenal hyperplasia was observed via image studies ( Figure 1A ). As steroidogenesis inhibitors are unavailable in China, mifepristone can aggravate hypokalemia, and the cortisol level remained unchangeable after short-acting octreotide injection, bilateral adrenalectomy was performed for rapid control of hypercortisolism. Transperitoneal approach was used with the patient positioned in left and right lateral positions for right and left glands, respectively. A meticulous surgical technique was used to best expose the adrenal veins to clip them before division followed by excising the glands. The patient had minimal blood pressure variations during surgery. After surgery, a 20mg dose of hydrocortisone per day was given. The level of serum potassium normalized without any supplementation. The level of serum sodium was around 140mmol/L. Blood pressure maintained between 100-110/60-70mmHg. ACTH level significantly decreased at the latest follow-up (3 months after surgery, Table 2 ), indicating adrenal glands to be the origin of excess ACTH. Consistently, the low power view of histopathological image showed a thickened adrenal medulla, more than a third of the total adrenal thickness in both glands, which met the criteria of adrenal medulla hyperplasia in WHO 2017 classification of endocrine tumors ( Figure 2A ). The high power view showed diffuse hyperplasia of the medullary cells, and the medullary cells showed size and shape variability in areas of diffuse hyperplasia ( Figure 2B ). The medullary cells stained positive for chromogranin A ( Figure 2C ). Histopathology revealed bilateral diffuse cortex hyperplasia ( Figure 2D ). Immunostaining showed sporadic positive ACTH staining ( Figure 3A ) located in adrenal medulla cells. To rule out the possibility of non-specific staining, ACTH staining was simultaneously performed in adrenal tissues from a patient undergoing adrenalectomy due to renal cell carcinoma, and no positive cells were spotted neither in adrenal cortex nor adrenal medulla ( Figures 3D, E ).\n\nFigure 1 The CT images of the adrenal glands for case1 (A), case 2 (B) and case 3 (C). Adrenal contrast-enhanced CT showed adrenal hyperplasia (arrows).\n\nFigure 2 Low power views showing the thickened medulla (black triangle) and hyperplastic adrenal cortex (black star) (A). High-power views of the medulla (B). Chromogranin expression in the medullary cells (C). High-power views of the cortex (D).\n\nFigure 3 ACTH immunostaining of the adrenal glands for case1 (A), case 2 (B), case 3 (C), adrenal cortex of normal control (D) and adrenal medulla of normal control (E). ACTH staining showed sporadic positive ACTH staining for case 1, numerous adrenal medulla cells positive for ACTH for case 2, focal positive ACTH staining for case 3 and negative ACTH staining for normal control.\n\nCase 2\n\nA 28-year-old man complained with a six-month history of acne and three-month history of moon face, general fatigue and hypertension. Physical examination revealed a blood pressure of 150/90 mmHg, weight of 78 kg, and height of 167 cm (BMI 27.9 Kg/m2). He displayed overt cushingoid features with central obesity, dorsocervical and supraclavicular fat pads, abdominal striae, skin bruises, acne, and facial plethora. Laboratory examination showed severe hypokalemia (1.2mmol/L). A 75-g OGTT confirmed diabetes mellitus with a fasting blood glucose level of 8.65 mmol/l and a 2-h glucose level of 17.12 mmol/L, although HbA1c level was only 5.6%. DXA showed severe osteoporosis with a Z-score of -4.0 at the L1-L4 spine. Endocrinological investigation ( Table 1 ) identified severe hypercortisolism with loss of circadian rhythm and elevated 24-h urinary cortisol levels. Plasma ACTH level was significantly elevated to 103 pmol/L, confirming ACTH-dependent Cushing’s syndrome. The serum cortisol level was not suppressed after a high dose dexamethasone suppression test (HDDST). MRI revealed no pituitary adenoma ( Supplementary Figure 1B ). We offered BIPSS for ACTH assays to identify the origin of ACTH, but the patient refused. Nonetheless, EAS was considered given the ACTH level, results of HDDST and pituitary MRI. No lesion was detected in thoracic CT scan. Abdominal CT showed hyperplasia of the right adrenal gland ( Figure 1B ). Pituitary MRI showed a mass in the left nasal cavity and left ethmoidal sinus ( Supplementary Figure 2 ), and PET-CT confirmed intense metabolic activity of the mass. The mass was thereafter biopsied. Pathology showed that the mass was composed of small round blue cells with a high nuclear-to-cytoplasmic ratio, rare nucleoli and a nuclear chromatin pattern typical of neuroendocrine-like tumors. The diagnosis of olfactory neuroblastoma was supported by immunohistochemical staining for multiple neuro-endocrine markers, such as CD56, synaptophysin, chromogranin A and S-100. Previously, more than 20 cases of olfactory neuroblastoma presenting with EAS have been reported (9, 10). However, biopsy did not show positive ACTH staining. Surgical removal of the tumor was delayed due to poor general condition of the patient. Upon admission, ketoconazole was still available. At a dose of 800mg/d, the serum cortisol level dropped from 3577.9 to 1159.3nmol/L, but liver damage was already induced with ALT level reaching 300U/L. Therefore, ketoconazole was discontinued and bilateral adrenalectomy was next performed. Similarly, no sudden rise of blood pressure was observed during surgery. After surgery, cushingoid features gradually disappeared. Blood pressure, blood glucose and potassium levels returned to normal ranges without medication. He needed a 7.5-mg dose of prednisone acetate per day. At 3 month after surgery, the ACTH level decreased to 4.06 pmol/L. As the general condition significantly improved, the patient next underwent transnasal endoscopic resection of the tumour mass. ACTH and CRH staining were both negative for the tumor, whereas histopathology showed an increased adrenal medullary cell mass and diffuse hyperplasia of the medullary cells in both adrenal glands ( Figures 2A, B ). The medullary cells stained positive for chromogranin A ( Figure 2C ). Histopathology also revealed bilateral diffuse cortex hyperplasia ( Figure 2D ). Immunohistochemical staining showed numerous adrenal medulla cells positive for ACTH ( Figure 3B ). A year after bilateral adrenalectomy, the patient was admitted for regular follow-up. The 8AM ACTH markedly elevated to 54.2pmol/L but was suppressed below 1.11pmol/L after 1mg dexamethasone administration, suggesting that the up-regulated ACTH level was a result of adrenocortical insufficiency. The patient is currently under regular follow-up and remains well for 7 years.\n\nCase 3\n\nA 31-year-old man presented with a two-month history of general fatigue, acne, moon face and hyperpigmentation. Physical examination revealed a blood pressure of 130/90 mmHg, weight of 99 kg, and height of 177 cm (BMI 31.6 Kg/m2). He showed cushingoid features including moon face, supraclavicular fat accumulation, buffalo hump, facial and truncal acne, ecchymoses and striae. Laboratory examination showed hypokalemia. The level of HbA1c was 5.4%. A 75-g OGTT showed normal glucose homeostasis. Z score at L1-L4 spine was 0.2. The serum levels of ACTH, cortisol, and 24-h urine free cortisol were markedly elevated ( Table 1 ). Results of LDDST showed a cortisol value of 840.21 nmol/L after the dexamethasone administration. There was no suppression after HDDST. MRI of the pituitary gland did not showed signs of pituitary adenoma ( Supplementary Figure 1C ). Just like case 1, ACTH max/ACTH basal was as high as 5.77 after desmopressin stimulation. BIPSS showed that there was no evidence of a central-to-peripheral gradient of ACTH at baseline or after desmopressin stimulation. According to these findings, the patient was diagnosed with EAS. Thoracic CT scan was normal. Abdominal CT only showed nodular hyperplasia of the left adrenal gland ( Figure 1C ). The 18F-PET/CT showed increased uptake in both adrenal glands. Octreotide scanning also revealed negative results. As steroidogenesis inhibitors were unavailable, bilateral adrenalectomy was then performed via the same approach as case 1 without arterial variations. After surgery, a 20mg dose of hydrocortisone per day was added. Cushingoid features gradually disappeared. The levels of serum potassium remained normal without potassium supplement. Similarly, immunohistochemical staining showed focal positive ACTH staining in hyperplastic adrenal medulla cells ( Figures 2A–C , 3C ) and nodular hyperplasia of adrenal cortex in both adrenal glands ( Figure 2D ). ACTH level significantly decreased 3 months after surgery ( Table 2 ). At the latest follow-up, a year after surgery, the patient complained about hyperpigmentation. Laboratory tests showed that 8AM ACTH level relapsed to 86.1 pmol/L. After LDDST, ACTH level significantly decreased to 18.4 pmol/L. 68Ga-DOTATATE PET/CT and pituitary MRI still showed no signs for lesions. All the data indicated that increase of ACTH was the result of cortisol hypofunction. In order to suppress ACTH secretion, we added dexamethasone 0.1875mg at 10PM.\n\nDiscussion\n\nOur case series suggest that severe Cushing’s syndrome can be induced by ectopic production of ACTH caused by adrenal medulla hyperplasia, supported by a drastic decrease of ACTH level after bilateral adrenalectomy, positive ACTH staining in adrenal medulla cells, and the number of ACTH positive cells in proportion to serum ACTH level.\n\nBack in 1980s, researchers showed the presence of immunoreactive ACTH and corticotropin-releasing hormone (CRH) in adrenals (combined cortex and medulla) by radioimmunity assay, immunoaffinity chromatography, and gel filtration chromatography (11). Interestingly, in patients with proven deficiency of pituitary ACTH, administration of 100ug human CRH induced an increase in plasma ACTH level, indicating extra-pituitary source of ACTH (12). Animal experiments revealed the role of the adrenal medulla as the production site of ACTH after CRH stimulation (13). Subsequently, it was demonstrated that human adrenal medulla expressed CRH receptors (14). Strong evidence supports a local, intra-adrenal CRH/ACTH system (15). Adrenal medullary cells possess the potential to secret ACTH into plasma. So it would be reasonable to infer that in our series, the adrenal medulla was the source of ectopic ACTH secretion.\n\nCompared to pheochromocytomas, adrenal medullary hyperplasia is less common. Only case reports or small case series about adrenal medullary hyperplasia have been reported (16, 17), in which patients often represented with a medical history of symptoms and signs of excessive catecholamine excretion, slightly elevated level of catecholamine, and increased adrenal medullary tissue relative to the cortex. However, in our case series, blood pressure only slightly elevated for case 2, most probably related with hypercortisolism. Given the prominent Cushing’s syndrome in our series, the levels of catecholamine was not detected in any of the three cases. But absence of paroxysmal symptoms and blood pressure variations during the adrenal surgery made the possibility of catecholamine excess relatively low. We hypothesized that the potential of ACTH secretion might be limited to a certain subtype of adrenal medulla cells, and hyperplasia of such cells mainly resulted in hypercortisolism rather than excess catecholamine production. The underlying mechanism needs further exploration.\n\nOccult EAS is not rare. A lack of tumor identification has been documented from 12 to 36.5% in different series (1). In some cases, a non-metastatic well-differentiated and indolent neuroendocrine tumor can be discovered after several months or years of follow-up (4). However, some cases remain truly occult. Our findings provide reasonable explanations for, if not all, parts of these truly occult cases. The adrenal medulla has rarely been identified to be the ectopic source of ACTH before, and its incidence might have been underestimated. There might be two reasons. First, in cases with occult EAS, pharmacological treatments of hypercortisolism are fist-line choices in many countries (18), which would not affect the ACTH level. Without removal of adrenal glands, there would be no evidence to suggest adrenal medulla hyperplasia. Secondly, in cases with bilateral adrenalectomy to control hypercortisolism, the ACTH would rapidly relapse to a high level due to adrenocortical hypofunction. If in the short time-window when ACTH level dropped, the patients did not have the ACTH level checked, the clue would also have been missed.\n\nDifferential diagnosis between Cushing’s disease and occult EAS can be challenging. Typically, in EAS, the degree of ACTH hypersecretion is much higher compared to Cushing’s disease. CRH or desmopressin stimulation usually results in increase in ACTH and cortisol levels in Cushing’s disease, but not in EAS. The cortisol level is not suppressed with HDDST. However, these tests may not be completely reliable (19). A review concluded that the sensitivity of desmopressin stimulation in the differential diagnosis of ACTH-dependent Cushing’s syndrome was 83% and the specificity was only 62% (20). In certain researches, EAS patients even responded to desmopressin test in about 30-40% of cases (21). So if ACTH-dependent Cushing’s syndrome were biochemically supported and a pituitary adenoma was detected on MRI, the diagnosis of Cushing’s disease would have been arbitrarily made. However, given that pituitary adenoma can be detected in 5~20% normal people (22), we might have preformed pituitary resection to a patient with occult EAS and concomitant non-functional pituitary adenoma. So it must be born in mind that occult EAS is not rare (23). Under such circumstances, BIPSS is very important. BIPSS combined with CRH and/or desmopressin administration is considered the gold standard for distinguishing EAS from Cushing’s disease (24). Absence of a central to peripheral ACTH gradient confirms an ectopic source of ACTH secretion. EAS associated with adrenal medulla hyperplasia might raise another diagnostic problem as in case 2, when a tumor, which has been reported to be associated with EAS, is indeed identified. It is very likely that surgical excision of the tumor is the first-line choice as surgery offers a good chance for cure while maintains adrenal function. With no doubt, hypercortisolism would persist afterwards.\n\nDesmopressin is a long-acting vasopressin analog with selective V2 agonist activity (25). Pituitary ACTH-producing adenoma expresses V2 receptors (V2R). As a result, desmopressin administration produces a significant rise of ACTH secretion in the majority of patients with Cushing’s disease whereas patients with EAS were unresponsive (26). Since CRH is unavailable in China, desmopressin stimulation test instead is applied to distinguishing EAS from Cushing’s disease. Taken the ACTH max/ACTH basal ratio of 1. 5 as a cut point, a significant overlap of the ACTH response to the desmopressin test was found between patients with Cushing’s disease and EAS. But the ratio rarely exceeds 3 in EAS (20). However, we notice that after desmopressin stimulation, ACTH increment was up to 711% for case 1 and 577% for case 3. It has been reported that the adrenal medulla, from many species, exhibits V1 vasopressin receptors, and via V1 receptors, arginine-vasopressin stimulates intramedullary the CRH-ACTH system (27). So we hypothesize that the adrenal medulla also exhibit V2R and desmopressin stimulates the intramedullary ACTH production, making distinguishing adrenal medulla-originated EAS from Cushing’s disease more difficult.\n\nIn our study, age of three patients at diagnosis was relatively younger than that in previously published series regarding EAS (2–4, 23, 28, 29). The medical history was short, and most common signs were general fatigue and acne. Cushingoid features were absent in case 1 but evident in the other two cases. With respect to cortisol-induced comorbidities, marked hypokalemia was found in all three patients, but hyperglycemia and osteoporosis were present only in case 2. The clinical heterogeneity is probably due to the large span of ACTH levels from 19.8 to 103.0pmol/L. Bilateral adrenalectomy rapidly and effectively halted hypercortisolism in our case series. The surgery has been traditionally considered a safe option to achieve a radical and fast treatment of hypercortisolism. In a meta-analysis of 23 studies, 30-day morbidity and mortality were acceptable (18% and 3%, respectively) (30). Clinical remission of Cushing’s syndrome was greater than 95%. But the downside of bilateral adrenalectomy is also very obvious, including the need for lifelong glucocorticoid and mineralocorticoid replacement therapy, and the risk of adrenal crisis (4.1 to 9.1 per 100 patient-years). In recent guidelines and reviews regarding EAS, bilateral adrenalectomy has been reconsidered and restricted to very severe cases, when steroidogenesis inhibitors are unavailable, ineffective or poorly tolerated (18). The therapeutic effect of steroidogenesis inhibitors on adrenal medulla-originated EAS needs further exploration. When medical treatment fails, bilateral adrenalectomy should be performed as soon as possible. Survival of patients with EAS is dependent on tumor histology and by the severity of hypercortisolemia. Patients with SCLCs and thymic carcinoids seem to have the worst prognosis, while patients with tumors with endocrine differentiation have a better outcome. Adrenal medulla-originated EAS is relatively benign. Just as our case series, when hypercortisolemia is well controlled, the patients will survive with improved health-related quality of life.\n\nIn summary, our case series reveals the adrenal medulla to be a site of ectopic ACTH secretion, which is previously ignored. Adrenal medulla-originated EAS makes the differential diagnosis of ACTH-dependent Cushing’s syndrome much more difficult. Control of the hypercortisolism is mandatory for such patients. When steroidogenesis inhibitors are unavailable, response to somatostatin analogues is limited, or the adverse effects are intolerable, bilateral adrenalectomy is the last choice. If hypercortisolemia is promptly and effectively controlled, the prognosis is often favorable.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors.\n\nEthics Statement\n\nWritten 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\nYC analyzed the data. She was a major contributor in writing the manuscript. WG made substantial contributions in interpretation of data, and have been involved in revising the manuscript critically for important intellectual content. JL supervised histological examination. JD, JB, JTD, and SZ made substantial contributions to acquisition of data, or analysis. YM and ZL were the superior advisors. They agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors contributed to the article 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\nAcknowledgments\n\nWe thank Dr Nan Jin, Hong liao, Chunjing Zhu, Huali Ming and Zewei Li for kindly providing Figures 1 – 3 .\n\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fendo.2021.687809/full#supplementary-material\n\nSupplementary Figure 1 Pituitary MRI images for case1 (A), case 2 (B) and case 3 (C). Pituitary contrast-enhanced MRI did not showed signs of pituitary adenoma.\n\nClick here for additional data file.\n\nSupplementary Figure 2 Pituitary MRI image for case 2, revealing the presence of a mass in the left nasal cavity and left ethmoidal sinus (arrow).\n\nClick here for additional data file.\n\nClick here for additional data file.\n==== Refs\nReferences\n\n1 Alexandraki KI Grossman AB . The Ectopic ACTH Syndrome. Rev Endocrine Metab Disord (2010) 11 (2 ):117–26. 10.1007/s11154-010-9139-z\n2 Isidori AM Kaltsas GA Pozza C Frajese V Newell–Price J Reznek RH . 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\n3 Hernández I Espinosa-de-los-Monteros AL Mendoza V Cheng S Molina M Sosa E . Ectopic ACTH-Secreting Syndrome: A Single Center Experience Report With a High Prevalence of Occult Tumor. Arch Med Res (2006) 37 (8 ):976–80. 10.1016/j.arcmed.2006.05.015\n4 Espinosa-de-los-Monteros AL Ramírez-Rentería C Mercado M . Clinical Heterogeneity of the Ectopic Acth Syndrome: A Long-Term Follow Up Study. Endocrine Pract (2020) 26 (12 ):1435–41. 10.1016/j.eprac.2020.06.001\n5 Chen Y-y Li S-q Liu H-s Qin Y-z Li L Huang C . Ectopic Adrenocorticotropic Hormone Syndrome Caused by Neuroendocrine Tumors of the Thymus: 30-Year Experience With 16 Patients at a Single Institute in the People’s Republic of China. OncoTargets Ther (2016) 2193 . 10.2147/OTT.S100585\n6 Ballav C Naziat A Mihai R Karavitaki N Ansorge O Grossman AB . Mini-Review: Pheochromocytomas Causing the Ectopic ACTH Syndrome. Endocrine (2012) 42 (1 ):69–73. 10.1007/s12020-012-9646-7 22396144\n7 Falhammar H Stenman A Calissendorff J Juhlin CC . Presentation, Treatment, Histology, and Outcomes in Adrenal Medullary Hyperplasia Compared With Pheochromocytoma. 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"journal": "Frontiers in endocrinology",
"keywords": "ACTH-dependent Cushing’s syndrome; adrenal medullary hyperplasia; bilateral adrenalectomy; ectopic ACTH syndrome; immunohistochemical staining",
"medline_ta": "Front Endocrinol (Lausanne)",
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"title": "Case Report: Three Rare Cases of Ectopic ACTH Syndrome Caused by Adrenal Medullary Hyperplasia.",
"title_normalized": "case report three rare cases of ectopic acth syndrome caused by adrenal medullary hyperplasia"
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"abstract": "Hypnosedative-induced complex behaviors have gained increased attention in recent years as a potential complication of benzodiazepines and benzodiazepine-receptor agonist use. Sodium oxybate (SO), the sodium salt of γ-hydroxybutyrate, an inhibitory neurotransmitter, has been associated with dose-dependent rates of somnambulism; however, there is limited information about complex motor behaviors with SO. We describe a patient with narcolepsy-cataplexy who experienced one episode of sleep-driving and at least two sleep-related eating episodes with therapeutic doses of SO.",
"affiliations": "Department of Neurology, Sleep Medicine Division, University of Miami Miller School of Medicine, Miami, FL, USA. dwallace@med.miami.edu",
"authors": "Wallace|Douglas McKay|DM|;Maze|Tanisha|T|;Shafazand|Shirin|S|",
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"issue": "7(3)",
"journal": "Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine",
"keywords": "Sodium oxybate; narcolepsy; parasomnia; sleep driving; sleep related eating disorder",
"medline_ta": "J Clin Sleep Med",
"mesh_terms": "D000759:Adjuvants, Anesthesia; D000328:Adult; D001334:Automobile Driving; D001068:Feeding and Eating Disorders; D006801:Humans; D008297:Male; D009290:Narcolepsy; D020447:Parasomnias; D012893:Sleep Wake Disorders; D012978:Sodium Oxybate",
"nlm_unique_id": "101231977",
"other_id": null,
"pages": "310-1",
"pmc": null,
"pmid": "21677903",
"pubdate": "2011-06-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16895263;19193338;15586785;19968016;18998740",
"title": "Sodium oxybate-induced sleep driving and sleep-related eating disorder.",
"title_normalized": "sodium oxybate induced sleep driving and sleep related eating disorder"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2019-02740",
"fulfillexpeditecriteria": "1",
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"patient": {
"drug": [
{
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"activesubstance": {
"activesubstancename": "DULOXETINE HYDROCHLORIDE"
},
... |
{
"abstract": "Combination of dual antiplatelet therapy (DAPT) with glycoprotein (GP) IIb/IIIa inhibitors can increase bleeding risk. In this study, we aimed to investigate bleeding complications of different DAPTs with concomitant tirofiban use in patients with acute coronary syndrome (ACS).\n\n\n\nThis retrospective study included 224 consecutive ACS patients (mean age 56.6±11.1 years, 193 men) who were given conventional dose of tirofiban (25 µg/kg per 3 minutes followed by an infusion of 0.15 µg/kg/min for 24 hours) in addition to DAPT (300 mg aspirin followed by 100 mg/day + 600 mg clopidogrel followed by 75 mg/day or 180 mg ticagrelor followed by 90 mg twice daily or 60 mg prasugrel followed by 10 mg/day). Any intra-hospital bleeding complications were noted.\n\n\n\nOf the 224 patients, 115 were given ticagrelor and 32 were given prasugrel. Mean hemoglobin fall was similar between the patients taking ticagrelor/prasugrel and those taking clopidogrel. Ten patients taking ticagrelor and one patient taking prasugrel had hemoglobin fall ≥3 g/dL versus two patients in clopidogrel group (p=0.228). Gastrointestinal bleeding (two patients taking ticagrelor), hematoma at access site (three patients taking ticagrelor), and cardiac tamponade (two patients taking ticagrelor) rates were also similar. Creatinine levels were associated with hemoglobin fall ≥3 g/dL (p=0.032, Odds ratio 2.189, 95% confidence interval 1.070-4.479). There was no relation between hemoglobin fall ≥3 g/dL and antiplatelet agent, age, sex, hypertension, or diabetes.\n\n\n\nTirofiban may be given to patients receiving ticagrelor or prasugrel with a bleeding rate similar to clopidogrel. Close monitoring for bleeding risk is recommended, especially in patients with higher creatinine levels.",
"affiliations": "Department of Cardiology, Faculty of Medicine, Marmara University; İstanbul-Turkey.;Department of Cardiology, Faculty of Medicine, Marmara University; İstanbul-Turkey.;Department of Cardiology, Faculty of Medicine, Marmara University; İstanbul-Turkey.;Department of Cardiology, Faculty of Medicine, Marmara University; İstanbul-Turkey.;Department of Cardiology, Faculty of Medicine, Marmara University; İstanbul-Turkey.;Department of Cardiology, Faculty of Medicine, Marmara University; İstanbul-Turkey.;Department of Cardiology, Faculty of Medicine, Marmara University; İstanbul-Turkey.;Department of Cardiology, Faculty of Medicine, Marmara University; İstanbul-Turkey.;Department of Cardiology, Faculty of Medicine, Marmara University; İstanbul-Turkey.;Department of Cardiology, Faculty of Medicine, Marmara University; İstanbul-Turkey.",
"authors": "Tigen|Mustafa Kürşat|MK|;Özdil|Mehmet Hasan|MH|;Çinçin|Altuğ|A|;Gürel|Emre|E|;Sünbül|Murat|M|;Şahin|Anıl|A|;Güçtekin|Tuba|T|;Doğan|Zekeriya|Z|;Sayar|Nurten|N|;Özben|Beste|B|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D000068799:Prasugrel Hydrochloride; D000077466:Tirofiban",
"country": "Turkey",
"delete": false,
"doi": "10.5152/AnatolJCardiol.2021.27974",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2149-2263",
"issue": "25(10)",
"journal": "Anatolian journal of cardiology",
"keywords": null,
"medline_ta": "Anatol J Cardiol",
"mesh_terms": "D054058:Acute Coronary Syndrome; D000368:Aged; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction; D062645:Percutaneous Coronary Intervention; D010975:Platelet Aggregation Inhibitors; D000068799:Prasugrel Hydrochloride; D058921:Purinergic P2Y Receptor Antagonists; D012189:Retrospective Studies; D000077466:Tirofiban; D016896:Treatment Outcome",
"nlm_unique_id": "101652981",
"other_id": null,
"pages": "699-705",
"pmc": null,
"pmid": "34622784",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article",
"references": "20889993;9705684;19717846;19679245;20210836;29345590;33001202;31122865;16380591;31542257;21670242;31116032;12208224;31475799;28886621;15827315;26320110;27657930;28900715;33388397;33382055;24832461;27297843;22019823",
"title": "Bleeding risk with concomitant use of tirofiban and third-generation P2Y12 receptor antagonists in patients with acute myocardial infarction: A real-life data.",
"title_normalized": "bleeding risk with concomitant use of tirofiban and third generation p2y12 receptor antagonists in patients with acute myocardial infarction a real life data"
} | [
{
"companynumb": "TR-DSJP-DSE-2021-133882",
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"occurcountry": "TR",
"patient": {
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PRASUGREL HYDROCHLORIDE"
},
"drugadditional": "... |
{
"abstract": "Acute hepatitis E virus (HEV) infection is a leading cause of acute liver failure (ALF) in many developing countries, yet rarely identified in Western countries. Given that antibody testing for HEV infection is not routinely obtained, we hypothesized that HEV-related ALF might be present and unrecognized in North American ALF patients. Serum samples of 681 adults enrolled in the U.S. Acute Liver Failure Study Group were tested for anti-HEV immunoglobulin (Ig) M and anti-HEV IgG levels. Subjects with a detectable anti-HEV IgM also underwent testing for HEV RNA. Mean patient age was 41.8 years, 32.9% were male, and ALF etiologies included acetaminophen (APAP) hepatotoxicity (29%), indeterminate ALF (23%), idiosyncratic drug-induced liver injury DILI (22%), acute hepatitis B virus infection (12%), autoimmune hepatitis (12%), and pregnancy-related ALF (2%). Three men ages 36, 39, and 70 demonstrated repeatedly detectable anti-HEV IgM, but all were HEV-RNA negative and had other putative diagnoses. The latter 2 subjects died within 3 and 11 days of enrollment whereas the 36-year-old underwent emergency liver transplantation on study day 2. At admission, 294 (43.4%) of the ALF patients were anti-HEV IgG positive with the seroprevalence being highest in those from the Midwest (50%) and lowest in those from the Southeast (28%). Anti-HEV IgG+ subjects were significantly older, less likely to have APAP overdose, and had a lower overall 3-week survival compared to anti-HEV IgG- subjects (63% vs. 70%; P = 0.018).\n\n\n\nAcute HEV infection is very rare in adult Americans with ALF (i.e., 0.4%) and could not be implicated in any indeterminate, autoimmune, or pregnancy-related ALF cases. Past exposure to HEV with detectable anti-HEV IgG was significantly more common in the ALF patients compared to the general U.S.\n\n\n\n(Hepatology 2016;64:1870-1880).",
"affiliations": "Department of Internal Medicine, University of Michigan, Ann Arbor, MI.;National Institute of Allergy and Infectious Diseases, Bethesda, MD.;Department of Internal Medicine, Loyola Medical Center, Maywood, IL.;Einstein Medical Center, Philadelphia, PA.;Department of Internal Medicine, University of Pittsburgh, Pittsburgh, PA.;Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC.;University of Texas Southwestern, Dallas, TX.;National Institute of Allergy and Infectious Diseases, Bethesda, MD.;University of Texas Southwestern, Dallas, TX.",
"authors": "Fontana|Robert John|RJ|;Engle|Ronald E|RE|;Scaglione|Steven|S|;Araya|Victor|V|;Shaikh|Obaid|O|;Tillman|Holly|H|;Attar|Nahid|N|;Purcell|Robert H|RH|;Lee|William M|WM|;|||",
"chemical_list": "D006508:Hepatitis Antibodies; D007074:Immunoglobulin G; D007075:Immunoglobulin M",
"country": "United States",
"delete": false,
"doi": "10.1002/hep.28649",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0270-9139",
"issue": "64(6)",
"journal": "Hepatology (Baltimore, Md.)",
"keywords": null,
"medline_ta": "Hepatology",
"mesh_terms": "D000328:Adult; D000368:Aged; D005260:Female; D006508:Hepatitis Antibodies; D016751:Hepatitis E; D016752:Hepatitis E virus; D006801:Humans; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D017114:Liver Failure, Acute; D008297:Male; D011446:Prospective Studies; D016036:Seroepidemiologic Studies; D014481:United States",
"nlm_unique_id": "8302946",
"other_id": null,
"pages": "1870-1880",
"pmc": null,
"pmid": "27215797",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D064888:Observational Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "21855518;20336757;19790147;9275216;22114964;21274872;17606958;17125878;24824965;12143058;14624381;25912835;12454155;12853389;22549004;18192058;9500718;18983248;11773103;21274877;21262830;20145528;18785952;17439518;23347695;25819381;12484709;23013075;18825709;24210958;16964546;17850420;23780824;18287603;19473098;17489963",
"title": "The role of hepatitis E virus infection in adult Americans with acute liver failure.",
"title_normalized": "the role of hepatitis e virus infection in adult americans with acute liver failure"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2016US-119703",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXYCODONE"
},
"druga... |
{
"abstract": "Scleroderma renal crisis (SRC) is a rare complication of systemic sclerosis (SSc) but can be severe enough to require temporary or permanent renal replacement therapy. Moderate to high dose corticosteroid use is recognized as a major risk factor for SRC. Furthermore, there have been reports of thrombotic microangiopathy precipitated by cyclosporine in patients with SSc. In this article, we report a patient with SRC induced by tacrolimus and corticosteroids. The aim of this work is to call attention to the risk of tacrolimus use in patients with SSc.",
"affiliations": "1Department of Rheumatic Diseases, Tokyo Metropolitan Tama Medical Center, Fuchu-shi, Tokyo, Japan; 2Department of Nephrology, Tokyo Kyosai Hospital, Meguro-ku, Tokyo, Japan; 3Hiramatsu Naika Clinic, Kokubunji, Tokyo, Japan; and 4Department of Nephrology, Tokyo Metropolitan Tama Medical Center, Fuchu-shi, Tokyo, Japan.",
"authors": "Nunokawa|Takahiro|T|;Akazawa|Masanobu|M|;Yokogawa|Naoto|N|;Shimada|Kota|K|;Hiramatsu|Kazuko|K|;Nishio|Yasuhide|Y|;Sugii|Shoji|S|",
"chemical_list": "D011239:Prednisolone; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": "10.1097/MJT.0b013e3182583ba1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-2765",
"issue": "21(5)",
"journal": "American journal of therapeutics",
"keywords": null,
"medline_ta": "Am J Ther",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D005260:Female; D006801:Humans; D011239:Prednisolone; D012595:Scleroderma, Systemic; D016559:Tacrolimus; D057049:Thrombotic Microangiopathies",
"nlm_unique_id": "9441347",
"other_id": null,
"pages": "e130-3",
"pmc": null,
"pmid": "22836123",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Late-onset scleroderma renal crisis induced by tacrolimus and prednisolone: a case report.",
"title_normalized": "late onset scleroderma renal crisis induced by tacrolimus and prednisolone a case report"
} | [
{
"companynumb": "JP-MYLANLABS-2014M1015512",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "Immune checkpoint inhibitors (ICIs) significantly prolong survival in patients with metastatic melanoma but can lead to serious immune-related adverse events. In this report, we described a case of atypical neuropathy caused by nivolumab plus ipilimumab combination therapy before primary tumor resection. In our case, not only demyelinating neuropathy, but also muscle weakness and unilateral facial nerve palsy developed and manifested as severe and diverse symptoms. Moreover, unlike spontaneously developing demyelinating peripheral neuropathy, the present case suggested the therapeutic effects of high-dose methylprednisolone monotherapy for the treatment of ICIs-induced immune-related demyelinating peripheral neuropathy.",
"affiliations": "Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai, Japan.;Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai, Japan.;Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan.;Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.;Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.;Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai, Japan.",
"authors": "Kambayashi|Yumi|Y|;Fujimura|Taku|T|;Kuroda|Hiroshi|H|;Otsuka|Atsushi|A|;Irie|Hiroyuki|H|;Aiba|Setsuya|S|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000506976",
"fulltext": "\n==== Front\nCase Rep Oncol\nCase Rep Oncol\nCRO\nCase Reports in Oncology\n1662-6575 S. 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.com \n\n10.1159/000506976\ncro-0013-0474\nCase Report\nSevere Demyelinating Neuropathy in an Advanced Melanoma Patient Treated with Nivolumab plus Ipilimumab Combined Therapy\nKambayashi Yumi a* Fujimura Taku a Kuroda Hiroshi b Otsuka Atsushi c Irie Hiroyuki c Aiba Setsuya a aDepartment of Dermatology, Tohoku University Graduate School of Medicine, Sendai, Japan\nbDepartment of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan\ncDepartment of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan\n*Yumi Kambayashi, Department of Dermatology, Tohoku University Graduate School of Medicine, Seiryo-machi 1-1, Aoba-ku, Sendai 980-8574 (Japan), yumi1001@hosp.tohoku.ac.jp\nJan-Apr 2020 \n30 4 2020 \n30 4 2020 \n13 1 474 477\n4 3 2020 4 3 2020 2020 Copyright © 2020 by S. Karger AG, Basel2020This 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.Immune checkpoint inhibitors (ICIs) significantly prolong survival in patients with metastatic melanoma but can lead to serious immune-related adverse events. In this report, we described a case of atypical neuropathy caused by nivolumab plus ipilimumab combination therapy before primary tumor resection. In our case, not only demyelinating neuropathy, but also muscle weakness and unilateral facial nerve palsy developed and manifested as severe and diverse symptoms. Moreover, unlike spontaneously developing demyelinating peripheral neuropathy, the present case suggested the therapeutic effects of high-dose methylprednisolone monotherapy for the treatment of ICIs-induced immune-related demyelinating peripheral neuropathy.\n\nKeywords\nDemyelinating peripheral neuropathyNivolumab plus ipilimumab combined therapyAdvanced melanomaImmune-related adverse eventHigh-dose methylprednisolone monotherapy\n==== Body\nIntroduction\nImmune checkpoint inhibitors (ICIs), such as anti-PD1 antibodies and anti-CTLA4 antibodies, significantly prolong survival in patients with metastatic melanoma. However, ICIs can also lead to serious immune-related adverse events, especially with the administration of nivolumab plus ipilimumab (N + I) combined therapy [1]. In this report, we describe the case of a patient with advanced melanoma treated with N + I combined therapy, which led to the development of severe demyelinating peripheral neuropathy. Interestingly, this patient showed HLA-DQB1 polymorphisms (DQB1*040101 and *060401) that might have been associated with the immune-mediated neuropathy [2].\n\nCase Presentation\nWe had previously reported on a 64-year-old Japanese man in Frontiers in Medicine in 2019 [3]. Since his melanoma had metastasized to multiple organs (skin, muscle, lymph nodes, oropharynx, lung, peritoneum, spleen, and bone), we administered ipilimumab (3 mg/kg) plus nivolumab (80 mg/body) (N + I) combined therapy prior to tumor resection. Ten days after the initial treatment, small areas of erythema and papules developed over approximately 30% of the body (grade 3), although these improved with oral prednisolone (PSL) at 30 mg/day. The primary tumor was resected 18 days after the first administration of ICIs. Four cycles of the combination therapy were completed over 10 weeks without any severe adverse events other than the rash. Ten days after the fourth administration of N + I combined therapy, he complained of strong pain in the right eye, numbness in the right face, and blurred vision in both eyes. We consulted an ophthalmologist, and bilateral uveitis (grade 2) was diagnosed.\n\nIn addition to bilateral uveitis, he complained about hypesthesia and pain in the territory of the right maxillary nerve and dysesthesia in all 4 limbs (grade 2–3) at the same moment. We consulted neurologists, who diagnosed drug-induced polyneuropathy. The patient was intravenously administered methylprednisolone (mPSL) at a dose of 1 mg/kg/day. Brain magnetic resonance imaging revealed enhancement on the right trigeminal nerve, which was considered to represent the source of right facial pain. Twelve weeks after the first administration of ICIs, he developed right peripheral facial nerve palsy, weakness in all the limbs (most prominently in the right upper limb), with diminished deep tendon reflexes in the lower limbs, and sensory impairment with dysesthesia and paresthesia in the distal limbs. Moreover, he became unable to stand and walk independently due to limb weakness with generalized areflexia 13 days after the onset of pain in the right eye. Nerve conduction studies for the right ulnar nerve and posterior tibial nerve revealed prolonged distal latency, conduction block, and decreased conduction velocity, suggesting demyelinating neuropathy (Fig. 1). We finally diagnosed immune-related demyelinating peripheral neuropathy and, therefore, increased the dose of mPSL to 2 mg/kg/day for 3 weeks. Motor and sensory symptoms subsequently showed gradual improvement.\n\nAfter 3 weeks, we gradually tapered the dose of intravenous mPSL from 2 to 1 mg/kg/day, then switched to oral PSL at a dose of 60 mg/day and tapered that by decreasing the dose by 5 mg/day every other week. Muscle weakness ameliorated in parallel with the improvement of nerve conduction studies. At 87 days after the development of right eye pain, he was able to walk unassisted, but mild facial nerve palsy remained.\n\nTo further clarify the immunological background that might correlate with immune-related demyelinating peripheral neuropathy, we performed the human leukocyte antigen (HLA) analysis, which revealed that this patient possessed HLA-DQB1 polymorphisms (DQB1*040101 and *060401).\n\nDiscussion\nIn this report, we have described a case of immune-related demyelinating peripheral neuropathy with cranial neuropathy caused by N + I combined therapy for advanced melanoma, successfully treated with high-dose mPSL (2 mg/kg/day). Neurotoxicity is a rare immune-related adverse event in patients who have been treated with ICIs [4]. Indeed, the frequency of neurotoxicity is 1% with anti-CTLA4 antibody monotherapy, 3% with anti-PD-1 antibody monotherapy, and 14% with N + I combined therapy [4]. The onset period appears to be about 12 months after starting monotherapy, whereas symptoms manifest within the first 3 months in combination therapy [4]. Histological findings for neuropathy caused by ICIs include dense infiltration of lymphocytes around microvessels associated with nerves, suggesting that this neuropathy might be similar to autoimmune inflammatory neuropathy [5]. Since melanocytes and Schwann cells share several similar antigens, such as S100, treatment with ICIs against melanoma might lead to the development of autoimmune reactions against Schwann cells [6]. In addition, in the present case, we administered N + I combined therapy in a neoadjuvant setting, which could have strongly induced melanoma-reactive T-cell clones at the tumor site [7], leading to migration into peripheral blood and the development of widespread autoimmune-like neuropathy. Indeed, various neurotoxicities caused by ICIs have been reported, including peripheral neuropathy, Guillain-Barré syndrome, cranial nerve palsy, demyelinating disease, myasthenia gravis syndrome, meningitis, encephalitis, central nervous system demyelination, optic neuritis, transverse myelitis, and ipsilateral mononeuritis, such as Bell's palsy [4]. For ICIs-related neuropathies, such as those mentioned above, several treatments have been reported, generally starting with oral or intravenous injection of PSL at 0.5–1.0 mg/kg bodyweight, mPSL at 1–2 mg/kg, and then consideration of intravenous immunoglobulin and plasmapheresis as additional therapies for steroid-resistant patients [4]. Approximately one-third of patients who develop immune-related neurotoxicity remain with some degree of residual dysfunction [4]. On the other hand, patients who developed neurotoxicity from ICIs have shown longer progression-free and overall survival than those who did not.\n\nIn this report, we described an atypical neuropathy caused by N + I combination therapy before primary tumor resection. Although the clinical type of demyelinating neuropathy with weakness of the whole body including the face was Guillain-Barré syndrome-like in our present case, the response to steroids was similar to chronic demyelinating neuropathy, which was represented by chronic inflammatory demyelinating polyneuropathy. Ten months after symptom onset, facial nerve palsy remains despite continued administration of PSL at 8 mg/day. Unlike spontaneously developing demyelinating peripheral neuropathy, the present case suggests that high-dose mPSL monotherapy, without intravenous immunoglobulin, is useful for treating ICIs-induced immune-related demyelinating peripheral neuropathy.\n\nStatement of Ethics\nThe patient has given his written informed consent to the publication of his case.\n\nDisclosure Statement\nThe authors have no conflicting interests to declare.\n\nFunding Sources\nThere were no funding sources.\n\nAuthor Contributions\nY. Kambayashi designed the research study. Y. Kambayashi, T. Fujimura, and H. Kuroda treated the patient and acquired the clinical data. A. Otsuka and H. Irie performed HLA typing. Y. Kambayashi, T. Fujimura, and H. Kuroda wrote the manuscript. T. Fujimura and S. Aiba supervised the study.\n\nFig. 1 Nerve conduction studies in the present case. a Motor conduction study of the right ulnar nerve shows prolonged latency in proximal stimulations, conduction block between the wrist and elbow, and decreased conduction velocity between the wrist and elbow and across the elbow. b Motor conduction study of the right posterior tibial nerve shows prolonged latency in proximal stimulation, conduction block between the ankle and popliteal fossa, and decreased conduction velocity between the ankle and popliteal fossa.\n==== Refs\nReferences\n1 Wolchok JD Chiarion-Sileni V Gonzalez R Rutkowski P Grob JJ Cowey CL Overall survival with combined nivolumab and ipilimumab in advanced melanoma N Engl J Med 2017 377 (14) 1345 56 28889792 \n2 Hayat S Jahan I Das A Hassan Z Howlader ZH Mahmud I Human leukocyte antigen-DQB1 polymorphisms and haplotype patterns in Guillain-Barré syndrome Ann Clin Transl Neurol 2019 6 (9) 1849 57 31469245 \n3 Fujimura T Kambayashi Y Sato Y Tanita K Amagai R Hashimoto A Successful treatment of unresectable advanced melanoma by administration of nivolumab with ipilimumab before primary tumor resection Front Med (Lausanne) 2019 6 140 31297373 \n4 Spain L Tippu Z Larkin JM Carr A Turajlic S How we treat neurological toxicity from immune checkpoint inhibitors ESMO open 2019 4 (Suppl 4) e000540 31423344 \n5 Spain L Walls G Julve M O'Meara K Schmid T Kalaitzaki E Neurotoxicity from immune-checkpoint inhibition in the treatment of melanoma: A single centre experience and review of the literature Ann Oncol 2017 28 (2) 377 85 28426103 \n6 Liao B Shroff S Kamiya-Matsuoka C Tummala S Atypical neurological complications of ipilimumab therapy in patients with metastatic melanoma Neuro-oncology 2014 16 (4) 589 93 24482447 \n7 Blank CU Rozeman EA Fanchi LF Sikorska K van de Wiel B Kvistborg P Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage iii melanoma Nat Med 2018 24 (11) 1655 61 30297911\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "13(1)",
"journal": "Case reports in oncology",
"keywords": "Advanced melanoma; Demyelinating peripheral neuropathy; High-dose methylprednisolone monotherapy; Immune-related adverse event; Nivolumab plus ipilimumab combined therapy",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "474-477",
"pmc": null,
"pmid": "32508619",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "24482447;28426103;31423344;28889792;31297373;31469245;30297911",
"title": "Severe Demyelinating Neuropathy in an Advanced Melanoma Patient Treated with Nivolumab plus Ipilimumab Combined Therapy.",
"title_normalized": "severe demyelinating neuropathy in an advanced melanoma patient treated with nivolumab plus ipilimumab combined therapy"
} | [
{
"companynumb": "JP-ONO-2020JP005330",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "ENCORAFENIB"
},
"drugadditional": null,
"... |
{
"abstract": "Cavitary pneumonia in immunocompromised patients is a challenging entity. Establishing accurate diagnosis and starting effective antibiotics are essential steps towards improving outcome. A 58-year-old stem cell transplant patient was admitted to the hospital with necrotizing pneumonia caused by nocardia. The disease progressed despite of aggrieve antimicrobial therapy. Nocardiosis continues to be a difficult disease to diagnose and treat.",
"affiliations": "Department of Internal Medicine, Texas Tech University Health Sciences Center, Amarillo, TX, USA.;Section of Infectious Diseases, Department of Internal Medicine, Texas Tech University Health Sciences Center, Amarillo, TX, USA.",
"authors": "Thakore|Sanket R|SR|;Khasawneh|Faisal A|FA|0000-0002-4127-6391",
"chemical_list": null,
"country": "Egypt",
"delete": false,
"doi": "10.1155/2016/3049298",
"fulltext": "\n==== Front\nCan J Infect Dis Med MicrobiolCan J Infect Dis Med MicrobiolCJIDMMThe Canadian Journal of Infectious Diseases & Medical Microbiology = Journal Canadien des Maladies Infectieuses et de la Microbiologie Médicale1712-95321918-1493Hindawi Publishing Corporation 10.1155/2016/3049298Case ReportA 58-Year-Old Female with Progressive Cough and Right Shoulder Pain Thakore Sanket R. \n1\nhttp://orcid.org/0000-0002-4127-6391Khasawneh Faisal A. \n2\n\n*\n1Department of Internal Medicine, Texas Tech University Health Sciences Center, Amarillo, TX, USA2Section of Infectious Diseases, Department of Internal Medicine, Texas Tech University Health Sciences Center, Amarillo, TX, USA*Faisal A. Khasawneh: faisal.khasawneh@advancedicucare.com2016 31 10 2016 2016 304929819 3 2015 7 12 2015 Copyright © 2016 S. R. Thakore and F. A. Khasawneh.2016This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Cavitary pneumonia in immunocompromised patients is a challenging entity. Establishing accurate diagnosis and starting effective antibiotics are essential steps towards improving outcome. A 58-year-old stem cell transplant patient was admitted to the hospital with necrotizing pneumonia caused by nocardia. The disease progressed despite of aggrieve antimicrobial therapy. Nocardiosis continues to be a difficult disease to diagnose and treat.\n==== Body\n1. Case Presentation\nA 58-year-old female after allogeneic stem cell transplant (SCT) for acute myelogenous leukemia (AML) presented with cough productive of brown sputum and right shoulder pain. Her symptoms progressed over the course of 2 weeks. She did not have fever, chills, or shortness of breath. She denied chest pain, vomiting, or diarrhea and she did not report headache, loss of consciousness, or seizures.\n\nShe was diagnosed with AML 2 years ago for which she underwent allogeneic SCT. Thereafter she developed chronic graft versus host disease (cGVHD), which was treated with steroids and mycophenolate mofetil. Her home medications included prednisone, mycophenolate mofetil, and dapsone.\n\nOn examination, she was afebrile with a heart rate of 57, blood pressure of 150/74, and oxygen saturation of 93% on room air. Lung examination revealed reduced air entry and rhonchi over the right upper lung zone. Heart exam revealed regular heart sounds without murmurs and her abdomen was soft without tenderness or organomegaly.\n\nLaboratory tests showed white blood cell count of 7.6 × 109 cells/L (88% neutrophils), hemoglobin of 94 g/L, platelets of 34 × 109 cells/L, and creatinine of 70 μmol/L. Chest computed tomography (CT) scan was done and is shown in Figure 1. Bronchoalveolar (BAL) stains and cultures were negative for bacteria, mycobacteria, and fungi. Serum as well as BAL galactomannan and serum cryptococcal antigen were negative. Her prednisone dose was reduced and she was discharged home on ertapenem and voriconazole that were given on empirical basis.\n\nThe patient's symptoms persisted, so a follow-up chest CT scan was done 2 weeks into treatment (Figure 2). She was readmitted to the hospital and started on broad-spectrum antibiotics: linezolid, imipenem, amikacin, and liposomal amphotericin B. Her vital signs on admission were stable with an oxygen saturation of 93% on room air. Labs were within her baseline. A repeated BAL was performed.\n\nWhat is your diagnosis?\n\n2. Diagnosis\nBAL stains were negative but bacterial cultures grew few branching gram-positive rods that were identified to be N. farcinica. Susceptibility testing was not performed. Liposomal amphotericin B and amikacin were stopped and she continued taking linezolid and imipenem. Trimethoprim/sulfamethoxazole (TMP/SMX) could not be used because she was allergic to sulfa drugs and, unfortunately, sulfa desensitization was not considered. Head CT scan was done and was negative for any brain lesions. Her cough and chest pain worsened and she developed progressive shortness of breath and fevers. Amikacin was added to the regimen without significant improvement in symptoms. She elected to pursue comfort care measures and was discharged to hospice.\n\n3. Discussion\nNocardia species are ubiquitous in nature. Nocardia is a gram-positive aerobic filamentous bacterium and, unlike mycobacteria, it has a “beaded” acid-fast appearance. Nocardia can resemble actinomyces species on gram stain; however the latter is anaerobic and does not take acid-fast bacilli stain [1, 2]. Nocardia is known to cause infections in immunocompromised and occasionally immunocompetent patients [3]. N. asteroides complex is the most commonly encountered and is comprised of N. abscessus, N. cyriacigeorgica, N. farcinica, and N. nova. Other nocardia species of medical importance include N. transvalensis complex, N. brasiliensis, and N. pseudobrasiliensis [1].\n\nThe numbers of reported N. farcinica infections are rising [4]. This is due to technological advancement in diagnostic methods and increasing numbers of immunocompromised hosts. Patients with impaired cell-mediated immunity such as those with lymphoma, leukemia, HIV infection, and organ transplantation and those on long-term steroid or other immunosuppressive therapy are especially at a high risk for this infection [3]. Organ transplantation was cited as one of the major predisposing factors for this infection. The risk of nocardia infection in solid organ transplant recipients is well recognized, but only few cases of nocardia infection after bone marrow transplantation have been reported [5]. Most SCT patients acquire nocardia infection during the first 2 years after transplantation [1].\n\nIn nocardiosis the lungs are the most frequently involved organ and the most common portal of entry. Pulmonary nocardiosis can present as an acute, subacute, or chronic infection. The symptoms may include productive or nonproductive cough, shortness of breath, chest pain, hemoptysis, fever, and night sweats. The radiologic manifestations are nonspecific and include nodules with or without cavitation, reticulonodular opacities, and pleural effusion [6]. In light of the above, pulmonary nocardiosis is easily misdiagnosed as bacterial pneumonia, tuberculosis, or other cavitary lung processes [7].\n\nExtrapulmonary nocardiosis is relatively common and occurs through contiguous spread within the thoracic cavity and hematogenous dissemination. The central nervous system (CNS) is the most common extrapulmonary system to be involved, and more than one intracranial abscess can be found [1]. Skin involvement as a primarily or secondarily affected organ has been described. Nocardia bacteremia is uncommon, but cases have been reported. Therefore, all patients with pulmonary nocardiosis should be carefully assessed for disseminated disease by at least a carful skin exam and brain CT scan.\n\nDelay in establishing the correct diagnosis is common due to the nonspecific clinical presentation and the difficulty in cultivating nocardia [1]. Microscopic examination of specimens submitted to the microbiology laboratory is the first step in providing a definitive diagnosis. Gram stain and modified acid-fast stain can give initial clue for the diagnosis meanwhile awaiting culture results. Cultures for nocardia require a minimum of 48–72 h before colonies become evident [8]. Because it requires selective cultures and takes longer than usual, it is important that physicians notify the microbiology laboratory personnel about suspecting this infection [7]. Identification of nocardia isolates at the species level by means of routine phenotypic testing is difficult; however, a simple identification scheme, based on a panel of nine conventional phenotypic and enzymatic tests, has been developed and validated for the rapid identification of the most common nocardia spp. [8]. With modern molecular techniques, such as polymerase chain reaction, restriction enzyme analysis, and 16S ribosomal RNA (rRNA) gene sequencing, faster and easier nocardia identification is possible; however, not all laboratories are equipped with these modern technologies [8]. According to some literature, sequence analysis of the 16S rRNA gene is becoming the gold standard for definitive species identification [9].\n\nThe choice of antibiotic therapy depends on the severity and localization of the infection, presence of dissemination, host's immune status, drug interactions and toxicity, and the nocardia species implicated [8]. It is critical to identify nocardia species, as studies have shown significant variability in antibiotic susceptibility among different species [5]. It is also crucial to do antimicrobial susceptibility testing whenever possible. The Clinical and Laboratory Standard Institute has approved standard susceptibility testing and interpretation method by microdilution in cation-supplemented Mueller-Hinton broth [8].\n\nSulfonamides continue to be the mainstay of therapy for nocardial infections. Sulfamethoxazole, with or without trimethoprim, and sulfisoxazole are commonly used. Ideally, the dosage should be adjusted to achieve peak blood levels of 100–150 mg/dL [5]. Unfortunately, resistance to sulfa drugs, especially among N. farcinica and N. otitidiscaviarum isolates, has been reported [8]. N farcinica also has a high degree of resistance to various other antibiotics, especially broad-spectrum cephalosporins [5].\n\nData from in vitro analyses of antimicrobial susceptibility patterns performed at the Centers for Disease Control and Prevention, Atlanta, GA, revealed that all N. farcinica isolates tested were resistant to ampicillin, cefixime, and tobramycin [10]. The majority were also resistant to rifampin (93%), cefamandole (89%), ceftriaxone (86%), erythromycin (86%), and trimethoprim (82%). The isolates were commonly susceptible to imipenem, dapsone, doxycycline, minocycline, and TMP/SMX (<14% resistant). Finally, all isolates were susceptible to amikacin [10]. For patients with life-threatening infection, it seems prudent to initiate therapy with two or three drugs with the aim of switching to oral monotherapy when the patient's condition is stable and the results of in vitro studies are available [11].\n\nCombination therapy with imipenem and cefotaxime, amikacin and TMP/SMX, imipenem and TMP/SMX, amikacin and cefotaxime, or amikacin and imipenem was shown to be superior to single-agent therapy [11]. Some experts are of the opinion that combination of imipenem with amikacin should be started as the first-line therapy for cerebral and pulmonary nocardiosis [1]. An advantage of amikacin and imipenem is their bactericidal activity, compared to the bacteriostatic activity of the sulfonamides [10].\n\nThere are no recommendations for prophylaxis against nocardia infection among immunocompromised hosts; however it has been observed that prevalence of nocardia infection is low among advanced HIV patients who are on daily TMP/SMX for Pneumocystis jiroveci prophylaxis. Interestingly intermittent TMP/SMX is not as effective in preventing nocardia as daily TMP/SMX [1]. Immunocompetent patients with pulmonary nocardiosis or disseminated nocardiosis outside the CNS should be treated for 6–12 months. In the case of immunocompromised patients, treatment should continue for 1 year and, if possible, the dose of the immune depressant drugs should be reduced [8].\n\n4. Conclusion\nThe diagnosis of pulmonary nocardiosis requires a high index of suspicion, as the presenting symptoms are nonspecific. One should always keep in mind nocardia infection when immunocompromised patients present with pulmonary infection. Physicians should notify the microbiology laboratory when nocardia is suspected. N. farcinica infection is potentially lethal because of its tendency to disseminate and its resistance to many antibiotics. Different nocardia species have variable antibiotic susceptibility pattern; this is why identification of nocardia to the species level is crucial. Sequence analysis of the 16S rRNA gene is becoming the gold standard for definitive species identification. It is also important to screen all patients with pulmonary nocardiosis for disseminated infection. It seems prudent to initiate therapy with two or three drugs with the aim of switching to monotherapy when the patient's condition is stable and the results of in vitro studies are available.\n\nCompeting Interests\nAll authors have no conflict of interests to report.\n\nFigure 1 Computed tomography scan sections of the lungs showing right-sided cavitary nodule abutting the chest wall.\n\nFigure 2 Computed tomography scan sections of the lungs showing progressive enlargement of the right-sided cavitary nodule and the development of new bilateral alveolar opacities.\n==== Refs\n1 Wilson J. W. Nocardiosis: updates and clinical overview Mayo Clinic Proceedings 2012 87 4 403 407 10.1016/j.mayocp.2011.11.016 2-s2.0-84859835515 22469352 \n2 Tachezy M. Simon P. Ilchmann C. Vashist Y. K. Izbicki J. R. Gawad K. A. Abscess of adrenal gland caused by disseminated subacute Nocardia farcinica pneumonia. A case report and mini-review of the literature BMC Infectious Diseases 2009 9, article 194 10.1186/1471-2334-9-194 2-s2.0-72549112073 \n3 Bocchino M. Paglia M. G. Marruchella A. Contini S. Festa A. Saltini C. Molecular diagnosis of fatal Nocardia farcinica pneumonia in an HIV-negative patient Respiration 2008 75 4 461 465 10.1159/000094390 2-s2.0-43649099165 16825752 \n4 Tremblay J. Thibert L. Alarie I. Valiquette L. Pépin J. Nocardiosis in Quebec, Canada, 1988–2008 Clinical Microbiology and Infection 2011 17 5 690 696 10.1111/j.1469-0691.2010.03306.x 2-s2.0-79955403374 20636427 \n5 Chouciño C. Goodman S. A. Greer J. P. Stein R. S. Wolff S. N. Dummer J. S. Nocardial infections in bone marrow transplant recipients Clinical Infectious Diseases 1996 23 5 1012 1019 10.1093/clinids/23.5.1012 2-s2.0-0029911038 8922795 \n6 Blackmon K. N. Ravenel J. G. Gomez J. M. Ciolino J. Wray D. W. Pulmonary nocardiosis: computed tomography features at diagnosis Journal of Thoracic Imaging 2011 26 3 224 229 10.1097/rti.0b013e3181f45dd5 2-s2.0-80051517624 21785288 \n7 Sawai T. Yoshioka S. Matsuo N. Suyama N. Kohno S. A case of community-acquired pneumonia due to influenza A virus and Nocardia farcinica co-infection Journal of Infection and Chemotherapy 2014 20 8 506 508 10.1016/j.jiac.2014.04.008 2-s2.0-84925884739 24855916 \n8 Martínez R. Reyes S. Menéndez R. Pulmonary nocardiosis: risk factors, clinical features, diagnosis and prognosis Current Opinion in Pulmonary Medicine 2008 14 3 219 227 10.1097/mcp.0b013e3282f85dd3 2-s2.0-42449161091 18427245 \n9 Park S.-D. Kim H. J. Jang I. H. First report of nocardia farcinica bursitis in a patient with diabetes mellitus Annals of Laboratory Medicine 2014 34 3 252 255 10.3343/alm.2014.34.3.252 2-s2.0-84900431869 24790916 \n10 Hitti W. Wolff M. Two cases of multidrug-resistant Nocardia farcinica infection in immunosuppressed patients and implications for empiric therapy European Journal of Clinical Microbiology & Infectious Diseases 2005 24 2 142 144 10.1007/s10096-005-1285-y 2-s2.0-16844363123 15692815 \n11 Bittar F. Stremler N. Audié J.-P. Nocardia farcinica lung infection in a patient with cystic fibrosis: a case report Journal of Medical Case Reports 2010 4, article 84 10.1186/1752-1947-4-84 2-s2.0-77952616856\n\n",
"fulltext_license": "CC BY",
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"journal": "The Canadian journal of infectious diseases & medical microbiology = Journal canadien des maladies infectieuses et de la microbiologie medicale",
"keywords": null,
"medline_ta": "Can J Infect Dis Med Microbiol",
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"title": "A 58-Year-Old Female with Progressive Cough and Right Shoulder Pain.",
"title_normalized": "a 58 year old female with progressive cough and right shoulder pain"
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"abstract": "Intracranial bleeding (ICB) is a feared complication of systemic anticoagulation. Factor Xa inhibitors (FXaI) are used frequently due to their improved safety profile and predictable kinetics. Andexanet alfa was recently approved for emergent reversal of FXaI agents but was not compared formally to 4-Factor Prothrombin Complex Concentrates (4FPCC) which are the current standard of care in many centers. The objective of this study is to formally evaluate the hemostatic efficacy of 4FPCC in patients with FXaI-associated ICB.\n\n\n\nWe performed a retrospective cohort study of patients receiving 4FPCC for the reversal of a FXaI in the setting of acute ICB. Hemostatic efficacy was adjudicated via evaluation of post-4FPCC CT scan using the criteria closely mirroring those outlined in Annexa-4 (excellent < 20% expansion, good > 20% but ≤ 35% expansion, poor > 35% expansion). Each image was reviewed by two neurointensivist attendings for grading. Mortality was assessed until date of discharge. Charts were screened for thrombotic events out to 30 days post-4FPCC administration.\n\n\n\nA total of 59 patients were included in the final analysis. The mean age in years was 78.5 ± 10.9 and 56% were male. Apixaban was the most common FXaI prescribed at the time of presentation (67.8%). Most patients were on FXaI therapy for stroke prevention in the setting of atrial fibrillation (81.3%). Median Glasgow Coma Scale at presentation was 15(IQR 12-15), with the most frequently presenting ICB type being intracerebral hemorrhage (52.5%). The mean dose of 4FPCC prescribed was 46.6 (± 8.2) units/kg. Of those receiving 4FPCC for FXaI ICB, 88% were graded as having an excellent or good hemostatic outcome with excellent interrater reliability. Survival was high at 89.8%, and thrombotic events were seen in seven patients (11.9%).\n\n\n\n4FPCC appears to be an effective and safe option for FXaI-associated ICB with outcomes comparable to andexanet alfa. A formal prospective evaluation of this strategy versus andexanet alpha including cost analysis is warranted.",
"affiliations": "Department of Critical Care Medicine, Mercy Hospital St. Louis, 615 S. New Ballas Road, St. Louis, MO, 63303, USA. Matthew.korobey@mercy.net.;Department of Critical Care Medicine, Mercy Hospital St. Louis, 615 S. New Ballas Road, St. Louis, MO, 63303, USA.;Department of Critical Care Medicine, Mercy Hospital St. Louis, 615 S. New Ballas Road, St. Louis, MO, 63303, USA.;St. Louis College of Pharmacy, St. Louis, USA.;Department of Critical Care Medicine, Mercy Hospital St. Louis, 615 S. New Ballas Road, St. Louis, MO, 63303, USA.",
"authors": "Korobey|Matthew J|MJ|;Sadaka|Farid|F|;Javed|Muhammad|M|;Moynihan|Meghin|M|;Alsaei|Ahmed|A|",
"chemical_list": "D000925:Anticoagulants; D001779:Blood Coagulation Factors; D065427:Factor Xa Inhibitors; D011994:Recombinant Proteins; C025667:prothrombin complex concentrates",
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"mesh_terms": "D000925:Anticoagulants; D001779:Blood Coagulation Factors; D065427:Factor Xa Inhibitors; D006801:Humans; D008297:Male; D011994:Recombinant Proteins; D015203:Reproducibility of Results; D012189:Retrospective Studies",
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"title": "Efficacy of 4-Factor Prothrombin Complex Concentrates in Factor Xa Inhibitor-Associated Intracranial Bleeding.",
"title_normalized": "efficacy of 4 factor prothrombin complex concentrates in factor xa inhibitor associated intracranial bleeding"
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"abstract": "Long-term outcomes after face transplantation are rarely reported in the scientific literature. Here we present outcome data of a partial face allograft recipient 10 years after transplantation.\n\n\n\nMedical records were reviewed for functional and psychosocial outcomes as well as complications. Histopathologic analyses of autopsy tissues and characterization of skin immune cells were performed.\n\n\n\nThe patient retained long-term motor and sensory function, though with a noticeable drop in sensory function after year 5. Social reintegration of the patient was marked by reconnection with his family and participation in public social activities. Immunosuppressive therapy consisted of tacrolimus (target levels 6-8 ng/mL after the first year), mycophenolate, and prednisone, while steroids were completely weaned between years 1 and 7. One acute cellular rejection episode of grade II or higher occurred on average per year and led to chronic skin changes (papillary dermal sclerosis with superficial hyalinization, epidermal thinning with loss of rete ridges, perieccrine fibrosis), but the allograft vessels, muscles, adipose tissue, and bone were spared. Allograft skin was characterized by increased number of CD4+ TNF-α/IL17A producing T-cells as compared with native skin. Long-term kidney function was maintained at 60 mL/min estimated glomerular filtration rate. Unfortunately, the preexisting hepatitis C virus infection with liver cirrhosis was resistant to 3 treatments with new direct-acting antivirals and eventually hepatocellular carcinoma developed, causing the patient's death 10 years after transplantation.\n\n\n\nThis report suggests that face transplants can maintain their function for at least 10 years. Chronic skin changes can occur independently of allograft vasculopathy.",
"affiliations": "Division of Plastic Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.;Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.;Schuster Transplantation Research Center, Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.;Division of Plastic Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Department of Hand, Plastic and Reconstructive Surgery, Microsurgery, Burn Trauma Center, BG Trauma Center Ludwigshafen, University of Heidelberg, Germany.;Division of Plastic Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.;Division of Plastic Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.;Division of Plastic Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.;Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.;Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.;Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.;Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.;Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.;Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.;Schuster Transplantation Research Center, Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.;Division of Plastic Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA. Electronic address: bpomahac@bwh.harvard.edu.",
"authors": "Kollar|Branislav|B|;Rizzo|Natalie M|NM|;Borges|Thiago J|TJ|;Haug|Valentin|V|;Abdulrazzak|Obada|O|;Kauke|Martin|M|;Safi|Ali-Farid|AF|;Lian|Christine G|CG|;Marty|Francisco M|FM|;Rutherford|Anna E|AE|;Mitchell|Richard N|RN|;Murphy|George F|GF|;Tullius|Stefan G|SG|;Riella|Leonardo V|LV|;Pomahac|Bohdan|B|",
"chemical_list": "D015704:CD4 Antigens; D007166:Immunosuppressive Agents; D020381:Interleukin-17; D014409:Tumor Necrosis Factor-alpha",
"country": "United States",
"delete": false,
"doi": "10.1016/j.surg.2020.01.010",
"fulltext": null,
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"issn_linking": "0039-6060",
"issue": "167(6)",
"journal": "Surgery",
"keywords": null,
"medline_ta": "Surgery",
"mesh_terms": "D064591:Allografts; D015704:CD4 Antigens; D006528:Carcinoma, Hepatocellular; D054445:Facial Transplantation; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D019698:Hepatitis C, Chronic; D006801:Humans; D007166:Immunosuppressive Agents; D020381:Interleukin-17; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D012867:Skin; D013601:T-Lymphocytes; D066027:Transplant Recipients; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "0417347",
"other_id": null,
"pages": "991-998",
"pmc": null,
"pmid": "32113580",
"pubdate": "2020-06",
"publication_types": "D016428:Journal Article; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": null,
"title": "Accelerated chronic skin changes without allograft vasculopathy: A 10-year outcome report after face transplantation.",
"title_normalized": "accelerated chronic skin changes without allograft vasculopathy a 10 year outcome report after face transplantation"
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"companynumb": "US-TEVA-2020-US-1796953",
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"abstract": "The treatment of advanced heart failure (HF) in children and infants poses a serious management problem. Heart failure in that patient group is usually of congenital aetiology. The treatment schedules for paediatric patients are in most cases adapted from the guidelines for treatment of adults. Up to 2009, the treatment of that extremely difficult group of patients was limited to pharmacological therapy and occasional heart transplantations. Constantly increasing problems with recruiting donors, especially for the paediatric group, contribute to the fact that mechanical support with the use of ventricular assist devices is for many children the only chance of surviving the period of waiting for a heart donor.\n\n\n\nThe aim of the study was to analyse the outcomes of circulatory support in Poland and to assess the advisability of this method for treatment of children with severe HF.\n\n\n\nThis treatment of paediatric patients is currently used in three Polish centres. From December 28, 2009 to August 1, 2015, 27 implantations of BerlinHeart EXCOR® mechanical circulatory support system were performed in children aged from one month to 16 years (10 patients below one year of age; 37%). Left ventricular assist devices were implanted to 21 patients, whereas the remaining children received biventricular support. The most common reason for using this method was HF developed in the course of cardiomyopathy. In one case, HF after Fontan operation was the indication.\n\n\n\nThe duration of the circulatory support period ranged from six to 1215 days. It was followed by successful heart transplantations in 10 (37%) patients, in five (18.1%) it resulted in regeneration of the heart, enabling explantation of the device, whereas three children are still waiting for transplantations. Nine (33%) children died during the therapy because of thromboembolic complications.\n\n\n\nAs follows from our data, circulatory support utilising the BerlinHeart EXCOR® system is an effective and promising method used as a bridge to cardiac transplantation, or for regeneration of the myocardium in paediatric patients. In the group of the youngest and the most difficult patients, the method requires close cooperation of the medical and nursing personnel.",
"affiliations": "Department of Cardiac Surgery, Heart Transplantation and Mechanical Circulatory Support for Children, Silesian Centre for Heart Diseases, Zabrze, Poland. pawlaks@poczta.fm;Department of Cardiac Surgery, Heart Transplantation and Mechanical Circulatory Support for Children, Silesian Centre for Heart Diseases, Zabrze, Poland;Department of Cardiac Surgery and Cardiac Intensive Care, University Children’s Hospital, Kraków, Poland;Department of Cardiac Surgery, Heart Transplantation and Mechanical Circulatory Support for Children, Silesian Centre for Heart Diseases, Zabrze, Poland;Department of Cardiac Surgery, Children’s Memorial Health Institute, Warsaw, Poland;Department of Cardiac Surgery, Heart Transplantation and Mechanical Circulatory Support for Children, Silesian Centre for Heart Diseases, Zabrze, Poland;Department of Cardiac Surgery, Heart Transplantation and Mechanical Circulatory Support for Children, Silesian Centre for Heart Diseases, Zabrze, Poland;Department of Congenital Heart Diseases and Paediatric Cardiology, Silesian Centre for Heart Diseases, Medical University of Silesia, Zabrze, Poland;Department of Cardiac Surgery, Children’s Memorial Health Institute, Warsaw, Poland;Chair and Clinical Department of Cardiac Surgery, Transplantation, Vascular, and Endovascular Surgery, Silesian Centre for Heart Diseases, Silesian Medical University, Zabrze, Poland",
"authors": "Pawlak|Szymon|S|;Przybylski|Roman|R|;Skalski|Janusz|J|;Śliwka|Joanna|J|;Kansy|Andrzej|A|;Grzybowski|Adam|A|;Wierzyk|Arkadiusz|A|;Białkowski|Jacek|J|;Maruszewski|Bohdan|B|;Zembala|Marian|M|",
"chemical_list": null,
"country": "Poland",
"delete": false,
"doi": "10.5603/KP.a2017.0201",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-9032",
"issue": "76(1)",
"journal": "Kardiologia polska",
"keywords": "heart failure; heart transplantation; mechanical circulatory support",
"medline_ta": "Kardiol Pol",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D006333:Heart Failure; D016027:Heart Transplantation; D006353:Heart-Assist Devices; D006801:Humans; D007223:Infant; D008297:Male; D011044:Poland; D016896:Treatment Outcome",
"nlm_unique_id": "0376352",
"other_id": null,
"pages": "83-90",
"pmc": null,
"pmid": "29168549",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "First Polish analysis of the treatment of advanced heart failure in children with the use of BerlinHeart EXCOR mechanical circulatory support.",
"title_normalized": "first polish analysis of the treatment of advanced heart failure in children with the use of berlinheart excor mechanical circulatory support"
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"abstract": "Spinal dural arteriovenous fistulas (SDAVFs) are often misdiagnosed as their symptoms are non-specific, leading to treatment delay and a poor outcome. We describe the case of a 53-year-old man with a history of progressive paraparesis that worsened abruptly after an epidural corticosteroid injection. We highlight here the need for high diagnostic suspicion for an SDAVF in patients deteriorating after an epidural injection and an indication of repeated spine imaging in such cases. Finally, this is the first reported case of an SDAVF in a HIV-positive patient and it emphasizes the need for a broad differential diagnosis.\nConsider an SDAVF in cases of slowly progressive paraparesis and hypoaesthesia, especially if symptoms worsen after an epidural injection.The need for an in-depth work-up including repeated angiographic explorations in cases where no malformation is found in a straightforward manner.In a patient infected with HIV, even though a broad range of neuromuscular diseases can be suspected, non-related aetiologies should not be forgotten.",
"affiliations": "Internal Medicine Department, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.;Centre de Référence Neuromusculaire, Service de Neurologie, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.;Interventional Neuroradiology Department, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.;Neurosurgery Department, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.;Centre de Référence Neuromusculaire, Service de Neurologie, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.",
"authors": "Le Goueff|Anouk|A|;Mavroudakis|Nicolas|N|;Mine|Benjamin|B|;De Witte|Olivier|O|;Remiche|Gauthier|G|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.12890/2020_001673",
"fulltext": null,
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"issn_linking": "2284-2594",
"issue": "7(10)",
"journal": "European journal of case reports in internal medicine",
"keywords": "Arteriovenous fistula; epidural analgesia; paraplegia; spinal cord",
"medline_ta": "Eur J Case Rep Intern Med",
"mesh_terms": null,
"nlm_unique_id": "101648453",
"other_id": null,
"pages": "001673",
"pmc": null,
"pmid": "33083349",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "17353341;19213818;22769730;29571868",
"title": "Acute Paraparesis after Epidural Corticosteroid Injection Revealing Spinal Dural Arteriovenous Fistula in a HIV Patient.",
"title_normalized": "acute paraparesis after epidural corticosteroid injection revealing spinal dural arteriovenous fistula in a hiv patient"
} | [
{
"companynumb": "BE-PFIZER INC-2020459010",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "CHOLESTYRAMINE"
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"abstract": "Lacosamide is a new antiepileptic drug (AED) apparently devoid of major pharmacokinetic interactions. Data from a small postmarketing assessment suggest people who had lacosamide co-prescribed with a voltage-gated sodium channel (VGSC)-blocking AED seemed more likely to discontinue lacosamide because of tolerability problems. Among 39 people with refractory epilepsy who developed neurotoxicity (diplopia, dizziness, drowsiness) on lacosamide treatment given in combination with VGSC-blocking AEDs, we identified 7 (17.9%) without any changes in serum levels of other AEDs in whom the symptoms were ameliorated by dose reduction of the concomitant VGSC-blocking AED. Symptoms in these people seem to have arisen from a pharmacodynamic interaction between lacosamide and other VGSC-blocking AEDs. Slow-inactivated VGSCs targeted by lacosamide might be more sensitive to the effects of conventional VGSC-blocking AEDs. Advising people to reduce concomitantly the conventional VGSC-blocking AEDs during lacosamide uptitration in cases of neurotoxicity might improve the tolerability of combination treatment.",
"affiliations": "Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.",
"authors": "Novy|Jan|J|;Patsalos|Philip N|PN|;Sander|Josemir W|JW|;Sisodiya|Sanjay M|SM|",
"chemical_list": "D000081:Acetamides; D000927:Anticonvulsants; D026941:Sodium Channel Blockers; D000078334:Lacosamide",
"country": "United States",
"delete": false,
"doi": "10.1016/j.yebeh.2010.10.002",
"fulltext": null,
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"issn_linking": "1525-5050",
"issue": "20(1)",
"journal": "Epilepsy & behavior : E&B",
"keywords": null,
"medline_ta": "Epilepsy Behav",
"mesh_terms": "D000081:Acetamides; D000328:Adult; D000368:Aged; D000927:Anticonvulsants; D004347:Drug Interactions; D004827:Epilepsy; D005260:Female; D006801:Humans; D000078334:Lacosamide; D008297:Male; D008875:Middle Aged; D020258:Neurotoxicity Syndromes; D026941:Sodium Channel Blockers",
"nlm_unique_id": "100892858",
"other_id": null,
"pages": "20-3",
"pmc": null,
"pmid": "21056937",
"pubdate": "2011-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Lacosamide neurotoxicity associated with concomitant use of sodium channel-blocking antiepileptic drugs: a pharmacodynamic interaction?",
"title_normalized": "lacosamide neurotoxicity associated with concomitant use of sodium channel blocking antiepileptic drugs a pharmacodynamic interaction"
} | [
{
"companynumb": "GB-Glenmark Generics Europe Ltd.-GGEL20110200063",
"fulfillexpeditecriteria": "1",
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"patient": {
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"activesubstancename": "TOPIRAMATE"
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{
"abstract": "BACKGROUND\nHepatitis-associated aplastic anemia is a common syndrome in patients with bone marrow failure. However, hepatitis-associated aplastic anemia is an immune-mediated disease that does not appear to be caused by any of the known hepatitis viruses including hepatitis C virus. In addition, to the best of our knowledge there are no reported cases of patients with chronic hepatitis C virus infection developing aplastic anemia associated with pegylated interferon alpha 2a treatment.\n\n\nMETHODS\nWe report the case of a 46-year-old Greek man who developed severe aplastic anemia during treatment with pegylated interferon alpha 2a for chronic hepatitis C virus infection. He presented with generalized purpura and bruising, as well as pallor of the skin and mucous membranes. His blood tests showed pancytopenia. He underwent allogeneic bone marrow transplantation after completing two courses of immunosuppressive therapy with antithymocyte globulin and cyclosporin A.\n\n\nCONCLUSIONS\nThe combination of a specific environmental precipitant represented by the hepatitis C virus infection, an altered metabolic detoxification pathway due to treatment with pegylated interferon alpha 2a and a facilitating genetic background such as polymorphism in metabolic detoxification pathways and specific human leukocyte antigen genes possibly conspired synergistically in the development of aplastic anemia in this patient. Our case clearly shows that the causative role of pegylated interferon alpha 2a in the development of aplastic anemia must not be ignored.",
"affiliations": "Department of Pathophysiology, Medical School, National University of Athens, Athens, Greece. mvoulgar@med.uoa.gr.",
"authors": "Ioannou|Savvas|S|;Hatzis|Gregorios|G|;Vlahadami|Ioanna|I|;Voulgarelis|Michael|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/1752-1947-4-268",
"fulltext": "\n==== Front\nJ Med Case ReportsJournal of Medical Case Reports1752-1947BioMed Central 1752-1947-4-2682070469910.1186/1752-1947-4-268Case ReportAplastic anemia associated with interferon alpha 2a in a patient with chronic hepatitis C virus infection: a case report Ioannou Savvas 1savvasdoc@hotmail.comHatzis Gregorios 1grhatzis@med.uoa.grVlahadami Ioanna 1ioannamd@yahoo.grVoulgarelis Michael 1mvoulgar@med.uoa.gr1 Department of Pathophysiology, Medical School, National University of Athens, Athens, Greece2010 12 8 2010 4 268 268 11 12 2009 12 8 2010 Copyright ©2010 Ioannou et al; licensee BioMed Central Ltd.2010Ioannou et al; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Introduction\nHepatitis-associated aplastic anemia is a common syndrome in patients with bone marrow failure. However, hepatitis-associated aplastic anemia is an immune-mediated disease that does not appear to be caused by any of the known hepatitis viruses including hepatitis C virus. In addition, to the best of our knowledge there are no reported cases of patients with chronic hepatitis C virus infection developing aplastic anemia associated with pegylated interferon alpha 2a treatment.\n\nCase presentation\nWe report the case of a 46-year-old Greek man who developed severe aplastic anemia during treatment with pegylated interferon alpha 2a for chronic hepatitis C virus infection. He presented with generalized purpura and bruising, as well as pallor of the skin and mucous membranes. His blood tests showed pancytopenia. He underwent allogeneic bone marrow transplantation after completing two courses of immunosuppressive therapy with antithymocyte globulin and cyclosporin A.\n\nConclusions\nThe combination of a specific environmental precipitant represented by the hepatitis C virus infection, an altered metabolic detoxification pathway due to treatment with pegylated interferon alpha 2a and a facilitating genetic background such as polymorphism in metabolic detoxification pathways and specific human leukocyte antigen genes possibly conspired synergistically in the development of aplastic anemia in this patient. Our case clearly shows that the causative role of pegylated interferon alpha 2a in the development of aplastic anemia must not be ignored.\n==== Body\nIntroduction\nHepatitis C virus (HCV) infection is a major public health issue. In developed countries, HCV accounts for 20% of cases of acute hepatitis, 70% of cases of chronic hepatitis, 40% of cases of end-stage cirrhosis, 60% of cases of hepatocellular carcinoma, and 30% of liver transplants [1]. Moreover, extrahepatic manifestations of chronic HCV infection are clinically present in almost 40% of infected patients. These manifestations include essential mixed cryoglobulinemia, sicca syndrome, membranoproliferative glomerulonephritis, thrombocytopenia, and autoimmune hemolytic anemia (AIHA) [2].\n\nHepatitis-associated aplastic anemia (HAA) is a not uncommon syndrome in patients with bone marrow failure, with hepatitis documented in 2 to 5% of cases of aplastic anemia (AA) occurring in the West [3,4] and 4 to 10% in the Far East [5]. Characteristically, the HAA syndrome is more prevalent among young men. The hepatitis generally follows a benign course, but the onset of AA two to three months later is usually fatal if left untreated. HAA may be induced by the presence of HCV or hepatitis B virus infection, and also by infections with other viruses such as human immunodeficiency virus (HIV), Epstein-Barr virus (EBV), transfusion-transmitted virus and echovirus [6]. However, most cases of HAA are seronegative for the known hepatitis viruses, including hepatitis A, B, C, and G (GB virus C) [7]. The clinical features of the syndrome and the patient's response to immunosuppressive treatment strongly indicate that the liver and marrow abnormalities in patients with HAA are immune-mediated [8,9].\n\nPegylated interferon alpha 2a (PEG-IFN-α 2a) or 2b plus ribavirin is currently the standard regimen for patients with HCV infection. A wide range of adverse reactions, including flu-like symptoms, nausea, anorexia, diarrhea, psychiatric symptoms, alopecia, injection-site reactions, leukopenia, thrombocytopenia, hemolytic anemia, cough, dyspnea, rash, pruritus, insomnia, and ataxia, have been associated with PEG-IFN-α 2a plus ribavirin treatment. Treatment with interferon (IFN)-α has also been reported to trigger autoimmune phenomena in up to 3% of cases, with AIHA being the most prevalent and most significant phenomena seen in clinical practice [10]. Furthermore, due to its inhibition of cellular growth, interference with oncogene expression and augmentation of lymphocyte cytotoxicity for target cells, IFN-α may cause bone marrow suppression, including potentially severe cytopenias and, very rarely, AA [11].\n\nThe primary observed serious adverse side effect of ribavirin treatment is hemolytic anemia. Ribavirin is an antiviral nucleoside analogue; the mechanism of ribavirin-induced hemolytic anemia has not been clearly established. Anemia is most likely related to extensive ribavirin accumulation in erythrocytes subsequent to active unidirectional transmembraneous transport. Ribavirin exerts its toxicity through an inhibition of intracellular energy metabolism and oxidative membrane damage, leading to an accelerated extravascular hemolysis by the reticulo-endothelial system [12]. Lau et al. describe how ribavirin, following uptake into cells, is phosphorylated and converted to ribavirin triphosphates, which then must be dephosphorylated for elimination from the cells [13]. However, because red blood cells lack dephosphorylation enzymes, ribavirin accumulates in cells and destroys them, causing hemolytic anemia. Severe anemia develops in about 10% of patients treated with ribavirin, and they require close monitoring of hemoglobin (Hb) levels and often ribavirin dose reduction, which may compromise sustained virologic response.\n\nHerein, we report the development of AA in a patient with chronic HCV infection following treatment with PEG-IFN-α 2a plus ribavirin. By reviewing the literature on the subject and the course of the patient's disease, we have come to the conclusion that, on balance, the development of AA was a side effect of the patient's treatment with PEG-IFN-α 2a within a facilitating genetic and environmental background.\n\nCase presentation\nA 46-year-old Greek man was diagnosed with HCV infection (genotype 4 h) and a combination treatment of PEG-IFN-α 2a (180 μg, weekly) and ribavirin (1200 mg/day) was commenced for a period of 48 weeks. Before starting the combination treatment his blood tests were normal with a platelet count of 250,000 cells/mm3, Hb of 16.3 g/dl, and a white blood cell (WBC) count of 6300 cells/mm3. The treatment was well tolerated by the patient with a normalization of his liver function tests. Four months later he was referred to the department of pathophysiology with a bleeding tendency and unexplained fatigue of recent onset. No contact with a benzene or pesticide was mentioned by the patient. A physical examination revealed generalized purpura and bruising, and pallor of the skin and mucous membranes. The patient's liver, spleen and lymph nodes were not enlarged. Routine blood work showed severe pancytopenia with a platelet count of 20,000 cells/mm3, Hb of 7.9 g/dl, reticulocytes at 0% and a WBC count of 600 cells/mm3 with an absolute neutrophil count of 180 cells/mm3. Further investigation showed the patient had a normal liver function test and normal prothrombin time. On admission, his serum HCV ribonucleic acid (RNA) levels were more than 1 × 106 units/ml. Serology for HIV, and hepatitis A and B viruses was negative, as were immunoglobulin (Ig) M antibodies against cytomegalovirus, parvovirus B19, herpes simplex viruses 1 and 2, and EBV. Further investigations showed the following: urea 20 mg/dl (normal range 17 to 50 mg/dl), creatinine 1.0 mg/dl (normal range 0.7 to 1.4 mg/dl), sodium 139 mMol/L (normal range 136 to 145 mMol/L), potassium 3.8 mMol/L (normal range 3.5 to 5.0 mMol/L), glucose 99 mg/dl (normal range 74 to 115 mg/dl), calcium 8.8 mg/dl (normal range 8.6 to 10.2 mg/dl), amylase 48 U/L (normal range 20 to 104 U/L), creatine phosphokinase 200 U/L (normal range 20 to 190 U/L), lactate dehydrogenase 296 U/L (normal range 200 to 460 U/L), uric acid 4.6 mg/dl (normal range 3.5 to 7.2 mg/dl), erythrocyte sedimentation rate 34 mm in the first hour (normal range 0 to 20 mm), and C-reactive protein 37.4 mg/L (normal range 0 to 5 mg/L). Screening for several autoantibodies was negative. Thyroid function tests and complement serum levels were normal. A serum protein electrophoresis showed no hypogammaglobulinemia or abnormal bands. A computed tomography examination of the patient's abdomen and thorax was unremarkable. The patient's bone marrow biopsy was profoundly hypocellular with a decrease in all haematopoietic cells (Figure 1); the bone marrow space was composed mostly of fat cells and marrow stroma. The CD34 cell population was more than 1%. Malignant infiltrates or fibrosis were absent. Fluorescence-activated cell sorting analysis of the patient's bone marrow showed decreased marrow elements with normal lymphocyte gate. A cytogenetic examination showed the patient had a normal karyotype. The presence of paroxysmal nocturnal hemoglobulinuria was excluded by flow cytometry with the use of anti-CD55 and anti-CD59 antibodies. Human leukocyte antigen (HLA) typing revealed the presence of DRB1*0701 and DRB1*1501 alleles. HLA matching identified a sister with an identical HLA type.\n\nFigure 1 A bone marrow biopsy showing the absence of hematopoietic tissue and its replacement with fat. Hematoxylin & eosin staining. 20× magnification.\n\nThe diagnosis of severe AA was made in the patient. Treatment with PEG-IFN-α 2a and ribavirin were discontinued. However, after two weeks, the pancytopenia did not resolve and the patient was started on immunosuppressive therapy with rabbit antithymocyte globulin (Thymo-globulin, Genzyme; 15 mg/kg/day, for five consecutive days) and cyclosporin A (6 mg/kg/day, in divided doses every 12 hours). Prophylaxis against serum sickness was instituted with methylprednisolone (2 mg/kg/day) for five days with subsequent halving of the dose every week until discontinuation on day 28. The patient had a partial response that was noted on day 60 with a platelet count of 27,000 cells/mm3, Hb of 9.3 g/dl and WBC of 5000 cells/mm3. The patient was dependent on red blood cell and platelet transfusions and was on granulocyte colony stimulating factor (400 μg/m2/day, three times a week). Therefore, on day 120 a second course of antithymocyte globulin therapy was given. The patient received a full cyclosporin A dose for six months, after which cyclosporin A was tapered off slowly (0.5 mg/kg/month). During the period of aplasia, the patient was persistently pyrexial and broadspectrum antibiotics in the form of an antipseudomonal penicillin (piperacillin/tazobactam) and a carbapenem (meropenem) were administered consecutively, as well as an antifungal agent (liposomal amphotericin B).\n\nEight months after the first course of immunosuppressive treatment, the patient's Hb was 10.6 g/dl, platelet count was 32,000 cells/mm3 and WBC was 3590 cells/mm3 with an absolute neutrophil count of 2261 cells/mm3. At that time the patient was still receiving blood and platelet transfusions. His serum HCV RNA levels were more than 1 × 106 units/ml indicating that the patient was continuously viremic. His liver function tests remained normal during follow up. The patient underwent allogeneic bone marrow transplantation. He experienced a hemorrhagic stroke due to prolonged thrombocytopenia and died during the recovery phase.\n\nDiscussion\nAA is characterized by a diminished number of or absent bone marrow precursor cells and peripheral cytopenias. The disease is estimated to occur in two to four people per million per year [14,15]. Numerous studies have shown that AA behaves as an immune-mediated disease. Cytotoxic T cells expressing T-helper 1 cytokines, especially IFN-γ, have been implicated in the pathophysiology of T cell-induced, Fas-mediated stem cell apoptosis of CD34 target stem cells [16]. Why T cells are activated in patients with AA is unclear. A number of reports have documented a significantly increased incidence of HLA-DR15 in patients with AA [17]. Additionally, in a recent study, HLA-DRB1 gene analysis showed an increased prevalence of DRB1*07 in patients with AA compared with the normal population, at 15.7% and 8.3%, respectively. This raises the possibility that HLA-DRB1*07 plays a significant role in the development of AA [18]. Our patient had both DRB1*0701 and DRB1*1501 alleles, which may indicate that their presence is likely to allow for preferential presentation of peptides, such as viruses or drugs, to specific T cells, driving the autoimmune T cell-mediated destruction of the patient's hematopoietic cells. This process might have been further enhanced both in quantity and quality by the action of the IFN-α treatment that the patient received.\n\nHowever, the association of AA and chronic HCV infection remains ill-defined. In a recent report, there were two cases of patients with AA, unrelated to IFN-α therapy, among 35 patients with chronic HCV infection [19]. Another case of a patient with severe AA associated with HCV infection has also been reported [20]. Several other studies have shown that the prevalence of anti-HCV antibodies in patients with HAA receiving blood transfusions increases with the duration and number of transfusions, and is therefore probably transfusion related [21]. Taking these data into account and considering our patient's clinical course (normal liver function tests at presentation, late onset of AA), it is unlikely that the HCV infection alone was the cause of his ensuing AA.\n\nBone marrow aplasia may also occur as an idiosyncratic drug reaction, with a sudden onset after several months of therapy, and it is usually irreversible. In this regard, two cases of patients with bone marrow hypoplasia and fibrosis following IFN-α treatment have been reported in the literature [22]. A severe and persistent pancytopenia has also been described in a 42-year-old woman with a non-Hodgkin's lymphoma following a course of 10 days of intramuscular leukocyte IFN-α [23]. Aslam and Singh reported a case of AA with IFN-β 1a in a patient with multiple sclerosis [24]. However, to date, there have been no reports of patients with severe AA associated with PEG-IFN-α 2a in chronic HCV infection.\n\nSome reports have suggested a genetic predisposition to bone marrow injury in patients with an idiosyncratic drug reaction. In such cases, direct toxicity may occur, possibly due to genetically determined differences in metabolic detoxification pathways [25,26]. Interestingly, the most commonly used dose of IFN-α in humans inhibits cytochrome P450, thus decreasing the hepatic clearance of some drugs, and this inhibition persists during IFN-α therapy leading to various forms of hepatic and extrahepatic toxicity [27].\n\nOn the other hand, clinical characteristics and circumstantial evidence suggest that idiosyncratic drug reactions are caused by reactive metabolites and are immune-mediated. The possible mechanisms of stem cell damage by drug-mediated immune damage have not been clearly defined. One suggestion mechanism is the 'spoiled membrane hypothesis', which envisages aberrant stem cell antigens as a result of drug action [28]. Another possibility that has not been widely explored is that drug-induced AA is uncommon because it requires a coincident event at or near the time the drug is given. We could speculate that such an event might be a virus infection such as with HCV. Therefore, we suggest that the combination of a specific environmental precipitant represented by the HCV infection, an aberrant expression of cellular proteins in the patient's bone marrow cells caused by a disturbed PEG-IFN-α 2a-associated drug metabolic detoxification pathway, and a facilitating genetic background (specific HLA genes) offering a more effective presentation of viral and drug metabolites to the T cells conspired, possibly synergistically, in the initiation of the destructive immune attack towards the patient's bone marrow cells and the development of severe AA in our patient.\n\nThe approach to treating a patient with medication-induced AA entails stopping the offending drug while supporting the patient during the period of pancytopenia. The therapeutic issue revolves around the dilemma of a period of initial observation versus aggressive therapy, such as immunosuppression or bone marrow transplantation. Waiting for a week and then conducting a repeat bone marrow biopsy may avoid potential side effects associated with the therapy without foreclosing on a definitive treatment, which is to be promptly instituted in the absence of signs of recovery.\n\nConclusions\nWe present a case of a 46-year-old man who developed severe AA while being treated with PEG-IFN-α 2a for chronic HCV infection. To the best of our knowledge, this is the first report of a patient with this complication associated with PEG-IFN-α 2a in the growing body of literature. As health care providers, physicians should be aware of this rare but life-threatening complication of PEG-IFN-α 2a treatment.\n\nAbbreviations\nAA: aplastic anemia; AIHA: autoimmune hemolytic anemia; EBV: Epstein-Barr virus; HAA: hepatitis-associated aplastic anemia; Hb: hemoglobin; HCV: hepatitis C virus; HIV: human immunodeficiency virus; HLA: human leukocyte antigen; IFN: interferon; Ig: immunoglobulin; PEG-IFN-α 2a: pegylated interferon alpha 2a; RNA: ribonucleic acid; WBC: white blood cells.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors' contributions\nSI and MV were responsible for writing the manuscript. IV and GH provided clinical details and contributed to the final manuscript. All authors read and approved the final manuscript.\n==== Refs\nEASL International Consensus Conference on Hepatitis C Consensus statement J Hepatol 1999 30 956 961 10.1016/S0168-8278(99)80154-8 10365827 \nPalekar NA Harrison SA Extrahepatic manifestations of hepatitis C South Med J 2005 98 1019 1023 10.1097/01.smj.0000182873.62872.22 16295816 \nBottiger LE Westerholm B Aplastic anaemia. III. Aplastic anaemia and infectious hepatitis Acta Med Scand 1972 192 323 6 5081070 \nMary JY Baumelou E Guiguet M Epidemiology of aplastic anemia in France: A prospective multicentric study Blood 1990 75 1646 53 2183887 \nYoung NS Issaragrasil S Chieh CW Takaku F Aplastic anaemia in the Orient Br J Haematol 1986 62 1 6 10.1111/j.1365-2141.1986.tb02893.x 3942690 \nGonzalez-Casas R Jones EA Moreno-Otero R Spectrum of anemia associated with chronic liver disease World J Gastroenterol 2009 15 4653 4658 10.3748/wjg.15.4653 19787828 \nBrown KE Tisdale J Barrett AJ Dunbar CE Young NS Hepatitis-associated aplastic anemia N Engl J Med 1997 336 1059 1064 10.1056/NEJM199704103361504 9091802 \nGonzalez-Casas R Garcia-Buey L Jones EA Gisbert JP Moreno-Otero R Systematic review: hepatitis-associated aplastic anaemia-a syndrome associated with abnormal immunological function Aliment Pharmacol Ther 2009 30 436 443 10.1111/j.1365-2036.2009.04060.x 19508613 \nLu J Basu A Melenhorst JJ Young NS Brown KE Analysis of T-cell repertoire in hepatitis-associated aplastic anemia Blood 2004 103 4588 4593 10.1182/blood-2003-11-3959 14988156 \nConrad B Potential mechanisms of interferon-alpha induced autoimmunity Autoimmunity 2003 36 519 523 10.1080/08916930310001602137 14984029 \nPlatanias LC Fish EN Signaling pathways activated by interferons Exp Hematol 1999 27 1583 1592 10.1016/S0301-472X(99)00109-5 10560905 \nRussmann S Grattagliano I Portincasa P Palmieri VO Palasciano G Ribavirin-induced anemia: mechanisms, risk factors and related targets for future research Curr Med Chem 2006 13 3351 3357 10.2174/092986706778773059 17168855 \nLau JY Tam RC Liang TJ Hong Z Mechanism of action of ribavirin in the combination treatment of chronic HCV infection Hepatology 2002 35 1002 1009 10.1053/jhep.2002.32672 11981750 \nYoung NS Acquired aplastic anemia Ann Intern Med 2002 136 534 46 11926789 \nWallerstein RO Condit PK Kasper CK Statewide study of chloramphenicol therapy and fatal aplastic anemia JAMA 1969 208 2045 50 10.1001/jama.208.11.2045 5818983 \nYoung NS Calado RT Scheinberg P Current concepts in the pathophysiology and treatment of aplastic anemia Blood 2006 108 2509 2519 10.1182/blood-2006-03-010777 16778145 \nSugimori C Yamazaki H Feng X Mochizuki K Kondo Y Takami A Chuhjo T Kimura A Teramura M Mizoguchi H Omine M Nakao S Roles of DRB1 *1501 and DRB1 *1502 in the pathogenesis of aplastic anemia Exp Hematol 2007 35 13 20 10.1016/j.exphem.2006.09.002 17198869 \nYari F Sobhani M Vaziri MZ Bagheri N Sabaghi F Talebian A Association of aplastic anaemia and Fanconi's disease with HLA-DRB1 alleles Int J Immunogenet 2008 35 453 456 10.1111/j.1744-313X.2008.00810.x 19046304 \nRamos-Casals M García-Carrasco M López-Medrano F Trejo O Forns X López-Guillermo A Muñoz C Ingelmo M Font J Severe autoimmune cytopenias in treatment-naive hepatitis C virus infection: clinical description of 35 cases Medicine (Baltimore) 2003 82 87 96 10.1097/00005792-200303000-00003 12640185 \nGruber A Grillner L Norder H Magnius L Björkholm M Severe aplastic anemia associated with seronegative community-acquired hepatitis C virus infection Ann Hematol 1993 66 157 159 10.1007/BF01697628 7682449 \nPaquette RL Kuramoto K Tran L Sopher G Nimer SD Zeldis JB Hepatitis C virus infection in acquired aplastic anaemia Am J Hematol 1998 58 122 126 10.1002/(SICI)1096-8652(199806)58:2<122::AID-AJH6>3.0.CO;2-U 9625579 \nHoffmann A Kirn E Krueger GR Fischer R Bone marrow hypoplasia and fibrosis following interferon treatment In Vivo 1994 8 605 612 7893989 \nMangan KF Zidar B Shadduck RK Zeigler Z Winkelstein A Interferon-induced aplasia: evidence for T-cell-mediated suppression of hematopoiesis and recovery after treatment with horse antihuman thymocyte globulin Am J Hematol 1985 19 401 413 10.1002/ajh.2830190411 2411129 \nAslam AK Singh T Aplastic anemia associated with interferon beta-1a Am J Ther 2002 9 522 523 10.1097/00045391-200211000-00011 12424511 \nLee KA Kim SH Woo HY Hong YJ Increased frequencies of glutathione S-transferase (GSTM1 and GSTT1) gene deletions in Korean patients with acquired aplastic anemia Blood 2001 98 3483 3485 10.1182/blood.V98.12.3483 11719393 \nPoonkuzhali B Shaji RV Salamun DE George B Srivastava A Chandy M Cytochrome P4501A1 and glutathione S transferase gene polymorphisms in patients with aplastic anemia in India Acta Haematol 2005 114 127 132 10.1159/000087885 16227674 \nIsrael BC Blouin R McIntyre W Shedlofsky S Effects of interferon-? monotherapy on hepatic drug metabolism in cancer patients Br J Pharmac 1993 36 229 235 \nWaring JF Anderson MG Idiosyncratic toxicity: mechanistic insights gained from analysis of prior compounds Curr Opin Drug Discov Devel 2005 8 59 65 15679173\n\n",
"fulltext_license": "CC BY",
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"journal": "Journal of medical case reports",
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"medline_ta": "J Med Case Rep",
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"references": "2183887;7682449;17168855;11926789;11981750;9114909;14984029;16778145;10560905;19787828;9625579;15679173;10365827;7893989;2411129;3942690;17198869;14988156;16227674;12640185;5081070;19046304;5818983;11719393;12424511;16295816;9091802;19508613",
"title": "Aplastic anemia associated with interferon alpha 2a in a patient with chronic hepatitis C virus infection: a case report.",
"title_normalized": "aplastic anemia associated with interferon alpha 2a in a patient with chronic hepatitis c virus infection a case report"
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"abstract": "Talimogene laherparepvec (TVEC) is an FDA-approved oncolytic herpes virus used to treat unresectable stage IIIB to IV metastatic melanoma via intralesional injection. This study aims to characterize the efficacy TVEC in patients with unresectable stage IIIB to IV melanoma.\n\n\n\nWe performed a multi-institutional, IRB-approved review of all patients who received TVEC at 3 centers from October 2015 to October 2018. Clinicopathologic characteristics, TVEC treatment data, and outcomes were assessed.\n\n\n\nOne hundred and twenty-one patients received TVEC, of which 80 patients had available treatment response data with at least 3-month follow-up. Anatomic sites treated were 19 (24%) head and neck, 9 (11%) upper extremity, 12 (15%) torso, and 40 (50%) lower extremity. Thirty-four (42.5%) patients did not receive therapy before TVEC. Side effects were mild and self-limited, most commonly flu-like symptoms seen in 22 (28%) patients. Median follow-up was 9 months (range 3 to 28 months), with complete local response in 31 (39%) and partial response in 14 (18%) patients. Of complete responders, 29 (37%) had no evidence of disease at last follow-up and received a median of 6 (range 2 to 12) cycles of therapy.\n\n\n\nTalimogene laherparepvec is a well-tolerated, durable treatment option for patients with unresectable locoregional melanoma, particularly in stage IIIB/C disease. Additionally, we found that TVEC can be administered safely across anatomic sites that are otherwise not amenable to other local therapies.",
"affiliations": "Division of Surgical Oncology and Endocrine Surgery, Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC.;Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL.;Division of Surgical Oncology, Department of Surgery, Emory University School of Medicine, Atlanta, GA.;Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL.;Division of Hematology and Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.;Division of Surgical Oncology, Department of Surgery, Emory University School of Medicine, Atlanta, GA.;Division of Surgical Oncology, Department of Surgery, Emory University School of Medicine, Atlanta, GA.;Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL.;Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL.;Division of Surgical Oncology and Endocrine Surgery, Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC. Electronic address: david_ollila@med.unc.edu.",
"authors": "Louie|Raphael J|RJ|;Perez|Matthew C|MC|;Jajja|Mohammad Raheel|MR|;Sun|James|J|;Collichio|Frances|F|;Delman|Keith A|KA|;Lowe|Michael|M|;Sarnaik|Amod A|AA|;Zager|Jonathan S|JS|;Ollila|David W|DW|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D001688:Biological Products; C000629782:talimogene laherparepvec",
"country": "United States",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000074322:Antineoplastic Agents, Immunological; D001688:Biological Products; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D018259:Herpesvirus 1, Human; D006801:Humans; D015552:Injections, Intralesional; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D009367:Neoplasm Staging; D050130:Oncolytic Virotherapy; D012189:Retrospective Studies; D012878:Skin Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "9431305",
"other_id": null,
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"pubdate": "2019-04",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Real-World Outcomes of Talimogene Laherparepvec Therapy: A Multi-Institutional Experience.",
"title_normalized": "real world outcomes of talimogene laherparepvec therapy a multi institutional experience"
} | [
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"abstract": "A 64-year-old woman was diagnosed with advanced gastric cancer with solitary liver metastasis. Although the HER2 status of the tumor was IHC2+, no further examination for HER2 status using FISH was performed. Four courses of S-1 and cisplatin chemotherapy were administered. The primary lesion and metastatic lesion were confirmed to have partially regressed. After 4 courses of chemotherapy, an open total gastrectomy, D2 dissection, pancreatosplenectomy, and posterior segmental hepatectomy were performed. Her postoperative course was uneventful. On histopathology, cancer cells were found in the resected stomach and resected liver. However, the HER2 statuses of the resected specimens were negative. After discharge, she received S-1 therapy for 1 year. Upon evaluation 1 year and 1 month postoperatively, the tumor marker CA19-9 was elevated. An enhanced CT scan showed multiple lung metastases and lymph node metastases in the pancreatic tail. Three courses of XELOX therapy(capecitabine and oxaliplatin)were administered. However, tumor marker levels continued to increase, and the metastasis continued to enlarge. Although the HER2 status of the resected site was negative, the HER2 status of the biopsy specimen before chemotherapy was positive on FISH. Therefore, weekly paclitaxel and trastuzumab therapy was initiated and repeated for 6 courses, after which an enhanced CT showed significant reduction(nearly CR)of multiple lung metastases and lymph node metastases. This suggests that HER2-negative conversion had occurred at the resected site. However, the HER2 status of the metastatic sites was considered positive.",
"affiliations": "Dept. of Surgery, Yokohama Ekisaikai Hospital.",
"authors": "Horii|Nobutoshi|N|;Morioka|Daisuke|D|;Yamaguchi|Kazuya|K|;Sato|Yoshiki|Y|",
"chemical_list": "D000970:Antineoplastic Agents; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; D000068878:Trastuzumab",
"country": "Japan",
"delete": false,
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"issue": "43(10)",
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"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D017024:Chemotherapy, Adjuvant; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008875:Middle Aged; D018719:Receptor, ErbB-2; D012008:Recurrence; D013274:Stomach Neoplasms; D000068878:Trastuzumab",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1207-1209",
"pmc": null,
"pmid": "27760939",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Remarkable Response to Trastuzumab Observed in a Case of Gastric Cancer with HER2-Negative Conversion.",
"title_normalized": "remarkable response to trastuzumab observed in a case of gastric cancer with her2 negative conversion"
} | [
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"activesubstancename": "CAPECITABINE"
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{
"abstract": "Cerebellar changes have been reported in relationship to epilepsy alone as well as to phenytoin therapy for the control of seizures. The cliniconeuropathological correlation between these changes and epilepsy or the anticonvulsant is usually complicated by the presence of both variables. Experimental evidence suggests that phenytoin alone may be sufficient to cause cerebellar changes following intoxication. We report a case of cerebellar degeneration in a patient treated with isoniazid and prophylactically treated wtih phenytoin who never had a seizure.",
"affiliations": null,
"authors": "Rapport|R L|RL|;Shaw|C M|CM|",
"chemical_list": "D010672:Phenytoin; D007538:Isoniazid",
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"mesh_terms": "D002531:Cerebellum; D004827:Epilepsy; D005260:Female; D005911:Gliosis; D006801:Humans; D007538:Isoniazid; D008875:Middle Aged; D009410:Nerve Degeneration; D009457:Neuroglia; D010672:Phenytoin; D011689:Purkinje Cells; D014390:Tuberculosis, Meningeal",
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"references": null,
"title": "Phenytoin-related cerebellar degeneration without seizures.",
"title_normalized": "phenytoin related cerebellar degeneration without seizures"
} | [
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"abstract": "Ephedrine decongestant products are widely used. Common side effects include palpitations, nervousness, and headache. More severe adverse reactions include cardiomyopathy and vasospasm. We report the case of an otherwise healthy 37-year-old woman who presented with acute-onset quadriplegia and heart failure. She had a normal chest radiograph on admission, but developed marked pulmonary edema and bilateral effusions the next day. Echocardiography revealed a left ventricular ejection fraction of 0.18 and no obvious intrinsic pathologic condition such as foramen narrowing on spinal imaging. Laboratory screening was positive for methamphetamines in the urine, and the patient admitted to having used, over the past several weeks, multiple ephedrine-containing products for allergy-symptom relief. She was ultimately diagnosed with an acute catecholamine-induced cardiomyopathy and spinal artery vasospasm consequential to excessive use of decongestants. Her symptoms resolved completely with supportive care and appropriate heart-failure management. An echocardiogram 2 weeks after admission showed improvement of the left ventricular ejection fraction to 0.33. Ten months after the event, the patient was entirely asymptomatic and showed further improvement of her ejection fraction to 0.45. To our knowledge, ours is the first report of spinal artery vasospasm resulting in quadriplegia in a human being after ephedrine ingestion.",
"affiliations": null,
"authors": "Snipelisky|David F|DF|;Kurklinsky|Andrew K|AK|;Chirila|Razvan|R|",
"chemical_list": "D014663:Nasal Decongestants; D004809:Ephedrine",
"country": "United States",
"delete": false,
"doi": "10.14503/THIJ-14-4487",
"fulltext": null,
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"issue": "42(6)",
"journal": "Texas Heart Institute journal",
"keywords": "Cardiomyopathies/chemically induced; catecholamines; central nervous system stimulants/adverse effects; ephedra/adverse effects; heart failure/chemically induced; plant preparations/adverse effects; quadriplegia; sympathomimetics; vasoconstrictor agents/adverse effects",
"medline_ta": "Tex Heart Inst J",
"mesh_terms": "D000328:Adult; D001158:Arteries; D009202:Cardiomyopathies; D004452:Echocardiography; D004562:Electrocardiography; D004809:Ephedrine; D005260:Female; D006333:Heart Failure; D006801:Humans; D014663:Nasal Decongestants; D011782:Quadriplegia; D020127:Recovery of Function; D013116:Spinal Cord; D013318:Stroke Volume; D013997:Time Factors; D016896:Treatment Outcome; D014661:Vasoconstriction; D016277:Ventricular Function, Left",
"nlm_unique_id": "8214622",
"other_id": null,
"pages": "575-8",
"pmc": null,
"pmid": "26664316",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19797977;14742827;4213103;18633017;11262584;10691253;7365503;18401217",
"title": "Transient Cardiomyopathy and Quadriplegia Induced by Ephedrine Decongestant.",
"title_normalized": "transient cardiomyopathy and quadriplegia induced by ephedrine decongestant"
} | [
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"activesubstancename": "OXYMETAZOLINE"
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... |
{
"abstract": "This report describes two cases of tachycardia-induced cardiomyopathy secondary to incessant ectopic atrial tachycardia (EAT) in an infant presenting with severe left ventricular dysfunction and hemodynamic instability. The two cases were managed differently. The first required mechanical ventilation and was resistant to conventional antiarrhythmic drugs. After the initiation of enteral ivabradine (0.15mg/kg) the heart rate slowed with significant improvement in hemodynamics, peripheral perfusion and sinus rhythm was restored after 12 hours. Ivabradine was continued and the patient was discharged home after 10 days of hospitalization. The second case was managed by early initiation of ivabradine and resulted in restoration of sinus rhythm within 4 hours, thus avoiding trials of conventional anti-arrhythmic drugs with unstable hemodynamic profile. The infant was discharged after 5 days of hospitalization on ivabradine..",
"affiliations": "Department of Pediatrics, Krishna Maternity Home and Children Hospital, Tirunelveli, Tamil Nadu, India.;Department of Pediatrics (Cardiology), Oregon Health and Science University, Portland, Oregon, USA.;Department of Pediatrics, Krishna Maternity Home and Children Hospital, Tirunelveli, Tamil Nadu, India.;Department of Pediatrics, Krishna Maternity Home and Children Hospital, Tirunelveli, Tamil Nadu, India.;Department of Pediatrics, Krishna Maternity Home and Children Hospital, Tirunelveli, Tamil Nadu, India.;Department of Pediatrics, Royal hospital, Tirunelveli, India.;Department of Pediatrics, Royal hospital, Tirunelveli, India.;Department of Pediatric Cardiology, Amrita Institute of Medical Sciences, Kochi, Kerala, India.",
"authors": "Karmegaraj|Balaganesh|B|;Balaji|Seshadri|S|;Raju|Prasanna Narayanan|PN|;Subramanian|Pradheep|P|;Subramanian|Raju|R|;Ibrahim|Syed|S|;Razeen|Mohamed|M|;Krishnakumar|Raman|R|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/apc.apc_37_21",
"fulltext": "\n==== Front\nAnn Pediatr Cardiol\nAnn Pediatr Cardiol\nAPC\nAnnals of Pediatric Cardiology\n0974-2069\n0974-5149\nWolters Kluwer - Medknow India\n\nAPC-14-422\n10.4103/apc.apc_37_21\nCase Report\nTachycardia-induced cardiomyopathy secondary to incessant ectopic atrial tachycardia in two infants: Potential new indication for early initiation of enteral ivabradine\nKarmegaraj Balaganesh 12\nBalaji Seshadri 3\nRaju Prasanna Narayanan 1\nSubramanian Pradheep 1\nSubramanian Raju 1\nIbrahim Syed 4\nRazeen Mohamed 4\nKrishnakumar Raman 2\n1 Department of Pediatrics, Krishna Maternity Home and Children Hospital, Tirunelveli, Tamil Nadu, India\n2 Department of Pediatric Cardiology, Amrita Institute of Medical Sciences, Kochi, Kerala, India\n3 Department of Pediatrics (Cardiology), Oregon Health and Science University, Portland, Oregon, USA\n4 Department of Pediatrics, Royal hospital, Tirunelveli, India\nAddress for correspondence: Dr. Balaganesh Karmegaraj, Sowmi Fetal and Pediatric Cardiac Centre, Tirunelveli, Tamil Nadu, India. Department of Pediatric Cardiology, Amrita Institute of Medical Sciences, Kochi, Kerala, India. E-mail: pedsheartkbg@gmail.com\nJul-Sep 2021\n20 8 2021\n14 3 422427\n20 2 2021\n26 5 2021\n05 6 2021\nCopyright: © 2021 Annals of Pediatric Cardiology\n2021\nhttps://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.\nThis report describes two cases of tachycardia-induced cardiomyopathy secondary to incessant ectopic atrial tachycardia (EAT) in an infant presenting with severe left ventricular dysfunction and hemodynamic instability. The two cases were managed differently. The first required mechanical ventilation and was resistant to conventional antiarrhythmic drugs. After the initiation of enteral ivabradine (0.15mg/kg) the heart rate slowed with significant improvement in hemodynamics, peripheral perfusion and sinus rhythm was restored after 12 hours. Ivabradine was continued and the patient was discharged home after 10 days of hospitalization. The second case was managed by early initiation of ivabradine and resulted in restoration of sinus rhythm within 4 hours, thus avoiding trials of conventional anti-arrhythmic drugs with unstable hemodynamic profile. The infant was discharged after 5 days of hospitalization on ivabradine..\n\nEctopic atrial tachycardia\ninfant\nivabradine\ntachycardia-induced cardiomyopathy\n==== Body\npmcINTRODUCTION\n\nIncreased automaticity is the underlying mechanism of several pediatric tachyarrhythmias including EAT. Ivabradine is a selective inhibitor of the hyperpolarization-activated cyclic nucleotide-gated channels involved in the funny current responsible for spontaneous depolarization of cardiac pacemaker cells. By inhibition of the funny current and reduction of automaticity, ivabradine represents a potential therapy for these conditions with hemodynamically neutral profile in contrast to many of the conventional antiarrhythmic drugs. Ivabradine demonstrates use dependence, resulting in a greater effect at higher heart rates. Ivabradine has been utilized so far in the literature for treatment in children with heart failure, EAT, multifocal atrial tachycardia, congenital, and postoperative junctional ectopic tachycardias.[1234567] We report here, the utility of ivabradinein two hemodynamically unstable infants with tachycardia-induced cardiomyopathy secondary to EAT. The two were managed differently, with earlier utilisation of ivabradine in the second patient, having learned from the first patient.\n\nCASE REPORT\n\nCase 1\n\nA 60-day-old male weighing 5 kg was referred for cardiac evaluation in view of suspicion of dilated cardiomyopathy. Physical examination revealed tachycardia and tachypnea with decreased pulses and peripheral perfusion. Chest radiograph showed a cardiothoracic ratio of 70%. The 12-lead electrocardiogram (ECG) showed a regular narrow QRS tachycardia with a rapid ventricular rate of 250 bpm with a long RP interval and abnormal peaked P-wave morphology. Differential diagnosis of ectopic atrial tachycardia (EAT) and permanent junctional reciprocating tachycardia were considered. The P waves were negative in V1 and aVR and positive in leads II, III, and aVF suggestive of EAT of superolateral crista terminalis origin [Figure 1]. Echocardiography showed severe left ventricular (LV) dysfunction with an ejection fraction (EF) of 17% with significant LV dilatation (LVIDd 3.58 cm [Z score + 5.60]).The coronary artery origins and aortic arch were normal. Serum electrolytes and renal function were normal. Severe acute respiratory syndrome coronavirus 2 polymerase chain reaction was negative and antibodies levels were normal. All serum inflammatory/cardiac markers were normal (C-reactive protein, ferritin, troponin I, and CK MB). The NT pro-BNP level was grossly elevated (31,500 pg/ml [normal <125]). Adenosine given during the tachycardia resulted in transient slowing of the heart rate from 250 to 187 bpm followed by reappearance of the tachycardia [Figure 2a and b]. The tachycardia persisted despite giving three doses of bolus intravenous metoprolol and metoprolol infusion. The infant was hemodynamically unstable with poor perfusion, decreased urine output, and low blood pressure (mean 20 mmHg). Hence, synchronized cardioversion with 5J was given with no benefit. Intravenous digoxin 15 μg/kg given over 30 min resulted in decrease in heart rate (107 bpm) followed by severe bradycardia (65 bpm) and cardiac arrest. ECG during the time of bradycardia showed multiple P waves with periods of flat isoelectric line confirming EAT [Figure 2c]. After cardiopulmonary resuscitation (0.4 ml of 1 in 10,000 dilution adrenaline single dose) and mechanical ventilation, heart rate picked up and tachyarrhythmia persisted. Furosemide (1 mg/kg/day), milrinone (0.5 mcg/kg/min), and amiodarone infusion (25 mcg/kg/min for 4 h followed by 15 mcg/kg/min for 24 h) were started in view of severe LV dysfunction and persistent tachyarrhythmia. There was no improvement in the hemodynamics and tachycardia persisted even after continuous metoprolol and amiodarone infusion for 2 h. Hence, enteral sotalol (1 mg/kg) was started. Despite all the above pharmacological interventions for 10 h since admission, the tachyarrhythmia persisted and the mean blood pressure was persistently low with poor urine output. Repeat synchronized cardioversion with 5J resulted in conversion of the rhythm to ventricular fibrillation. Unsynchronized cardioversion 10J thrice resulted in termination of VF and the EAT restarted. The child remained with a poor urine output (<0.3 ml/kg/hr) and hypotension, with mean blood pressure <25 mmHg for >6 h.\n\nFigure 1 The 12-lead electrocardiogram showing a regular narrow QRS tachycardia with a rapid ventricular rate of 250 bpm with a long RP interval. The P waves were negative in V1 and aVR and positive in leads II, III, and aVF suggestive of ectopic atrial tachycardia of superolateral crista terminalis origin\n\nFigure 2 (a and b) Adenosine given during the tachycardia, resulting in transient slowing of the heart rate from 250 bpm to 187 bpm followed by reappearance of the tachycardia. (c) Electrocardiogram during the time of bradycardia following administration of intravenous digoxin showing multiple P waves with periods of flat isoelectric line confirming ectopic atrial tachycardia. (Ectopic P waves marked in red arrows)\n\nConsidering the hemodynamic instability and persistence of tachyarrhythmia despite using most of the conventional antiarrhythmic drugs, we administered enteral ivabradine. Within 45 min of the initiation of ivabradine (0.15 mg/kg), the heart rate slowed down to 190 bpm with significant improvement in the hemodynamics and perfusion (mean BP 40 mmHg). Metoprolol infusion was stopped and amiodarone infusion was continued for 24 h and then stopped. The heart rhythm became sinus after 12 h of enteral ivabradine and digoxin [Figure 3]. The LVEF improved from 17% to 33% after 24 h of ivabradine. The LVIDd started decreasing (LVIDd Z score + 4.26). He was extubated after 48 h of ventilation and put on high flow nasal cannula in view of respiratory distress and moderate LV dysfunction. He had one transient episode of tachyarrhythmia (250 bpm) which lasted for 2 min and terminated by itself. Hence, oral propranolol was added. Milrinone infusion was tapered and stopped with subsequent addition of enalapril. The LV function and LVIDd recovered completely (EF 58%; LVIDd 2 cm (Z score-0.22) after 7 days of achievement of sinus rhythm. The timeline of events which happened during the first 24 h was shown in Figure 4. He was discharged after 10 days of hospitalization on oral ivabradine (0.15 mg/kg twice a day), digoxin (5 μg/kg twice a day), and propranolol (0.5 mg/kg twice a day). The efficacy of the treatment was monitored by patch ambulatory ECG (aECG) recorder for 7 days after discharge. The aECG recordings were predominant in sinus rhythm with short episodes of ectopic atrial rhythm. The average heart rate was 132 bpm (58–163). At follow-up after 3 months, ECG was in sinus rhythm and the LV function (EF 70%) is normal. The developmental milestones are appropriate for the age.\n\nFigure 3 Electrocardiogram showing sinus rhythm\n\nFigure 4 Timeline of events which happened during the 1st 24 h of management\n\nCase 2\n\nA 30 day old boy weighing 3 kg was referred to our pediatric intensive care unit in view of significant respiratory distress and cardiogenic shock. Physical examination revealed tachycardia (200bpm), and tachypnoea with decreased pulses and poor peripheral perfusion. Blood gas showed severe metabolic acidosis (pH 6.9; HCO3 3.6 mol/L; PCO2 15mmHg). The baby was resuscitated with intravenous fluid and sodium bicarbonate correction.The 12-lead electrocardiogram (ECG) showed a regular narrow QRS tachycardia with a rapid ventricular rate of 187 bpm with long RP interval and abnormal peaked P wave morphology.The P waves were biphasic in V1 and positive in leads II, III and aVF suggestive of EAT [Figure 5]. Chest radiograph showed a cardiothoracic ratio of 75%. Echocardiography showed severe left ventricular (LV) dysfunction [ejection fraction (EF) 19%] with significant LV dilatation [LVIDd 2.5cm (Z score +3.18)]. SARS-CoV-2 PCR was negative and antibodies levels were normal. Adenosine given during the tachycardia, resulted in transient termination of the tachyarrhythmia followed by reappearance [Figure 6]. Enteral ivabradine (0.15mg/kg) was given resulting in gradual reduction of heart rate one hour after initiation and the rhythm became sinus after 4 hours. Enteral digoxin (10mcg/kg/day) was added one hour after ivabradine. There was significant improvement in the hemodynamics and perfusion (mean BP 25 mmHg). Blood gas after stabilization revealed improvement in the metabolic acidosis (pH 7.49; HCO3 16.6 mol/L; PCO2 22mmHg). However the respiratory distress and LV dysfunction persisted. Supportive care including bubble continuous positive airway pressure, milrinone and furosemide infusion were provided for the LV dysfunction. He symptomatically improved with supportive care and it was weaned off after 24 hours. LV dimension [LVIDd 1.6cm (Z score -1.29)] and function (EF 55%) improved significantly after 72 hours. He was discharged after 5 days of hospitalization on oral ivabradine (0.15mg/kg twice a day), and digoxin (5mcg/kg twice a day). The timeline of events which happened during the first 72 hours isshown in the Figure 7.\n\nFigure 5 The 12-lead electrocardiogram (ECG) showing a regular narrow QRS tachycardia with a rapid ventricular rate of 187 bpm with long RP interval and abnormal peaked P wave morphology. The P waves were biphasic in V1 and positive in leads II, III and aVF suggestive of ectopic atrial tachycardia (EAT) of crista terminalis origin\n\nFigure 6 (a) Adenosine given during the tachycardia, showing transient termination of the tachyarrhythmia followed by reappearance. (b) ECG showing sinus rhythm after initiation of ivabradine\n\nFigure 7 Timeline of events which happened during the first 72 hours of management in case 2\n\nDISCUSSION\n\nEAT can be defined as a supraventricular tachycardia initiated and sustained by an automatic nonsinus atrial pacemaker, characterized by distinctly visible P waves with an abnormal frontal plane axis and atrial activation sequence.[8] EAT has a variable response to adenosine and may produce transient rate slowing, which is thought to be secondary to the antiadrenergic effect of adenosine. Adenosine A1 receptors are located on the SA node, AV node, and atrial myocytes. Activation of A1 receptor hyperpolarizes the cells of the SA node to give sinus slowing or arrest and on the AV node to give a transient heart block. Tachycardias originating in the atrium such as EAT do not rely on the SA or AV node and thus are not typically terminated by adenosine, although the transient AV block may help elucidate the tachycardia mechanism by allowing examination of the atrial electrical activity.[9] It can be resistant to conventional antiarrhythmic drugs and lead to tachycardia-induced cardiomyopathy (TCM). The incidence of TCM secondary to EAT was 22.6% in children.[10] Independent factors associated with a good response to pharmacological therapy include a younger age at presentation and nonincessant tachycardia. Children <3 years of age respond well to antiarrhythmic therapy and have a high incidence of spontaneous resolution of EAT and thus warrant a trial of antiarrhythmic therapy.[1112] Pharmacological treatment is a safe and effective treatment strategy for infants with TCM which may avoid unnecessary ablation or at least postpone it till the procedure would be safer.[13] However, in medically resistant cases, radiofrequency catheter ablation in infants and small children is a promising alternative.[14] Ablation is successful in all ages. EAT recurrence was less common with electronanatomic mapping compared to conventional mapping techniques.[12]\n\nFrom a clinical point of view, children with TCM will have features similar to dilated cardiomyopathy but with better prognosis with significant improvement of LV function after rhythm or rate control. It is characterized by significant changes in cardiomyocyte and mitochondrial morphology with reduced myocardial fibrosis and T cells when compared to dilated and ischemic cardiomyopathy. Internal organization of mitochondria and their distribution within the cardiomyocytes is critical for optimal production and distribution of ATP. In tachyarrhythmia, there is increased ATP demand resulting in suboptimal mitochondrial function leading to decreased myocardial contractility. Enrichment of mitochondria at intercalated discs was observed in the endomyocardial biopsy samples of TCM patients. These findings suggest that rate control or restoration of sinus rhythm will result in significant recovery of the LV function in children with TCM.[15] Factors associated with faster recovery include younger age, higher presenting heart rate, use of mechanical circulatory support, and higher LVEF.[16]\n\nOur first case was refractory to most of the conventional antiarrhythmic drugs. Considering the age, hemodynamic instability, and unavailability of electrophysiology laboratory, we started oral ivabradine based on the literature, and this was associated with a good response.[234] While conversion to sinus due to a delayed effect of amiodarone cannot be completely excluded, this is unlikely as sustained sinus rhythm was achieved with ivabradine despite stopping amiodarone. This was again evident on the second case where early initiation of ivabradine resulted in early achievement of sinus rhythm.\n\nIvabradine is a specific inhibitor of HCN channels and a pure heart rate lowering agent. It has no effect on action potential duration, intraventricular conduction, myocardial contraction, and relaxation at therapeutic levels. It inhibits both HCN4 and HCN1 isoforms in the human heart. It exhibits use dependence with greater effects at faster heart rates. Ivabradine is an established therapy for heart failure, junctional ectopic tachycardia, inappropriate sinus tachycardia and stable angina pectoris.[17 Ivabradine is effective in a subset of patients with incessant EAT originating in the atrial appendages than other atrial sites. Failure of complete atrialization of the sinus venosus might result in focal automaticity at ectopic atrial sites. Persistence of original embryonic cells with abnormal automaticity in the atrial appendages might be responsible for incessant EAT.[16]\n\nIn the first case apart from intravenous digoxin, enteral ivabradine was the only drug which reduced the heart rate without compromising the hemodynamics (which occurred with intravenous digoxin). Since ivabradine has a hemodynamically neutral profile when compared to many of the conventional antiarrhythmic drugs, it can be initiated early in the management plan in hemodynamically compromised patients due to severe LV dysfunction. This might have avoided unnecessary cardioversion and initiation of antiarrhythmic drugs with unstable hemodynamic profile and this was especially evident in the second case.[1618] A recent report showed that enteral ivabradine was effective in an infant with multifocal atrial tachycardia with severe ventricular dysfunction requiring mechanical support.[7] Thus, early initiation of ivabradine in automatic tachyarrhythmias with severe LV dysfunction and unstable hemodynamics may avoid unnecessary cardioversion, invasive procedures, and initiation of antiarrhythmic drugs with unstable hemodynamic profile. The positive response to ivabradine potentially implicates the funny current in the pathogenesis of EAT.[16]\n\nCONCLUSION\n\nThis case highlights the potential new role of ivabradine in hemodynamically compromised children with EAT. Further prospective studies are warranted to prove the benefit of early initiation of ivabradine in hemodynamically compromised infants.\n\nDeclaration of patient consent\n\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\n\nNil.\n\nConflicts of interest\n\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n\n1 Bonnet D Berger F Jokinen E Kantor PF Daubeney PE Ivabradine in children with dilated cardiomyopathy and symptomatic chronic heart failure J Am Coll Cardiol 2017 70 1262 72 28859790\n2 Janson CM Tan RB Iyer VR Vogel RL Vetter VL Shah MJ Ivabradine for treatment of tachyarrhythmias in children and young adults HeartRhythm Case Rep 2019 5 333 7 31285993\n3 Michel H Heißenhuber F Wellmann S Melter M Gerling S Ectopic atrial tachycardia in a 12-month-old girl treated with ivabradine and beta-blocker, a case report Front Pediatr 2020 8 313 32612966\n4 Bohora S Lokhandwala Y Parekh P Vasavda A Reversal of tachycardiomyopathy due to left atrial tachycardia by ivabradine J Cardiovasc Electrophysiol 2011 22 340 2 20653812\n5 Ergul Y Ozturk E Ozgur S Ozyurt A Cilsal E Guzeltas A Ivabradine is an effective antiarrhythmic therapy for congenital junctional ectopic tachycardia-induced cardiomyopathy during infancy: Case studies Pacing Clin Electrophysiol 2018 41 1372 7 29856078\n6 Krishna MR Kunde MF Kumar RK Balaji S Ivabradine in post-operative junctional ectopic tachycardia (JET): Breaking new ground Pediatr Cardiol 2019 40 1284 8 31317219\n7 Cohen MI Cohen JA Shope C Stollar L Collazo L Ivabradine as a stabilising anti-arrhythmic agent for multifocal atrial tachycardia Cardiol Young 2020 30 899 902 32519627\n8 Naheed ZJ Strasburger JF Benson DW Jr Deal BJ Natural history and management strategies of automatic atrial tachycardia in children Am J Cardiol 1995 75 405 7 7856541\n9 Wilbur SL Marchlinski FE Adenosine as an antiarrhythmic agent Am J Cardiol 1997 79 30 7 9223361\n10 Ge H Li X Liu H Jiang H Predictors of pharmacological therapy of ectopic atrial tachycardia in children Pediatr Cardiol 2017 38 289 95 27882422\n11 Salerno JC Kertesz NJ Friedman RA Fenrich AL Jr Clinical course of atrial ectopic tachycardia is age-dependent: Results and treatment in children <3 or>or = 3 years of age J Am Coll Cardiol 2004 43 438 44 15013128\n12 Kang KT Etheridge SP Kantoch MJ Tisma-Dupanovic S Bradley DJ Balaji S Current management of focal atrial tachycardia in children: A multicenter experience Circ Arrhythm Electrophysiol 2014 7 664 70 25015944\n13 Juneja R Shah S Naik N Kothari SS Saxena A Talwar KK Management of cardiomyopathy resulting from incessant supraventricular tachycardia in infants and children Indian Heart J 2002 54 176 80 12086381\n14 Case CL Gillette PC Oslizlok PC Knick BJ Blair HL Radiofrequency catheter ablation of incessant, medically resistant supraventricular tachycardia in infants and small children J Am Coll Cardiol 1992 20 1405 10 1430691\n15 Mueller KA Heinzmann D Klingel K Fallier-Becker P Kandolf R Kilias A Histopathological and immunological characteristics of tachycardia-induced cardiomyopathy J Am Coll Cardiol 2017 69 2160 72 28449778\n16 Moore JP Patel PA Shannon KM Albers EL Salerno JC Stein MA Predictors of myocardial recovery in pediatric tachycardia-induced cardiomyopathy Heart Rhythm 2014 11 1163 9 24751393\n17 Banavalikar B Shenthar J Padmanabhan D Valappil SP Singha SI Kottayan A Clinical and electrophysiological correlates of incessant ivabradine-sensitive atrial tachycardia Circ Arrhythm Electrophysiol 2019 12 e007387 31345093\n18 Maghrabi K Uzun O Kirsh JA Balaji S Von Bergen NH Sanatani S Cardiovascular collapse with intravenous amiodarone in children: a multi-center retrospective cohort study Pediatr Cardiol 2019 40 925 33 30929065\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0974-5149",
"issue": "14(3)",
"journal": "Annals of pediatric cardiology",
"keywords": "Ectopic atrial tachycardia; infant; ivabradine; tachycardia-induced cardiomyopathy",
"medline_ta": "Ann Pediatr Cardiol",
"mesh_terms": null,
"nlm_unique_id": "101495459",
"other_id": null,
"pages": "422-427",
"pmc": null,
"pmid": "34667421",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "32519627;1430691;25015944;12086381;31285993;27882422;29856078;30929065;15013128;20653812;24751393;9223361;28449778;31345093;7856541;32612966;31317219;28859790",
"title": "Tachycardia-induced cardiomyopathy secondary to incessant ectopic atrial tachycardia in two infants: Potential new indication for early initiation of enteral ivabradine.",
"title_normalized": "tachycardia induced cardiomyopathy secondary to incessant ectopic atrial tachycardia in two infants potential new indication for early initiation of enteral ivabradine"
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"activesubstancename": "AMIODARONE"
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{
"abstract": "We report the first published case of aggressive diffuse large B-cell (non-Hodgkin) lymphoma in a 35-year-old pregnant woman who had Crohn disease and was taking long-term thiopurine therapy: the patient developed placental insufficiency, and there was intrauterine fetal death.",
"affiliations": "Gastroenterology and Hepatology Unit.;Department of Clinical Haematology.;Departmemt of Anatomical Pathology, ACT Pathology.;Departmemt of Anatomical Pathology, ACT Pathology.;Fetal Medicine Unit, Centenary Hospital for Women and Children, Canberra Hospital, Canberra, New South Wales, Australia.;Gastroenterology and Hepatology Unit.;Gastroenterology and Hepatology Unit.;Gastroenterology and Hepatology Unit.",
"authors": "Chen|G|G|;Crispin|P|P|;Cherian|M|M|;Dahlstrom|J E|JE|;Sethna|F F|FF|;Kaye|G|G|;Pavli|P|P|;Subramaniam|K|K|",
"chemical_list": "D001379:Azathioprine",
"country": "Australia",
"delete": false,
"doi": "10.1111/imj.12957",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1444-0903",
"issue": "46(1)",
"journal": "Internal medicine journal",
"keywords": "Crohn disease; non-Hodgkin lymphoma; placental insufficiency; thiopurines",
"medline_ta": "Intern Med J",
"mesh_terms": "D000328:Adult; D001379:Azathioprine; D003424:Crohn Disease; D005260:Female; D005313:Fetal Death; D006801:Humans; D008228:Lymphoma, Non-Hodgkin; D010920:Placenta; D010927:Placental Insufficiency; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic",
"nlm_unique_id": "101092952",
"other_id": null,
"pages": "102-5",
"pmc": null,
"pmid": "26813900",
"pubdate": "2016-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Placental involvement by non-Hodgkin lymphoma in a Crohn disease patient on long-term thiopurine therapy.",
"title_normalized": "placental involvement by non hodgkin lymphoma in a crohn disease patient on long term thiopurine therapy"
} | [
{
"companynumb": "AU-ALCAMI_CORPORATION-USA-POI0581201800007",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
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"activesubstance": {
"activesubstancename": "LACTULOSE"
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{
"abstract": "BACKGROUND\nHigh platelet reactivity (HPR) to clopidogrel is associated with an increased risk of ischaemic complications during and after coronary interventions and concerns up to 50% of patients undergoing PCI.\n\n\nOBJECTIVE\nThe aim of the study was to identify patients with HPR to clopidogrel using bedside clinical information obtained in the Stent Thrombosis In Belgium (STIB) trial.\n\n\nMETHODS\nData on platelet reactivity using the VerifyNow® point-of-care assay were obtained in 844 patients undergoing PCI for stable coronary artery disease 12 to 24 hours after a 600-mg loading dose of clopidogrel was given. Demographic, clinical and baseline routine biological tests were obtained and compared with P2Y12 reaction units (PRU). Patients with PRU>230 (HPR) were considered as non-responders to clopidogrel.\n\n\nRESULTS\nHPR was observed in 424/844 pts. Age, weight, body mass index (BMI), HPR to aspirin, diabetes, renal failure (MDRD<60 ml/min), haemoglobin (Hb), haematocrit, fibrinogen, glycaemia and glycated haemoglobin were associated with HPR to clopidogrel. In multivariate analysis, only Hb (OR: 0.77), BMI (OR: 1.06) and diabetes (OR: 1.62) emerged as independent risk factors. Hb<13.9 g/dl, BMI>28 kg/m2 and presence of diabetes were equally associated to predict HPR and can be added to derive a simple score to predict clopidogrel resistance. Although 38.5% of patients without a single clinical predictor still have HPR, 2/3 patients with 2 or 3 risk factors are resistant to clopidogrel.\n\n\nCONCLUSIONS\nSTIB HPR score allows identification of patients with a high probability of resistance to clopidogrel based on diabetes, Hb<13.9 g/dl and BMI>28 kg/m2. This bedside clinical test could be useful for the identification of patients in whom another P2Y12 inhibitor should be recommended before and after PCI.",
"affiliations": null,
"authors": "Legrand|Delphine|D|;Barbato|Emanuele|E|;Chenu|Patrick|P|;Magne|Julien|J|;Vrolix|Mathias|M|;Wijns|William|W|;Legrand|Victor|V|;|||",
"chemical_list": "D015415:Biomarkers; D006454:Hemoglobins; C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D000077144:Clopidogrel; D013988:Ticlopidine",
"country": "England",
"delete": false,
"doi": "10.2143/AC.70.5.3110511",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-5385",
"issue": "70(5)",
"journal": "Acta cardiologica",
"keywords": "Clopidogrel resistance; VerifyNow; bleeding; coronary disease; ischaemic events",
"medline_ta": "Acta Cardiol",
"mesh_terms": "D000368:Aged; D060050:Angina, Stable; D015906:Angioplasty, Balloon, Coronary; D001530:Belgium; D015415:Biomarkers; D001792:Blood Platelets; D015992:Body Mass Index; D016009:Chi-Square Distribution; D000077144:Clopidogrel; D015897:Comorbidity; D003661:Decision Support Techniques; D048909:Diabetes Complications; D004351:Drug Resistance; D005260:Female; D006454:Hemoglobins; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009765:Obesity; D016017:Odds Ratio; D010974:Platelet Aggregation; D010975:Platelet Aggregation Inhibitors; D010979:Platelet Function Tests; D000067716:Point-of-Care Testing; D011237:Predictive Value of Tests; D011446:Prospective Studies; D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D012307:Risk Factors; D013988:Ticlopidine; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "0370570",
"other_id": null,
"pages": "516-21",
"pmc": null,
"pmid": "26567810",
"pubdate": "2015-10",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "The STIB score: a simple clinical test to predict clopidogrel resistance.",
"title_normalized": "the stib score a simple clinical test to predict clopidogrel resistance"
} | [
{
"companynumb": "BE-SA-2014SA032287",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
"drugadditional": null,
... |
{
"abstract": "As the world responds to the global crisis of the COVID-19 pandemic an increasing number of patients are experiencing increased morbidity as a result of multi-organ involvement. Of these, a small proportion will progress to end-stage lung disease, become dialysis dependent, or both. Herein, we describe the first reported case of a successful combined lung and kidney transplantation in a patient with COVID-19. Lung transplantation, isolated or combined with other organs, is feasible and should be considered for select patients impacted by this deadly disease.",
"affiliations": "Department of Cardiothoracic Surgery, Stanford University, Stanford, CA.;Department of Cardiothoracic Surgery, Stanford University, Stanford, CA.;Department of Cardiothoracic Surgery, Stanford University, Stanford, CA.;Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University, Stanford, CA.;Department of Medicine, Division of Pulmonary, Allergy, and Critical Care, Stanford University, Stanford, CA.;Department of Cardiothoracic Surgery, Stanford University, Stanford, CA.;Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University, Stanford, CA.;Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University, Stanford, CA.;Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University, Stanford, CA.;Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University, Stanford, CA.;Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University, Stanford, CA.;Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University, Stanford, CA.;Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University, Stanford, CA.;Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University, Stanford, CA.;Department of Medicine, Division of Pulmonary, Allergy, and Critical Care, Stanford University, Stanford, CA.;Department of Surgery, Division of Abdominal Transplantation, Stanford University, Stanford, CA.;Department of Cardiothoracic Surgery, Stanford University, Stanford, CA.;Department of Cardiothoracic Surgery, Stanford University, Stanford, CA.;Department of Cardiothoracic Surgery, Stanford University, Stanford, CA.;Department of Cardiothoracic Surgery, Stanford University, Stanford, CA.;Department of Cardiothoracic Surgery, Stanford University, Stanford, CA.;Department of Cardiothoracic Surgery, Stanford University, Stanford, CA.;Department of Pathology, Stanford University, Stanford, CA.;Department of Pathology, Stanford University, Stanford, CA.;Department of Medicine, Division of Pulmonary, Allergy, and Critical Care, Stanford University, Stanford, CA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA.;Department of Medicine, Division of Pulmonary, Allergy, and Critical Care, Stanford University, Stanford, CA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA.;Department of Medicine, Division of Pulmonary, Allergy, and Critical Care, Stanford University, Stanford, CA.;Department of Cardiothoracic Surgery, Stanford University, Stanford, CA. Electronic address: joswoo@stanford.edu.",
"authors": "Guenthart|Brandon A|BA|;Krishnan|Aravind|A|;Alassar|Aiman|A|;Madhok|Jai|J|;Kakol|Monika|M|;Miller|Shari|S|;Cole|Sheela Pai|SP|;Rao|Vidya K|VK|;Acero|Natalia Martinez|NM|;Hill|Charles C|CC|;Cheung|Cindy|C|;Jackson|Ethan C|EC|;Feinstein|Igor|I|;Tsai|Albert H|AH|;Mooney|Joshua J|JJ|;Pham|Thomas|T|;Elliott|Irmina A|IA|;Liou|Douglas Z|DZ|;La Francesca|Saverio|S|;Shudo|Yasuhiro|Y|;Hiesinger|William|W|;MacArthur|John W|JW|;Brar|Nivaz|N|;Berry|Gerald J|GJ|;McCarra|Matthew B|MB|;Desai|Tushar J|TJ|;Dhillon|Gundeep S|GS|;Woo|Y Joseph|YJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.healun.2021.02.015",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1053-2498",
"issue": "40(8)",
"journal": "The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation",
"keywords": "COVID-19, lung transplant; ECMO; kidney transplant; multi-organ transplant",
"medline_ta": "J Heart Lung Transplant",
"mesh_terms": "D058186:Acute Kidney Injury; D000086382:COVID-19; D006801:Humans; D016030:Kidney Transplantation; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D012128:Respiratory Distress Syndrome",
"nlm_unique_id": "9102703",
"other_id": null,
"pages": "856-859",
"pmc": null,
"pmid": "34059432",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "First lung and kidney multi-organ transplant following COVID-19 Infection.",
"title_normalized": "first lung and kidney multi organ transplant following covid 19 infection"
} | [
{
"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2022-08886",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugad... |
{
"abstract": "BACKGROUND\nFanconi anemia (FA) predisposes to hematologic disorders and myeloid neoplasia in childhood and to solid cancers, mainly oral carcinomas, in early adulthood. Few cases of solid cancers have been reported in childhood.\n\n\nMETHODS\nWe conducted a national retrospective study of solid tumors occurring in patients registered with or determined to have FA during childhood in France. Phenotypic features, tumor type, cancer treatment, and outcome were analyzed. Whenever available, fresh-frozen tumors were analyzed by microarray-based comparative genomics hybridization.\n\n\nRESULTS\nWe identified eight patients with FA with solid tumor from 1986 to 2012. For two patients, the diagnosis of FA was unknown at the time of cancer diagnosis. Moreover, we identified one fetus with a brain tumor. All patients showed failure to thrive and had dysmorphic features and abnormal skin pigmentation. Seven patients had BRCA2/FANCD1 mutations; five of these featured more than one malignancy and the median age at the time of cancer diagnosis was 11 months (range 0.4-3 years). Solid tumor types included five nephroblastomas, two rhabdomyosarcomas, two neuroblastomas, and three brain tumors. Two children died from the toxic effects of chemotherapy, two patients from the cancer, and one patient from secondary leukemia. Only one BRCA2 patient was alive more than 3 years after diagnosis, after tailored chemotherapy.\n\n\nCONCLUSIONS\nSolid tumors are rare in FA during childhood, except in patients with BRCA2/FANCD1 mutations. The proper genetic diagnosis is mandatory to tailor the treatment.",
"affiliations": "Department of Pediatrics, Curie Institute, Paris, France.",
"authors": "Malric|Aurore|A|;Defachelles|Anne-Sophie|AS|;Leblanc|Thierry|T|;Lescoeur|Brigitte|B|;Lacour|Brigitte|B|;Peuchmaur|Michel|M|;Maurage|Claude-Alain|CA|;Pierron|Gaëlle|G|;Guillemot|Delphine|D|;d'Enghien|Catherine Dubois|CD|;Soulier|Jean|J|;Stoppa-Lyonnet|Dominique|D|;Bourdeaut|Franck|F|",
"chemical_list": "D024682:BRCA2 Protein; C551750:BRCA2 protein, human",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.25303",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "62(3)",
"journal": "Pediatric blood & cancer",
"keywords": "BRCA2; Fanconi anemia; cancer genetics; pediatric oncology; rhabdomyosarcoma",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D024682:BRCA2 Protein; D002648:Child; D002675:Child, Preschool; D055028:Comparative Genomic Hybridization; D018572:Disease-Free Survival; D005199:Fanconi Anemia; D005260:Female; D005602:France; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007680:Kidney Neoplasms; D008297:Male; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D012208:Rhabdomyosarcoma; D015996:Survival Rate; D009396:Wilms Tumor",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "463-70",
"pmc": null,
"pmid": "25381700",
"pubdate": "2015-03",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Fanconi anemia and solid malignancies in childhood: a national retrospective study.",
"title_normalized": "fanconi anemia and solid malignancies in childhood a national retrospective study"
} | [
{
"companynumb": "PHHY2015FR081460",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Hemophagocytic lymphohistiocytosis (HLH) is a rare and aggressive syndrome of excessive cytokine requiring prompt recognition and aggressive therapy.\n\n\n\nWe aimed to systematically characterize HLH in moderate-to-severe inflammatory bowel disease (IBD).\n\n\n\nWe performed a systematic review of the literature (PubMED; EMBASE) and FDA Adverse Event Reporting System in accordance with the PRISMA statement. Use of biologics was used as a surrogate definition for disease severity (consistent with usual and contemporary clinical management), to enable identification of rare HLH cases with the highest fidelity.\n\n\n\n58 cases of HLH occurring in IBD patients are known (mean age: 26.0 years, 70% male, 83% with Crohn's disease, mean disease duration 7.0 years). 34.5% of patients were undergoing induction therapy at HLH diagnosis. All cases occurred on patients exposed to anti-TNF agents, but cases with anti-integrin or anti-IL-12/23 exposure were reported. 2/3 of cases did not report prior AZA/6MP exposure. Underlying opportunistic infection or lymphoma was found in > 80% of cases. Survival was 70% if promptly recognized and treated. Five patients restarted biologics after HLH resolved, and one patient developed recurrent HLH.\n\n\n\nHLH is rare among IBD patients exposed to biologic therapy. Most cases had an identifiable infection or malignancy at the time of diagnosis as well as history of immunomodulator use. Risk factors may include younger age, male gender, presence of Crohn's disease, and induction phase of treatment. Our study is not intended to assess risk of HLH with specific IBD therapies.",
"affiliations": "Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH, 03766, USA.;Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH, 03766, USA.;Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH, 03766, USA.;Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH, 03766, USA. eric.d.shah@hitchcock.org.",
"authors": "Coburn|Elliot S|ES|;Siegel|Corey A|CA|;Winter|Michael|M|;Shah|Eric D|ED|0000-0003-3611-8628",
"chemical_list": "D001688:Biological Products; D007155:Immunologic Factors; D000079424:Tumor Necrosis Factor Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1007/s10620-020-06252-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-2116",
"issue": "66(3)",
"journal": "Digestive diseases and sciences",
"keywords": "Drug exposure; Inflammatory response; Macrophage activation syndrome; Rare events",
"medline_ta": "Dig Dis Sci",
"mesh_terms": "D000328:Adult; D001688:Biological Products; D003424:Crohn Disease; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D015212:Inflammatory Bowel Diseases; D051359:Lymphohistiocytosis, Hemophagocytic; D008297:Male; D000079424:Tumor Necrosis Factor Inhibitors",
"nlm_unique_id": "7902782",
"other_id": null,
"pages": "843-854",
"pmc": null,
"pmid": "32300936",
"pubdate": "2021-03",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D013487:Research Support, U.S. Gov't, P.H.S.; D000078182:Systematic Review",
"references": "20608090;21793127",
"title": "Hemophagocytic Lymphohistiocytosis Occurring in Inflammatory Bowel Disease: Systematic Review.",
"title_normalized": "hemophagocytic lymphohistiocytosis occurring in inflammatory bowel disease systematic review"
} | [
{
"companynumb": "US-JNJFOC-20190716091",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "USTEKINUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "This case report concerns a 71 year old female patient who had a very low glycosylated hemoglobin (HbA1c) despite having a high level of fasting blood glucose. The patient had a decreased erythrocyte count, elevated red blood cell indices, and a reticulocyte count with no evidence of hemoglobinopathy. She reported receiving hydroxychloroquine treatment for systemic lupus erythematosus. Subsequent laboratory investigations revealed hemolysis with formation of cold agglutinin. Because cold agglutinins can interfere with HbA1c assays, the specimens were reanalyzed after warming. The complete blood count results improved, but the HbA1c result did not change. In patients in whom medications and/or medical conditions may interfere with HbA1c levels, alternative measures of glycemic control, such as fructosamine, could be beneficial.",
"affiliations": "Department of Clinical Biochemistry, Samyak Diagnostic Pvt Ltd., Jawalakhel, Kathmandu, Nepal.",
"authors": "Pant|Vivek|V|0000-0002-3967-1851",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/labmed/lmab082",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-5027",
"issue": null,
"journal": "Laboratory medicine",
"keywords": "cold agglutinin; complete blood count; false low HbA1c; fructosamine; high-performance liquid chromatography; systemic lupus erythematosus",
"medline_ta": "Lab Med",
"mesh_terms": null,
"nlm_unique_id": "0250641",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34611711",
"pubdate": "2021-10-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "HbA1c Below the Reportable Range.",
"title_normalized": "hba1c below the reportable range"
} | [
{
"companynumb": "NP-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-315699",
"fulfillexpeditecriteria": "1",
"occurcountry": "NP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
... |
{
"abstract": "OBJECTIVE\nCranial CT (CCT) scans and hospital admission are increasingly performed to rule out intracranial hemorrhage in patients after minor head injury (MHI), particularly in older patients and in those receiving antiplatelet therapy. This leads to high radiation exposure and a growing financial burden. The aim of this study was to determine whether the astroglial-derived protein S100B that is released into blood can be used as a reliable negative predictive tool for intracranial bleeding in patients after MHI, when they are older than 65 years or being treated with antiplatelet drugs (low-dose aspirin, clopidogrel).\n\n\nMETHODS\nThe authors conducted a prospective observational study in 2 trauma hospitals. A total of 782 patients with MHI (Glasgow Coma Scale Score 13-15) who were on medication with platelet aggregation inhibitors (PAIs) or were age 65 years and older, independent of antiplatelet therapy, were included. Clinical examination, bloodwork, observation, and CCT were performed in the traumatology emergency departments. When necessary, patients were admitted and observation took place on the ward; in these patients, CCT was performed during their hospital stay. Patients with severe trauma, focal neurological deficits, posttraumatic seizures, anticoagulant therapy, alcohol intoxication, coagulation disorder, blood sampling more than 3 hours after trauma, and unknown time of the trauma were excluded from the study. The median age of the patients was 83 years, and 69% were female. Sensitivity, specificity, and positive and negative predictive values of S100B with reference to CCT findings were calculated. The cutoff of S100B was set at 0.105 μg/L.\n\n\nRESULTS\nOf the 782 patients, 50 (6.4%) had intracranial bleeding. One patient with positive results on CCT scan showed an S100B level below 0.105 μg/L. Of all patients, 33.1% were below the cutoff. S100B showed a sensitivity of 98.0% (CI 89.5%-99.7%), a negative predictive value of 99.6% (CI 97.9%-99.9%), a specificity of 35.3% (CI 31.9%- 38.8%), and a positive predictive value of 9.4% (CI 7.2%-12.2%).\n\n\nCONCLUSIONS\nLevels of S100B below 0.105 μg/L can accurately predict normal CCT findings after MHI in older patients and in those treated with PAIs. Combining conventional decision criteria with measurement of S100B can reduce the CCT scan and hospital admission rates by approximately 30%.",
"affiliations": "Trauma Hospital Meidling;;Department of Traumatology, Donauspital; and.;Trauma Hospital Meidling;;Trauma Hospital Meidling;;Trauma Hospital Meidling;;Trauma Hospital Meidling;;Department of Radiology, Kaiser-Franz-Josef-Spital, Vienna; and.;Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Austria.;Trauma Hospital Meidling;;Department of Traumatology, Donauspital; and.",
"authors": "Thaler|Heinrich Wolfgang|HW|;Schmidsfeld|Jochen|J|;Pusch|Michael|M|;Pienaar|Simon|S|;Wunderer|Jörg|J|;Pittermann|Paul|P|;Valenta|Rosmarie|R|;Gleiss|Andreas|A|;Fialka|Christian|C|;Mousavi|Mehdi|M|",
"chemical_list": "D015415:Biomarkers; D010975:Platelet Aggregation Inhibitors; D064568:S100 Calcium Binding Protein beta Subunit; C579160:S100B protein, human; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin",
"country": "United States",
"delete": false,
"doi": "10.3171/2014.12.JNS142276",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-3085",
"issue": "123(5)",
"journal": "Journal of neurosurgery",
"keywords": "CCT = cranial CT; ED = emergency department; GCS = Glasgow Coma Scale; IQR = interquartile range; MHI = minor head injury; NPV = negative predictive value; PAI = platelet aggregation inhibitor; PPV = positive predictive value; S100B; intracranial hemorrhage; minor head injury; older patients; platelet aggregation inhibitors; traumatic brain injury",
"medline_ta": "J Neurosurg",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001241:Aspirin; D015415:Biomarkers; D000077144:Clopidogrel; D006259:Craniocerebral Trauma; D005260:Female; D015600:Glasgow Coma Scale; D006801:Humans; D020198:Intracranial Hemorrhage, Traumatic; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors; D011237:Predictive Value of Tests; D011446:Prospective Studies; D064568:S100 Calcium Binding Protein beta Subunit; D013988:Ticlopidine",
"nlm_unique_id": "0253357",
"other_id": null,
"pages": "1202-8",
"pmc": null,
"pmid": "26148794",
"pubdate": "2015-11",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Evaluation of S100B in the diagnosis of suspected intracranial hemorrhage after minor head injury in patients who are receiving platelet aggregation inhibitors and in patients 65 years of age and older.",
"title_normalized": "evaluation of s100b in the diagnosis of suspected intracranial hemorrhage after minor head injury in patients who are receiving platelet aggregation inhibitors and in patients 65 years of age and older"
} | [
{
"companynumb": "AT-BAYER-2015-387420",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "Long-term success of cART is possible if the regimen is convenient and less-toxic. This study assessed the efficacy and safety of switching from a first-line NNRTI or boosted PI-based regimens to RPV-based regimens among virologically suppressed participants in resource-limited setting (RLS).\n\n\n\nThis is a prospective cohort study. Participants with plasma HIV-RNA < 50 copies/mL receiving cART were switched from a PI- or NNRTI-based, to a RPV-based regimen between January 2011 and April 2018. The primary endpoint was the proportion of patients with plasma HIV-1 RNA level < 50 copies/mL after 12 months of RPV. The secondary endpoint was the virological response at 24 months and safety endpoint (change in lipid profiles and kidney function from baseline to 12 months).\n\n\n\nA total of 320 participants were enrolled into the study. The rationale for switching to RPV was based on toxicity of the current regimen (57%) or desire to simplify cART (41%). Totally, 177 (55%) and 143 (45%) participants were on NNRTI and boosted PI, respectively, prior to switching to RPV. After 12 months, 298 (93%) participants maintained virological suppression. There were significant improvements in the lipid parameters: TC (- 21 (IQR - 47 to 1) mg/dL; p < 0.001), LDL (- 14 (IQR - 37 to 11) mg/dL; p < 0.001) and TG (- 22 (IQR - 74 to 10) mg/dL; p < 0.001). Also, there was a small but statistically significant decrease in eGFR (- 4.3 (IQR - 12 to 1.1) mL/min per 1.73m2; p < 0.001).\n\n\n\nIn RLS where integrase inhibitors are not affordable, RPV-based regimens are a good alternative option for PLHIV who cannot tolerate first-line NNRTI or boosted PI regimen, without prior NNRTI/PI resistance. Trial registration HIV-NAT 006 cohort, clinical trial number: NCT00411983.",
"affiliations": "HIV-NAT, Thai Red Cross AIDS Research Centre, 104 Ratchadamri Road, Pathumwan, Bangkok, 10330, Thailand. sivaporn.k@hivnat.org.;HIV-NAT, Thai Red Cross AIDS Research Centre, 104 Ratchadamri Road, Pathumwan, Bangkok, 10330, Thailand.;HIV-NAT, Thai Red Cross AIDS Research Centre, 104 Ratchadamri Road, Pathumwan, Bangkok, 10330, Thailand.;HIV-NAT, Thai Red Cross AIDS Research Centre, 104 Ratchadamri Road, Pathumwan, Bangkok, 10330, Thailand.;HIV-NAT, Thai Red Cross AIDS Research Centre, 104 Ratchadamri Road, Pathumwan, Bangkok, 10330, Thailand.;HIV-NAT, Thai Red Cross AIDS Research Centre, 104 Ratchadamri Road, Pathumwan, Bangkok, 10330, Thailand.",
"authors": "Gatechompol|Sivaporn|S|;Avihingsanon|Anchalee|A|;Apornpong|Tanakorn|T|;Han|Win Min|WM|;Kerr|Stephen J|SJ|;Ruxrungtham|Kiat|K|",
"chemical_list": "D019380:Anti-HIV Agents; D008055:Lipids; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D000068696:Rilpivirine",
"country": "England",
"delete": false,
"doi": "10.1186/s12981-019-0222-6",
"fulltext": "\n==== Front\nAIDS Res TherAIDS Res TherAIDS Research and Therapy1742-6405BioMed Central London 22210.1186/s12981-019-0222-6ResearchEfficacy and improvement of lipid profile after switching to rilpivirine in resource limited setting: real life clinical practice Gatechompol Sivaporn 662 652 3040sivaporn.k@hivnat.org 12Avihingsanon Anchalee anchaleea2009@gmail.com 12Apornpong Tanakorn tanakorn.a@hivnat.org 1Han Win Min win.m@hivnat.org 1Kerr Stephen J. stephen.k@hivnat.org 12Ruxrungtham Kiat rkiatchula@gmail.com 121 0000 0001 1018 2627grid.419934.2HIV-NAT, Thai Red Cross AIDS Research Centre, 104 Ratchadamri Road, Pathumwan, Bangkok, 10330 Thailand 2 0000 0001 1018 2627grid.419934.2Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Rama 4 Road, Pathumwan, Bangkok, 10330 Thailand 5 4 2019 5 4 2019 2019 16 722 12 2018 27 3 2019 © The Author(s) 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nLong-term success of cART is possible if the regimen is convenient and less-toxic. This study assessed the efficacy and safety of switching from a first-line NNRTI or boosted PI-based regimens to RPV-based regimens among virologically suppressed participants in resource-limited setting (RLS).\n\nMethods\nThis is a prospective cohort study. Participants with plasma HIV-RNA < 50 copies/mL receiving cART were switched from a PI- or NNRTI-based, to a RPV-based regimen between January 2011 and April 2018. The primary endpoint was the proportion of patients with plasma HIV-1 RNA level < 50 copies/mL after 12 months of RPV. The secondary endpoint was the virological response at 24 months and safety endpoint (change in lipid profiles and kidney function from baseline to 12 months).\n\nResults\nA total of 320 participants were enrolled into the study. The rationale for switching to RPV was based on toxicity of the current regimen (57%) or desire to simplify cART (41%). Totally, 177 (55%) and 143 (45%) participants were on NNRTI and boosted PI, respectively, prior to switching to RPV. After 12 months, 298 (93%) participants maintained virological suppression. There were significant improvements in the lipid parameters: TC (− 21 (IQR − 47 to 1) mg/dL; p < 0.001), LDL (− 14 (IQR − 37 to 11) mg/dL; p < 0.001) and TG (− 22 (IQR − 74 to 10) mg/dL; p < 0.001). Also, there was a small but statistically significant decrease in eGFR (− 4.3 (IQR − 12 to 1.1) mL/min per 1.73m2; p < 0.001).\n\nConclusions\nIn RLS where integrase inhibitors are not affordable, RPV-based regimens are a good alternative option for PLHIV who cannot tolerate first-line NNRTI or boosted PI regimen, without prior NNRTI/PI resistance.\n\nTrial registration HIV-NAT 006 cohort, clinical trial number: NCT00411983\n\nKeywords\nSwitchingRilpivirineResource limited settingDyslipidemiaHIVissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nFor the past decade, combined antiretroviral therapy (cART) has led to a marked reduction in mortality and morbidity among Human immunodeficiency virus (HIV)—infected participants worldwide [1, 2]. The participants on antiretroviral therapy can have life expectancy close to the general population [3]. However, life-long suppressive therapy is required. Currently, rapid cART initiation is recommended and thus, numbers of people living with HIV (PLHIV) on cART is on the rise [4]. Treatment fatigue and long-term adverse-effects.\n\n(AE) of cART can negatively impact participant’s adherence as well as the quality of life. The US Department of Health and Human Services (DHHS) guidelines estimate that treatment-related side effects lead to regimen discontinuation in up to 10% of clinical trial participants [5]. Therefore, there is a need for further simple, efficacious, well tolerated, affordable antiretroviral therapy (ART) regimens in low-and middle-income countries (LMIC) where the burden of HIV is greatest. Rilpivirine (RPV) is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) that has recently been approved for the treatment of HIV-1 infection [6]. In the pooled ECHO and THRIVE studies, RPV demonstrated non-inferior efficacy in reducing HIV-1 RNA to < 50 copies/mL at weeks 48 and 96; it was well tolerated compared to efavirenz (EFV) when used for first-line treatment in participants with a baseline viral load below 100,000 copies/mL [7–9].\n\nIn the United States and Europe, a single tablet regimen (STR) composed of rilpivirine/emtricitabine/tenofovir disoproxil fumarate (RPV/FTC/TDF) is approved for use in HIV-1—infected, anti-retroviral-naïve individuals with baseline HIV-1 RNA ≤ 100,000 copies/mL and for PLHIV with suppressed viral load without known NNRTI, Tenofovir Disoproxil Fumarate (TDF) or emtricitabine (FTC) [5]. Since, no teratogenicity was reported [10], RPV might also be a good option in women of childbearing potential. Additionally, RPV concentration were above the protein-binding adjusted EC90 in most pregnant women [11]. As RPV use for ARV naïve patients is restricted to PLHIV with baseline HIV RNA < 100,000 copies/mL, and as HIV Ribonucleic acid (RNA) testing prior to ART initiation may not always be available in many LMIC, RPV based ART would be better suited for PLHIV on stable ART with suppressed VL.\n\nRPV is well tolerated and convenient to take. It is also an attractive option for virologically suppressed treatment-experienced participants who are willing to switch their current treatment regimen to improve tolerability or convenience. However, RPV must be taken with a meal to enhance absorption and exposure [12] which may be cumbersome for some participants. Because RPV has to be taken with food, this may impact the efficacy of RPV in real clinical practice.\n\nPrevious studies have demonstrated that switching from ritonavir-boosted PI (PI/r) or NNRTI based regimen to RPV/FTC/TDF in virologically suppressed participants was effective and safe [13–15]. However, one observational study showed that at week 96, there were high rates of virological failure and treatment discontinuation because of the adverse events after switching to RPV based regimen [16].\n\nThere are a limited number of studies looking at switching to RPV-based regimens in real life clinical practice, especially in LMIC. Nowadays, there are new HIV regimens that have fewer side effects compared to the current regimens such as integrase inhibitors (INIs) which are expensive and are not available through the Thai National HIV program. Therefore, it is a challenge to manage participants who experience adverse effects or cannot tolerate 1st line NNRTI or protease inhibitor (PI) based regimens. As a result of this, we aimed to assess the efficacy and safety of switching from a first-line NNRTI or boosted PI-based regimens to RPV-based regimens among virologically suppressed Thai participants in real clinical practice.\n\nMethods\nStudy design and population\nFrom January 2011 to April 2018, we conducted a prospective cohort study at HIV-NAT, Thai Red Cross AIDS Research Centre (TRC-ARC), Bangkok, Thailand.\n\nParticipants without history of NNRTI failure with current plasma HIV-RNA < 50 copies/mL and receiving PI- or NNRTI-based regimens for more than 6 months were switched to RPV-based regimens; either with TDF + FTC, TDF + lamivudine (3TC) or abacavir (ABC) + 3TC. Participants were grouped according to their baseline regimens. Group 1 was composed of participants taking PI-based regimens before switching to RPV-based regimens; Group 2 was composed of participants taking NNRTI-based regimens before switching to RPV-based regimens. All participants were advised to take RPV with food.\n\nAt baseline, the following items were recorded: clinical characteristics, cART history, duration of HIV infection, duration of virological suppression before switching to RPV, comorbidities and reasons for switching to a RPV-based regimen. Baseline laboratory parameters were either collected at the time of switch or at the closest visit before the switch. Participants were asked to check viral load 3 to 6 months after switching to RPV regimen and then followed every 6 months for evaluate lipid profiles, kidney and liver function. All participants were advised to fast before blood chemistries were done. Data regarding AEs and treatment interruption were recorded when they were clinically observed.\n\nThe study was reviewed and approved by the institution’s review board. All participants voluntarily provided written informed consent prior to enrolling into the study.\n\nEfficacy and safety assessments\nThe primary objective of this study was to assess the virological response at 12 months after switching to a RPV-based regimen in virologically suppressed, HIV-1-infected participants who previously were on NNRTI or PI based regimens. Virological success was defined as participants with plasma HIV-1 RNA level was < 50 copies/mL at 12 months. Virological failure was defined as having a confirmed HIV-1 RNA level ≥ 50 copies/mL or an HIV-1 RNA level ≥ 50 copies/mL followed by RPV discontinuation.\n\nSecondary end points included virological response at 24 months and the safety end point was defined as the change in lipid profiles such as total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein cholesterol (LDL) and triglycerides (TG). Kidney function was measured by estimated glomerular filtration rate using the CKD-EPI and liver function (ALT) was recorded.\n\nStatistical analyses\nThe proportion of participants with plasma HIV-1 RNA level < 50 copies/mL after 12 and 24 months of RPV treatment was evaluated using the HIV-1 RNA level at that month. Participants who discontinued RPV treatment, had virological failure or were lost to follow-up were classified as having unfavorable outcomes. The analysis was intent-to-treat. The difference in proportions with virological suppression at 12 and 24 months between NNRTI and boosted PI groups were compared using a Chi square test.\n\nSample size was based on the precision of the 95% CI around the assumed prevalence of failure after switch. We assumed the failure rate would be 5%; if 300 patients were enrolled, the 95% CI around a 5% failure would run from 2.9 to 8.1, a precision of approximately − 2 to + 3%, and an acceptable level of accuracy.\n\nMean (SD), median (IQR), and frequencies (%) were used to describe the participants’ characteristics in each study group. Chi square and student t test or Mann–Whitney U tests were used to formally compare categorical and continuous variables between the two groups (PI- and NNRTI-pre-treated groups), respectively.\n\nChanges in CD4+ T-cell counts, estimated glomerular infiltration rate (eGFR), alanine aminotransferase (ALT), TC, TG, HDL and LDL from baseline to month 12 were analyzed using paired t-test or Wilcoxon signed-rank test whereas the difference of change between groups were used student t-test or Mann–Whitney U test.\n\nResults\nTotal of 362 participants were invited to the study but only 320 participants were enrolled. The reasons for not enrolling included having detectable viral load at baseline > 50 copies/mL (n = 22) and using previous regimens other than NNRTI and PI (n = 20). The enrollment period is between January 2011 and April 2017 but the follow up period up to April 2018. The majority of the participants were males (56%) and the median age was 46 (interquartile range (IQR) 41–50) years. Median duration of ART was 12 (IQR 8–16) years. Baseline median CD4 cell count was 674 (IQR 522–851) cells/mm3. Forty-five percent of all participants had viral load > 100,000 copies/mL before starting ART. TDF was used as Nucleoside reverse transcriptase inhibitors (NRTI) backbone component in 95% of participants and 6% of participants used ABC.\n\nThe rationale for switching to RPV was mainly due to toxic adverse-effects of the current regimen (57%) or desire to simplify cART (41%). Totally, 177 (55%) and 143 (45%) participants were on NNRTI and boosted PI, respectively, prior to a switch to RPV. The median duration of viral load suppression before switching to RPV was 8.6 (IQR 3.7–11.1) years. Median value of lipid profiles prior to switch were total cholesterol (TC) 210 (IQR 182–239) mg/dL; low-density lipoprotein cholesterol (LDL) 131 (IQR 107–153) mg/dL; high-density lipoprotein (HDL) 46 (IQR 38–53) mg/dL; and triglycerides (TG) 138 (IQR 94–206) mg/dL. Eighty-four participants (26.3%) took lipid lowering agent before the study entry and 29% of them discontinued lipid lowering agents within 12 months. The participants’ characteristics are shown in Table 1.Table 1 Baseline characteristic of patients\n\nCharacteristics\tTotal\n(N = 320)\tPI base\n(n = 143)\tNNRTI base\n(n = 177)\tp-value*\t\nAge, years, median (IQR)\t46 (41–50)\t46 (41–50)\t46 (41–50)\t0.45\t\nMale sex, n (%)\t178 (55.63)\t69 (48.25)\t109 (61.58)\t0.02\t\nBaseline body weight, Kg, median (IQR)\t61 (53–69)\t61 (54–69)\t61 (52–69)\t0.83\t\nDuration of HIV infection, year, median (IQR)\t14 (11–18)\t14 (11–19)\t15 (11–18)\t0.57\t\nDuration of ART, years, median (IQR)\t12 (8–16)\t12 (9–17)\t12 (5–16)\t0.13\t\nDuration of virological suppression, years, median (IQR)\t8.6 (3.7–11.1)\t8.6 (4.0–11.0)\t8.7 (3.5–11.3)\t0.90\t\nNadir CD4+ T-cell count, cells/μL, median (IQR)\t210 (121–294)\t203 (108–275)\t221 (136–304)\t0.16\t\nBaseline CD4+ T-cell count, cells/μL, median (IQR)\t674 (522–851)\t696 (541–870)\t649 (502–814)\t0.09\t\nHighest viral load before starting ART (n, %)\t\t\t\t0.62\t\n < 100,000 copies/mL\t151 (54.71)\t71 (56.35)\t80 (53.33)\t\t\n ≥ 100,000 copies/mL\t125 (45.29)\t55 (43.65)\t70 (46.67)\t\t\nHBsAg positive (n, %)\t37 (11.78)\t11 (7.80)\t26 (15.03)\t0.048\t\nAnti-HCV positive (n, %)\t13 (4.08)\t9 (6.34)\t4 (2.26)\t0.09\t\nPrevious treatment regimens, n (%)\t\t\t\tN/A\t\n EFV\t158 (49.38)\t0 (0)\t158 (89.27)\t\t\n NVP\t19 (5.94)\t0 (0)\t19 (10.73)\t\t\n SQV/r\t24 (7.50)\t24 (16.78)\t0 (0)\t\t\n LPV/r\t51 (15.94)\t51 (35.66)\t0 (0)\t\t\n ATV/r\t62 (19.38)\t62 (43.36)\t0 (0)\t\t\n DRV/r\t6 (1.88)\t6 (4.20)\t0 (0)\t\t\n Currently on treatment with TDF (n, %)\t305 (95.31)\t137 (95.8)\t168 (94.92)\t0.71\t\nBaseline laboratory\t\t\t\t\t\n Chol (mg/dL), median (IQR)\t210 (182–239)\t205 (182–242)\t211 (182–237)\t0.90\t\n TG (mg/dL), median (IQR)\t138 (94–206)\t163 (103–224)\t127 (85–192)\t0.002\t\n HDL (mg/dL), median (IQR)\t46 (38–53)\t43 (38–51)\t47 (39–55)\t0.01\t\n LDL (mg/dL), median (IQR)\t131 (107–153)\t129 (106–153)\t132 (107–154)\t0.51\t\n ALT (mg/dL), median (IQR)\t26 (19–39)\t24 (19–37)\t28 (21–41)\t0.02\t\n eGFR(CKD-EPI) (mL/min/1.73 m2), median (IQR)\t101.35 (88.02–109.19)\t99.4 (84.1–107.99)\t102.62 (92.66–110.72)\t0.01\t\n Creatinine (mg/dL), median (IQR)\t0.83 (0.72–0.96)\t0.84 (0.70–0.97)\t0.83 (0.72–0.95)\t0.74\t\nReason for switching to RPV\t\t\t\t< 0.001\t\n CNS toxicity\t89 (28.25)\t3 (2.11)\t86 (49.71)\t\t\n Simplify regimen\t128 (40.63)\t108 (76.06)\t20 (11.56)\t\t\n Dyslipidemia\t70 (22.22)\t21 (14.79)\t49 (28.32)\t\t\n Gynecomastia form EFV\t5 (1.59)\t0 (0)\t5 (2.89)\t\t\n EFV induce hepatitis\t2 (0.63)\t0 (0)\t2 (1.16)\t\t\n LPV/r GI side effect\t4 (1.27)\t4 (2.82)\t0 (0)\t\t\n Lipodystrophy\t9 (2.86)\t0 (0)\t9 (5.20)\t\t\n ATV induce gall stone\t1 (0.32)\t1 (0.70)\t0 (0)\t\t\n Other\t7 (2.22)\t5 (3.52)\t2 (1.16)\t\t\nART antiretroviral therapy, EFV efavirenz, NVP nevirapine, SQV/r ritonavir-boosted saquinavir, LPV/r ritonavir-boosted lopinavir, ATV/r ritonavir-boosted atazanavir, DVR/r ritonavir-boosted darunavir, TDF tenofovir, Chol cholesterol, TG triglyceride, HDL high-density lipoprotein, LDL low-density lipoprotein, ALT alanine transaminase, eGFR estimated glomerular infiltration rate, IQR interquartile range\n\n* P-value by Wilcoxon signed-rank test or t-test\n\n\n\nAfter 12 months switching to RPV, 298 (93%) participants maintained virological suppression (HIV RNA < 50 copies/mL). Of 22 participants with unfavorable outcomes, 10 (3.1%) participants discontinued RPV treatment, 7 (2.2%) participants had virological failure, and 5 (1.6%) participants were lost to follow-up during the study period (Fig. 1). There was no difference in virological suppression at month 12 between both NNRTI (165/177 = 93.2%) or boosted PI groups (133/143 = 93.0%; p = 0.94). Discontinuations of therapy occurred for the following reasons: 5 (1.6%) participants had adverse events (AE), 4 (1.5%) participants decided not to continue treatment with RPV-based regimen, and one participant died from coronary heart disease.Fig. 1 Proportion of patient with a viral load (VL) < 50 copies/mL after 12-months and 24-months follow-up. PI protease inhibitor, NNRTI non-nucleoside reverse transcriptase inhibitor\n\n\n\n\nSeven participants experienced at least one detectable HIV-RNA up to month 12. Among them, two participants had HIV-RNA > 100 copies/mL and one participant had HIV-RNA > 1000 copies/mL. Treatment interruptions due to AE-related issues were as follows: 2 participants had hepatitis events (Both of them had ALT > 5 times of UNL and returned to normal after discontinuing RPV. No liver biopsy was done), 1 participant had rash, 1 participant had lipodystrophy and 1 participant had QT prolongation. None of the virological failure participants reported any concomitant medication use during the study period.\n\nThe median duration of RPV treatment was 1.6 (IQR 1.2–3.0) years. There were 177 participants taking RPV-based regimens for more than 24 months and 86% of overall participants maintained virological suppression to this time point; 85.7% of boosted PI group vs. 86% of NNRTI group (p = 0.96)\n\nMedian change in TC, LDL, HDL, and TG from baseline to 12 months were compared (Fig. 2). There were significant improvements in lipid parameters: TC (− 21 (IQR − 47 to 1) mg/dL; p < 0.001), LDL (− 14 (IQR − 37 to 11) mg/dL; p < 0.001) and TG (− 22 (IQR − 74 to 10) mg/dL; p < 0.001). Additionally, the reduction of TG was higher in PI compared to NNRTI-pre-treated groups (− 43 (IQR − 101 to 1) vs − 12 (IQR − 53 to 16) mg/dL; p = 0.002).Fig. 2 Median changes in lipid profile from baseline to 12 months in patients switching to rilpivirine. HDL high-density lipoprotein, LDL low-density lipoprotein, TC total cholesterol, TG triglyceride\n\n\n\n\nWe found that estimated glomerular filtration rate (eGFR) had slightly decreased (− 4.3 (IQR − 12 to 1.1) mL/min per 1.73 m2; p < 0.001) in overall participants. There was no difference in the reduction of eGFR between PI- and NNRTI-pre-treated groups.\n\nThere was a small increase in alanine aminotransferase (ALT) in both groups with median change 5 U/L (IQR − 7 to 14.5; p < 0.001) and the participants in PI-pre-treated groups had increase in ALT more than those in NNRTI group (10 (IQR 2 to 19) VS. 0 (IQR − 12 to 10) U/L; p < 0.001). The median change in cluster of differentiation 4 (CD4) cell count at 12 months was significantly greater among NNRTI pre-treated groups (− 25 (IQR − 125 to 60) VS. 5 (− 78, 93); p = 0.01).\n\nDiscussion\nThis study demonstrated the efficacy and safety of switching from first line NNRTI- or PI- based to RPV-based regimen among HIV-1-infected Thai participants who had been virologically suppressed with no previous antiretroviral treatment failure. The overall virological suppression at 12 months was 93% among participants who switched to RPV-based regimens, with low rates of virological failure (2.2%) which was similar to previous study reports [14, 15, 17–19]. The randomized SPIRIT study, showed that 89.3% of treatment experienced participants who switched from ritonavir-boosted PI (PI/r)-based regimen to RPV/FTC/TDF were able to maintain viral suppression at week 48 compared to those who continued treatment with a PI/r regimen; indicating a low risk for virological failure [17]. Another study showed that switching from EFV/FTC/TDF to RPV/FTC/TDF a was safe and efficacious option for virologically suppressed HIV-infected participants who cannot tolerate EFV [18].\n\nOnly one participant with virological failure had viral load more than 1000 copies/mL and virological suppression was subsequently achieved by reintroducing previous ART. These findings suggest that switching to RPV in routine clinical practice is effective in maintaining virological suppression. Moreover, 86% of the participants remained virologically suppressed at 24 months which is higher than the rate reported by another study (72%) [16].\n\nThe main reasons for switching to RPV were toxic AE of the current regimen and simplification of cART. These results are consistent with other studies [14, 19, 20]. We observed a lower rate of RPV treatment discontinuation due to AE in our study compared to a previous study [21] (1.6% vs 7.2%).\n\nSwitching to RPV based regimen led to a significant improvement in fasting lipids levels from baseline to 12 months; TC, LDL and TG decreased in both groups but was markedly improved in the boosted PI pre-treated groups. This is in agreement with findings from other studies [15, 19].\n\nCardiovascular diseases have been recognized as the most common non- acquired immune deficiency syndrome (AIDS) causes of death among HIV-infected individuals on ART [22]. Hypercholesterolemia is known as a major risk factor and requires proper management to reduce cardiovascular disease risk. Therefore, in addition to smoking cessation and other lifestyle modifications, modification of the cART regimen may be additional strategy to reduce cardiovascular risk. However, the median ASCVD risk score did not show statistically significant changes over time in our study.\n\nRegarding renal safety, we found a slightly but statistically significant decrease in eGFR over the follow-up period. RPV is known to cause inhibition of the organic cation transporter in the basolateral membrane of the proximal tubular cell [23]. However, previous data confirmed that participants initially treated with RPV-based regimen had a small decrease in the eGFR that remained stable over the remaining study period [24].\n\nWe also found a small but significant increase in ALT values in both groups that was more pronounced in PI pre-treated group. There were two participants who discontinued RPV due to hepatitis (Grade 2–3). This finding is consistent with other studies [19, 21].\n\nOur study has some limitations. First, this is a prospective cohort study in real life setting, so confounding factors could not be completely ruled out. Second, the study populations were only from TRCARC, Bangkok, which may not represent the data from other hospitals in Thailand. Last, we did not have data on concomitant medications (i.e., proton-pump inhibitors), how RPV was taken (i.e., with or without food) and adherence which can interfere with the treatment outcome.\n\nConclusion\nIn many resource-limited settings (RLS), that integrase inhibitors is not affordable, RPV-based regimen would be a good alternative option for PLHIV with first line NNRTI or boosted PI intolerance and without prior NNRTI/PI resistance.\n\nAbbreviations\nAIDSacquired immune deficiency syndrome\n\nAEadverse event\n\nALTalanine aminotransferase\n\nARTantiretroviral therapy\n\ncARTcombined antiretroviral therapy\n\nCD4cluster of differentiation 4\n\nEFVefavirenz\n\nEFV/FTC/TDFefavirenz/emtricitabine/tenofovir disoproxil fumarate\n\neGFRestimated glomerular infiltration rate\n\nFTCemtricitabine\n\nHDLhigh-density lipoprotein\n\nHIVhuman immunodeficiency virus\n\nINIintegrase inhibitors\n\nIQRinterquartile range\n\nLDLlow-density lipoprotein cholesterol\n\nLMIClow- and middle-income countries\n\nNRTInucleoside reverse transcriptase inhibitors\n\nNNRTInucleoside reverse transcriptase inhibitors\n\nPIprotease inhibitor\n\nPI/rritonavir-boosted PI\n\nPLHIVpeople living with HIV\n\nRLSresource-limited settings\n\nRNAribonucleic acid\n\nRPVrilpivirine\n\nRPV/FTC/TDFrilpivirine/emtricitabine/tenofovir disoproxil fumarate\n\nSTRsingle tablet regimen\n\nTCtotal cholesterol\n\nTDFtenofovir disoproxil fumarate\n\nTDF + ABCtenofovir disoproxil fumarate + abacavir\n\nTDF + 3TCtenofovir disoproxil fumarate + lamivudine\n\nTGtriglycerides\n\nTRC-ARCThai Red Cross AIDS Research Centre\n\nAuthors’ contributions\nAA, SJK and KR contributed to the design of the prospective long-term cohort. SG, AA, and WMH took care of the patients. SJK and TA analyzed and interpreted the data. KR supervised the work. SG wrote the manuscript. AA, TA, WMH, SJK and KR provided critical feedback. All authors read and approved the final manuscript.\n\nAcknowledgements\nThe authors would like to thank all patients for participating in this study. This research was supported by HIV-NAT, Thai Red Cross AIDS Research Centre.\n\nCompeting interests\nAA participated in a company sponsored speaker’s bureau from Jensen-Cilag, Gilead and Bristol-Meyer Squibb. KR has received the Senior Research Scholar from Thailand Research Fund (TRF). He also has participated in a company sponsored speaker’s bureau from Abbott, Gilead, Bristol-Myers Squibb, Merck, Roche, Jensen-Cilag, GlaxoSmithKline, and GPO (Governmental pharmaceutical organization). The rest of the authors declare that they have no competing interests.\n\nAvailability of data and materials\nData were extracted from the electronic database of HIV-NAT 006 cohort.\n\nConsent for publication\nNot applicable.\n\nEthics approval and consent to participate\nThe study was reviewed and approved by the institution’s review board. All participants voluntarily provided written informed consent prior to enrolling into the study.\n\nFunding\nThis study has no funding.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Palella FJ Jr Delaney KM Moorman AC Loveless MO Fuhrer J Satten GA Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators N Engl J Med 1998 338 853 860 10.1056/NEJM199803263381301 9516219 \n2. Ledergerber B Egger M Opravil M Telenti A Hirschel B Battegay M Clinical progression and virological failure on highly active antiretroviral therapy in HIV-1 patients: a prospective cohort study. Swiss HIV Cohort Study Lancet 1999 353 863 868 10.1016/S0140-6736(99)01122-8 10093977 \n3. Teeraananchai S Chaivooth S Kerr SJ Bhakeecheep S Avihingsanon A Teeraratkul A Life expectancy after initiation of combination antiretroviral therapy in Thailand Antivir Ther 2017 22 393 402 10.3851/IMP3121 28054931 \n4. World Health Organization (WHO). Updated recommendations on first-line and second-line antiretroviral regimens and post exposure prophylaxis and recommendation on early infant diagnosis of HIV: interim guidance. http://www.who.int/hiv/pub/guidelines/ARV2018update/en/. Accessed 22 Nov 2018.\n5. Department of Health and Human Services (DHHS). Guideline for the use of antiretroviral agents in HIV-1-infected adult and adolescent http://aidsinfo.nih.gov/guidelines//html/1/adult-and-adolescent-arv/. Accessed 22 Nov 2018.\n6. Schafer JJ Short WR Rilpivirine, a novel non-nucleoside reverse transcriptase inhibitor for the management of HIV-1 infection: a systematic review Antivir Ther 2012 17 1495 1502 10.3851/IMP2254 22878339 \n7. Cohen CJ Molina JM Cassetti I Chetchotisakd P Lazzarin A Orkin C Week 96 efficacy and safety of rilpivirine in treatment-naive, HIV-1 patients in two Phase III randomized trials Aids 2013 27 939 950 10.1097/QAD.0b013e32835cee6e 23211772 \n8. Nelson MR Elion RA Cohen CJ Mills A Hodder SL Segal-Maurer S Rilpivirine versus efavirenz in HIV-1-infected subjects receiving emtricitabine/tenofovir DF: pooled 96-week data from ECHO and THRIVE Studies HIV Clin Trials 2013 14 81 91 10.1310/hct1403-81 23835510 \n9. Cohen CJ Molina JM Cahn P Clotet B Fourie J Grinsztejn B Efficacy and safety of rilpivirine (TMC278) versus efavirenz at 48 weeks in treatment-naive HIV-1-infected patients: pooled results from the phase 3 double-blind randomized ECHO and THRIVE Trials J Acquir Immune Defic Syndr 2012 60 33 42 10.1097/QAI.0b013e31824d006e 22343174 \n10. Janssen-Cilag SpA, Latina, Italy. Package insert for Edurant (rilpivirine) http://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/EDURANT-pi.pdf. Accessed 22 Nov 2018.\n11. Tran AH Best BM Stek A Wang J Capparelli EV Burchett SK Pharmacokinetics of Rilpivirine in HIV-Infected Pregnant Women J Acquir Immune Defic Syndr 2016 72 289 296 10.1097/QAI.0000000000000968 26918544 \n12. Crauwels HM van Heeswijk RP Buelens A Stevens M Boven K Hoetelmans RM Impact of food and different meal types on the pharmacokinetics of rilpivirine J Clin Pharmacol 2013 53 834 840 10.1002/jcph.107 23720136 \n13. Gazaignes S Resche-Rigon M Gatey C Yang C Denis B Fonsart J Efficacy and safety of a switch to rilpivirine-based regimens in treatment-experienced HIV-1-infected patients: a cohort study Antivir Ther 2016 21 329 336 10.3851/IMP3010 26566057 \n14. Gantner P Reinhart S Partisani M Baldeyrou M Batard ML Bernard-Henry C Switching to emtricitabine, tenofovir and rilpivirine as single tablet regimen in virologically suppressed HIV-1-infected patients: a cohort study HIV Med 2015 16 132 136 10.1111/hiv.12183 25124291 \n15. Pinnetti C Di Giambenedetto S Maggiolo F Fabbiani M Sterrantino G Latini A Switching to coformulated rilpivirine/emtricitabine/tenofovir in virologically suppressed patients: data from a multicenter cohort J Acquir Immune Defic Syndr 2015 70 e147 e150 10.1097/QAI.0000000000000727 26090757 \n16. Arrabal-Durán Paula Rodríguez-González Carmen G Chamorro-de-Vega Esther Gijón-Vidaurreta Paloma Herranz-Alonso Ana Sanjurjo-Sáez María Switching to a rilpivirine/emtricitabine/tenofovir single-tablet regimen in RNA-suppressed patients infected with human immunodeficiency virus 1: Effectiveness, safety and costs at 96 weeks International Journal of Clinical Practice 2017 71 8 e12968 10.1111/ijcp.12968 \n17. Palella FJ Jr Fisher M Tebas P Gazzard B Ruane P Van Lunzen J Simplification to rilpivirine/emtricitabine/tenofovir disoproxil fumarate from ritonavir-boosted protease inhibitor antiretroviral therapy in a randomized trial of HIV-1 RNA-suppressed participants Aids 2014 28 335 344 10.1097/QAD.0000000000000087 24670520 \n18. Mills AM Cohen C Dejesus E Brinson C Williams S Yale KL Efficacy and safety 48 weeks after switching from efavirenz to rilpivirine using emtricitabine/tenofovir disoproxil fumarate-based single-tablet regimens HIV Clin Trials 2013 14 216 223 10.1310/hct1405-216 24144898 \n19. Gianotti N Poli A Nozza S Spagnuolo V Tambussi G Bossolasco S Efficacy and safety in clinical practice of a rilpivirine, tenofovir and emtricitabine single-tablet regimen in virologically suppressed HIV-positive patients on stable antiretroviral therapy J Int AIDS Soc 2015 18 20037 10.7448/IAS.18.1.20037 26232000 \n20. Surgers L Valin N Viala C Boyd A Fonquernie L Girard PM Evaluation of the efficacy and safety of switching to tenofovir, emtricitabine, and rilpivirine in treatment-experienced patients J Acquir Immune Defic Syndr 2015 68 e10 e12 10.1097/QAI.0000000000000401 25321178 \n21. Bagella P De Socio GV Ricci E Menzaghi B Martinelli C Squillace N Durability, safety, and efficacy of rilpivirine in clinical practice: results from the SCOLTA Project Infect Drug Resist 2018 11 615 623 10.2147/IDR.S152090 29731650 \n22. Farahani M Mulinder H Farahani A Marlink R Prevalence and distribution of non-AIDS causes of death among HIV-infected individuals receiving antiretroviral therapy: a systematic review and meta-analysis Int J STD AIDS 2017 28 636 650 10.1177/0956462416632428 26868158 \n23. Gutierrez F Fulladosa X Barril G Domingo P Renal tubular transporter-mediated interactions of HIV drugs: implications for patient management AIDS Rev 2014 16 199 212 25350530 \n24. McLaughlin MM Guerrero AJ Merker A Renal effects of non-tenofovir antiretroviral therapy in patients living with HIV Drugs Context 2018 7 212519 10.7573/dic.212519 29623097\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1742-6405",
"issue": "16(1)",
"journal": "AIDS research and therapy",
"keywords": "Dyslipidemia; HIV; Resource limited setting; Rilpivirine; Switching",
"medline_ta": "AIDS Res Ther",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D057915:Drug Substitution; D005260:Female; D015658:HIV Infections; D015497:HIV-1; D006295:Health Resources; D006801:Humans; D008055:Lipids; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D000068696:Rilpivirine; D017211:Treatment Failure; D019562:Viral Load",
"nlm_unique_id": "101237921",
"other_id": null,
"pages": "7",
"pmc": null,
"pmid": "30953533",
"pubdate": "2019-04-05",
"publication_types": "D016428:Journal Article",
"references": "28054931;28722790;9516219;25124291;25321178;26566057;26918544;22878339;24670520;10093977;26090757;29623097;25350530;29731650;22343174;24144898;23835510;26232000;23720136;23211772;26868158",
"title": "Efficacy and improvement of lipid profile after switching to rilpivirine in resource limited setting: real life clinical practice.",
"title_normalized": "efficacy and improvement of lipid profile after switching to rilpivirine in resource limited setting real life clinical practice"
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"activesubstancename": "RILPIVIRINE HYDROCHLORIDE"
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{
"abstract": "Concurrent type 1 diabetes mellitus (T1DM) and idiopathic nephrotic syndrome is rare, and most previously reported cases were in children. We report the case of an adult woman who developed T1DM and minimal change nephrotic syndrome (MCNS) nearly simultaneously.\n\n\n\nA 24-year-old woman had first presented to another hospital with nausea, vomiting, and fatigue. She was diagnosed with diabetic ketoacidosis and T1DM on the basis of her hyperglycemia, ketoacidosis, and positive anti-glutamic acid decarboxylase antibody test result. Rapid infusion of normal saline and insulin administration alleviated hyperglycemia and ketoacidosis. Two weeks after admission, however, she developed nephrotic syndrome (NS) with rapidly decreasing urine volume. She was referred to our hospital with a diagnosis of acute kidney injury. Although she temporarily required dialysis and high doses of insulin, within 1 month NS and acute kidney injury had been alleviated by oral prednisolone and low-density lipoprotein apheresis. Renal biopsy showed minor glomerular abnormalities without diabetic nephropathy, so we diagnosed her with MCNS. Seven weeks after the discharge, NS relapsed, and cyclosporine was added to prednisolone. However, NS relapsed twice within the next 4 months, so we started her on rituximab. At 6 months after initiating rituximab therapy, she remained in complete remission. Her mother also had T1DM but not MCNS. The patient had HLA-DRB1*09:01/09:01, DQB1*03:03/03:03, and her mother had HLA-DRB1*04:05/09:01, DQB1*03:03/04:01.\n\n\n\nConcurrent T1DM and MCNS is rare and their coexistence might be coincidental. Alternatively, they might have been caused by an underlying, unidentified genetic predisposition. Previous reports and our patient's findings suggest that specific HLA alleles and haplotypes or a Th1/Th2 imbalance might be associated with T1DM and MCNS that occurred nearly simultaneously.",
"affiliations": "Department of Nephrology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan. ryuzou_nishizono@med.miyazaki-u.ac.jp.;Department of Nephrology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.;Department of Nephrology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.;Department of Nephrology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.;Department of Nephrology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.;Dialysis Division, University of Miyazaki Hospital, Miyazaki, Japan.;Department of Nephrology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.;Dialysis Division, University of Miyazaki Hospital, Miyazaki, Japan.",
"authors": "Nishizono|Ryuzoh|R|0000-0002-8185-618X;Kogou|Hiroki|H|;Ishizaki|Yuri|Y|;Minakawa|Akihiro|A|;Kikuchi|Masao|M|;Inagaki|Hiroko|H|;Sato|Yuji|Y|;Fujimoto|Shouichi|S|",
"chemical_list": "D005938:Glucocorticoids; D007004:Hypoglycemic Agents; D007328:Insulin; D011239:Prednisolone",
"country": "England",
"delete": false,
"doi": "10.1186/s12882-020-02071-6",
"fulltext": "\n==== Front\nBMC Nephrol\nBMC Nephrol\nBMC Nephrology\n1471-2369 BioMed Central London \n\n2071\n10.1186/s12882-020-02071-6\nCase Report\nConcurrent minimal change nephrotic syndrome and type 1 diabetes mellitus in an adult Japanese woman: a case report\nhttp://orcid.org/0000-0002-8185-618XNishizono Ryuzoh ryuzou_nishizono@med.miyazaki-u.ac.jp 1 Kogou Hiroki 1 Ishizaki Yuri 1 Minakawa Akihiro 1 Kikuchi Masao 1 Inagaki Hiroko 2 Sato Yuji 12 Fujimoto Shouichi 23 1 grid.410849.00000 0001 0657 3887Department of Nephrology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan \n2 grid.416001.20000 0004 0596 7181Dialysis Division, University of Miyazaki Hospital, Miyazaki, Japan \n3 grid.410849.00000 0001 0657 3887Department of Hemovascular Medicine and Artificial Organs, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan \n23 9 2020 \n23 9 2020 \n2020 \n21 41019 4 2020 15 9 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 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\nConcurrent type 1 diabetes mellitus (T1DM) and idiopathic nephrotic syndrome is rare, and most previously reported cases were in children. We report the case of an adult woman who developed T1DM and minimal change nephrotic syndrome (MCNS) nearly simultaneously.\n\nCase presentation\nA 24-year-old woman had first presented to another hospital with nausea, vomiting, and fatigue. She was diagnosed with diabetic ketoacidosis and T1DM on the basis of her hyperglycemia, ketoacidosis, and positive anti-glutamic acid decarboxylase antibody test result. Rapid infusion of normal saline and insulin administration alleviated hyperglycemia and ketoacidosis. Two weeks after admission, however, she developed nephrotic syndrome (NS) with rapidly decreasing urine volume. She was referred to our hospital with a diagnosis of acute kidney injury. Although she temporarily required dialysis and high doses of insulin, within 1 month NS and acute kidney injury had been alleviated by oral prednisolone and low-density lipoprotein apheresis. Renal biopsy showed minor glomerular abnormalities without diabetic nephropathy, so we diagnosed her with MCNS. Seven weeks after the discharge, NS relapsed, and cyclosporine was added to prednisolone. However, NS relapsed twice within the next 4 months, so we started her on rituximab. At 6 months after initiating rituximab therapy, she remained in complete remission.\n\nHer mother also had T1DM but not MCNS. The patient had HLA-DRB1*09:01/09:01, DQB1*03:03/03:03, and her mother had HLA-DRB1*04:05/09:01, DQB1*03:03/04:01.\n\nConclusions\nConcurrent T1DM and MCNS is rare and their coexistence might be coincidental. Alternatively, they might have been caused by an underlying, unidentified genetic predisposition. Previous reports and our patient’s findings suggest that specific HLA alleles and haplotypes or a Th1/Th2 imbalance might be associated with T1DM and MCNS that occurred nearly simultaneously.\n\nKeywords\nType 1 diabetes mellitusSteroid-sensitive nephrotic syndromeMinimal change nephrotic syndromeGenetic factorsissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nType 1 diabetes mellitus (T1DM) and idiopathic nephrotic syndrome are more common in children than in adults. The incidence of T1DM in Japanese children < 14 years of age is 1.4–2.25/100,000 [1], which is much lower than that in other countries, especially Finland (45.0–64.2/100,000 children < 15 years of age) [2]. Conversely, the estimated incidence of pediatric idiopathic nephrotic syndrome in Japan is 6.49 cases/100,000 [3], which is slightly higher than the average incidence in previous studies worldwide (4.7/100,000) [4]. Most cases of pediatric idiopathic nephrotic syndrome manifest as minimal change nephrotic syndrome (MCNS) in Japan, which is similar to that in other countries.\n\nSome case reports described children who had developed idiopathic nephrotic syndrome soon after being diagnosed with T1DM, whereas others, conversely, had developed T1DM soon after being diagnosed with idiopathic nephrotic syndrome [5–11]. Most patients with MCNS had neither diabetic nephropathy nor retinopathy. We report a rare case in which an adult woman developed T1DM and MCNS nearly simultaneously. We then discuss the patient’s genetic background.\n\nCase presentation\nA 24-year-old Japanese woman was admitted to another hospital with nausea, vomiting, and general fatigue. She had a 2-month history of strongly feeling thirsty, and she had lost 5 kg during that period. She had no history of infectious diseases such as bronchitis before feeling thirsty. Her only medical history was seasonal allergic rhinitis, but her family history included T1DM. Her mother was diagnosed with T1DM at 29 years of age. Blood tests in the present patient showed a high blood glucose level (340 mg/dL), ketoacidosis (pH 7.21; bicarbonate [HCO3], 8 mmol/L; anion gap, 21.3 mmol/L), and hemoglobin A1c (12.7%). The anti-glutamic acid decarboxylase antibody test result was 708 U/mL, and she was diagnosed with diabetic ketoacidosis and T1DM.\n\nHer symptoms, hyperglycemia, and ketoacidosis were alleviated by rapid normal saline infusion and insulin administration. Shortly after the first insulin lispro injection, however, she exhibited an itchy eruption, and the insulin lispro was changed to insulin aspart. Insulin glargine was also added. Two weeks after admission, the patient developed nephrotic syndrome, and her urine volume decreased rapidly. She was referred to our hospital with a diagnosis of acute kidney injury.\n\nOn admission, she was found to have gained 4 kg in weight within the past 2 weeks due to oliguria. Physical examination showed lower-leg pitting edema. Her blood pressure was 106/66 mmHg, and urinalysis and blood test results revealed findings that were consistent with nephrotic syndrome and renal dysfunction (Table 1). Her serum immunoglobulin E (IgE) level was very high (4882 IU/mL), and there was no eosinophilia.\nTable 1 Patient’s laboratory data at admission\n\n<Urinalysis>\t\n Urinary protein (g/day)\t10\t\n Urinary C-peptide (μg/day)\t17 (24–97)\t\n<Blood test>\t\n Total protein (g/dL)\t4.83\t\n Serum albumin (g/dL)\t1.28\t\n Blood urea nitrogen (mg/dL)\t54.0\t\n Serum creatinine (mg/dL)\t4.04\t\n Total cholesterol (mg/dL)\t434\t\n Plasma glucose (mg/dL)\t85\t\n Hemoglobin A1c (%)\t12.7\t\n Serum C-peptide (ng/mL)\t2.0 (1.2–2.0)\t\n Serum IgG (mg/dL)\t479 (861–1747)\t\n Serum IgE (IU/mL)\t4882 (3.7–311.6)\t\n Free triiodothyronine (FT3) (pg/mL)\t1.5 (1.88–3.18)\t\n Free thyroxine (FT4) (ng/dL)\t0.78 (0.7–1.48)\t\n Thyroid stimulating hormone (μIU/L)\t1.01 (0.35–4.94)\t\n Thyroglobulin antibody\tnegative\t\n Thyroid peroxidase antibody\tnegative\t\n Ant-GAD antibody (U/mL)\t708 (< 5.0)\t\n Anti-IA-2 antibody (U/mL)\t6.3 (< 0.6)\t\n Anti-insulin antibody\tnegative\t\n Anti-ZnT8 antibody\tnegative\t\n Anti-islet cell antibody\tnegative\t\n() normal range.\n\nIg Immunoglobulin, GAD Glutamic acid decarboxylase, IA-2 Insulinoma-associated antigen-2, ZnT8 Zinc transporter 8\n\n\n\nInsulin treatment for T1DM was continued, and hemodialysis was initiated on day 2 and continued three times per week because of acute kidney injury. A renal biopsy was performed on day 15 after admission. Among the 46 glomeruli that were obtained in the biopsy, one glomerulus showed global sclerosis, and the others showed some mesangial matrix expansion but without hypercellularity or extracapillary or endocapillary proliferation. The pathological diagnosis was minor glomerular abnormalities including immunofluorescence and electron micrographic studies (Fig. 1), and we diagnosed her with MCNS.\nFig. 1 Micrographs of renal biopsy findings. a Light micrograph of a glomerulus shows no evidence of diabetic nephropathy (periodic acid-Schiff stain). b Glomerulus shows positive immunofluorescence staining for immunoglobulin G (IgG) along a capillary wall. c Electron micrograph shows effacement of the podocyte foot process and a glomerular capillary membrane of normal thickness without evidence of capillary immune complex deposits. (A × 400; B × 400; C × 5000)\n\n\n\nThe patient’s clinical course is shown in Fig. 2. Treatment with oral prednisolone (PSL) at a dose of 0.8 mg/kg (50 mg/day) was started on day 22. Her urinary volume increased within 2 weeks, allowing discontinuation of hemodialysis on day 38, although her urinary protein remained at 5 g/day. Because nephrotic syndrome is not a result of MCNS but, rather, it is caused by focal segmental glomerulosclerosis (FSGS), we started low-density lipoprotein apheresis (LDL-A) on day 42. LDL-A was performed twice a week for 3 weeks. Her urinary protein decreased, and the urine volume gradually increased. On day 55, she was in complete remission. PSL was tapered by 10 mg every 2 weeks, and she was discharged from the hospital at a reduced PSL dose of 30 mg/day on day 71.\nFig. 2 Clinical course. *PMT, pulse methylprednisolone therapy: 500 mg of methylprednisolone intravenously for 3 days\n\n\n\nSeven weeks later, the patient had a relapse of nephrotic syndrome, and cyclosporine 1.5 mg/kg (75 mg/day) was added to PSL. However, NS relapsed twice within the next 4 months, so we started her on a single dose of rituximab (375 mg/m2) after explaining the prognosis of frequently relapsing nephrotic syndrome. Serum CD19/CD20 levels decreased to 0.1/0.0% after 1 month, and we discontinued cyclosporine. PSL was tapered from 30 mg/day to 5 mg/day over 6 months, and hemoglobin A1c remained at 7.1–7.9% with insulin treatment. At 6 months after initiating rituximab, she remained in complete remission without any reported side effects.\n\nTo investigate the genetic background of the co-occurrence of both diseases, we performed an HLA testing on the patient and her mother. The patient had HLA-DRB1*09:01/09:01, DQB1*03:03/03:03, and her mother had HLA-DRB1*04:05/09:01, DQB1*03:03/04:01.\n\nDiscussion and conclusions\nWe report the rare case of a young woman who developed T1DM and MCNS nearly simultaneously. We later found that her mother also had T1DM. The patient had no diabetic retinopathy or nephropathy, but her hemoglobin A1c was 12.7%. A previous report noted that the glomerular basement membrane was partially thickened in a patient 6 months after being diagnosed with diabetes mellitus [12, 13], but it was not thickened in our patient. A possible explanation is that she had developed subclinical acute-onset T1DM a few months before admission, which had manifested as a strong feeling of thirst during the 2 months before her admission. She had also lost weight (5 kg).\n\nAlthough renal biopsy showed minor glomerular abnormalities, it might have been FSGS because she required LDL-A as the initial treatment and her nephrotic syndrome relapsed several times. She had no diabetic nephropathy, but a trace of linear IgG deposition in the capillary walls was revealed by immunofluorescence staining. We could not determine whether the deposition was an immunological reaction or a non-specific change that is occasionally seen in MCNS/FSGS patients.\n\nIn the present case, we could control her hemoglobin A1c level, which was 7.1–7.9% after rituximab treatment despite T1DM and chronic steroid use. Additionally, the insulin dose did not need to be increased. Is immune intervention beneficial in T1DM patients? Some previous studies showed beneficial effects of immunosuppressants including rituximab in T1DM [14–18], but longer-term follow-up revealed a decline in the effect over time [19–23]. It is uncertain whether good glycemic control in the present case resulted from rituximab, but rituximab had a steroid-sparing effect and potentially contributed to preventing hyperglycemia.\n\nThe association between T1DM and idiopathic nephrotic syndrome has been known for more than 6 decades, but there are few reports of patients who had co-occurrence of these conditions (Table 2). Although the nature of this association remains unclear, several hypotheses have been offered. A few reports described that HLA loci, especially HLA-DR/DQ, might be associated with a genetic predisposition for the development of both diseases (Table 3). However, we must take into consideration that the genetic background of T1DM and nephrotic syndrome patients in Japan is different from that of patients from other countries. In Caucasians, nephrotic syndrome has been reported to be associated with HLA DR7, and the presence of the HLA-DRB1*03:01-DQB1*02:01 haplotype poses a high risk for developing T1DM. However, those HLA types are extremely rare in a general Japanese population [28].\nTable 2 Summary of previous reports of patients with nephrotic syndrome with type 1 diabetes mellitus that developed within 1 year\n\nReferences\tAge at onset of T1DM (years)\tAge at onset of NS (years)\tPathological diagnosis\tTreatment\tOutcome\t\nRobinson [12]\t8\t8\tNot done\tSteroid, Diuretics\tResolved completely\t\nUrizar [11]\t4\t4 (1 week after DM)\tNormal\tInsulin\tResolved completely\t\n8\t8\tMinimal focal glomerulitis\tSteroid\tResolved completely\t\n3.3\t4.3\tNormal\tSteroid\tResolved completely\t\n5\t5\tMinimal focal glomerulitis\tSteroid\tRecurrence\t\nRobbinson [10]\t3\t3 (2 months after DM)\tICGN\tSteroid\tResolved completely\t\nDornan [9]\t20\t20 (2 weeks after DM)\tMCD\tDiuretics\tResolved\t\n13\t13 (1 week after DM)\tNot done\t\tResolved spontaneously\t\nRego Filho [7]\t3.9\t3.9\tNot done\tSteroid, CPM\tResolved\t\nNakahara [23]\t8\t8\tMCD\tSteroid, CPM\t?\t\nAgras [24]\t3\t3 (10 months after DM)\tNot done\tSteroid, CPM\tResolved\t\nJameela [25]\t2.75\t2.75\tDiffuse expansion of mesangial matrix\tSteroid, CPM\tResolved\t\n1.5\t1.5\tDiffuse expansion of mesangial matrix\tSteroid, CPM\tResolved\t\nOtukesh [6]\t13 days\t13 days\tMGN\t?\t?\t\nT1DM Type 1 diabetes mellitus, NS Nephrotic syndrome, CPM Cyclophosphamide, MGN Membranous glomerulonephritis, MCD Minimal-change disease, ICGN Immune-complex glomerulonephritis\n\nTable 3 HLA class II antigens and DNA typing from previous reports and the present patient, and all these patients developed nephrotic syndrome and type 1 diabetes mellitus concurrently\n\nCase\tHLA class II\t\nRego Filho [7]\tDR 4, DR 8, DR 53\t\nPeces [26]\tDR 4, DR 7\t\nKagiyama [27]\tDR 2, DR 9\t\nAgras [24]\tDR 4, DR 11, DR 52, DR 53, DQ 7, DQ 8\t\nPresent case\tDR 9 (DRB 1*09:01), DQ 9 (DQB 1*03:03)\t\nHLA Human leukocyte antigen\n\n\n\nIn the Japanese population, HLA-DRB1*04:05, HLA-DRB1*09:01, HLA-DQB1*04:01, and HLA-DQB1*03:03 alleles are associated with susceptibility to T1DM. Additionally, HLA-DRB1*04:05-DQB1*04:01, HLA-DRB1*08:02-DQB1*03:02, and HLA-DRB1*09:01-DQB1*03:03 haplotypes are associated with susceptibility to T1DM [29]. Recently, it has been reported that the HLA-DRB1*08:02, HLA-DQB1*03:02 alleles, and the HLA-DRB1*08:02-DQB1*03:02 haplotype is highly associated with steroid-sensitive nephrotic syndrome in Japanese children [30]. Although we had speculated that our patient would have HLA-DRB1*08:02-DQB1*03:02, she had HLA-DRB1*09:01/09:01 and DQB1*03:03/03:03. Her mother had HLA-DRB1*04:05/09:01 and DQB1*04:01/03:03. Both the patient and her mother had specific HLA haplotypes that are highly associated with T1DM, but only the daughter developed MCNS. HLA-DRB1*09:01-DQB1*03:03-DPB1*02:01 and HLA-A*02:06-C*08:01-B*40:06-DRB1*09:01-DQB1*03:03 haplotypes have been reported to be associated with childhood steroid-sensitive nephrotic syndrome in Japan, so our patient might have either one of the two haplotypes [30].\n\nAnother hypothesis that explains concurrent T1DM and MCNS is Th1/Th2 imbalance [31–35]. Both diseases have a strong association with T-cell abnormalities, although the mechanisms are different. MCNS is known to be associated with allergic disease [36], and it has been reported to be associated with prevalent type 2 helper T-cell (Th2) responses. The association of T1DM with autoimmune disorders is also well known [37], and its association with prevalent type 1 helper T-cell (Th1) responses has been reported. However, neither Th1 predominance in T1DM nor Th2 predominance in MCNS has not been definitively identified [38, 39].\n\nPrevious case reports described that insulin treatment influenced T-cell differentiation and promoted a shift toward a Th2-type response [40–42]. These previous reports strongly suggested that insulin could function as a glucose-regulatory hormone and as a T-cell hormone, which enhances the Th2 response and consequently increases the in vitro production of Th2 profile cytokines such as interleukin (IL)-4 and IL-10 in patients who are at high risk of DM and T1DM.\n\nIn the present case, the patient developed T1DM first, followed by MCNS 2 weeks later. We speculate that these diseases were manifest via two different mechanisms. First, insulin lispro (or aspart) administration might cause a drastic shift in the Th1 response to a Th2 response. Second, insulin lispro may have triggered an allergic reaction causing MCNS because she developed an itchy eruption shortly after the first insulin lispro injection and had a high level of serum IgE. No previous reports, however, have demonstrated the simultaneous onset of T1DM and MCNS, and due to a Th1/Th2 imbalance, and we did not measure the Th1/Th2 ratios and serum cytokine levels that were secreted by Th1 and Th2.\n\nIn summary, we report the rare case of an adult woman with acute kidney injury that resulted from MCNS, which had developed soon after she was diagnosed with diabetic ketoacidosis that was caused by T1DM. The mechanism by which T1DM and MCNS occurred concurrently remains unclear, although some previous reports and our case indicate that genetic factors (e.g., specific HLA alleles and haplotypes) or a Th1/Th2 imbalance might be associated with the onset of these two diseases.\n\nSupplementary information\n\nAdditional file 1.\n\n\n \n\nAbbreviations\nT1DMType 1 diabetes mellitus\n\nNSNephrotic syndrome\n\nMCNSMinimal change nephrotic syndrome\n\nIgImmunoglobulin\n\nGADGlutamic acid decarboxylase\n\nIA-2Insulinoma-associated antigen-2\n\nZnT8Zinc transporter 8\n\nCPMCyclophosphamide\n\nLDL-ALow-density lipoprotein apheresis\n\nMGNMembranous glomerulonephritis\n\nMCDMinimal-change disease\n\nFSGSFocal segmental glomerulosclerosis\n\nICGNImmune-complex glomerulonephritis\n\nHLAHuman leukocyte antigen\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nSupplementary information\nSupplementary information accompanies this paper at 10.1186/s12882-020-02071-6.\n\nWe thank Nancy Schatken, BS, MT (ASCP), from Edanz Group (https://en-author-services.edanzgroup.com/ac), for editing a draft of this manuscript.\n\nAuthors’ contributions\nRN and SF planned and wrote the case report. RN, HK, YI, MK, and HI clinically cared for the patient and participated in clinical data acquisition. MK, YS, and YI performed the renal biopsy. AM pathologically diagnosed the patient and revised the manuscript. RN, MK, YS, and SF analyzed the patient’s clinical course and interpreted the data. RN wrote a draft of the manuscript, and YS and SF revised it critically. All authors read and approved the final manuscript.\n\nFunding\nNot applicable.\n\nAvailability of data and materials\nAll data supporting the case are included in the manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Onda Y Sugihara S Ogata T Yokoya S Yokoyama T Tajima N Type 1 diabetes (T1D) study group. 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Herold KC Gitelman S Greenbaum C Immune tolerance network ITN007AI study group treatment of patients with new onset type 1 diabetes with a single course of anti-CD3 mAb Teplizumab preserves insulin production for up to 5 years Clin Immunol 2009 132 166 173 19443276 \n21. Keymeulen B Walter M Mathieu C Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual beta cell mass Diabetologia. 2010 53 614 623 20225393 \n22. Orban T Bundy B Becker DJ Type 1 diabetes TrialNet Abatacept study group. Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: follow-up one year after cessation of treatment Diabetes Care 2014 37 4 1069 1075 24296850 \n23. Nakahara C Kamoda T Kinugasa H Simultaneous onset of nephrotic syndrome and insulin-dependent diabetes mellitus in a case with hypereosinophilia syndrome Clin Nephrol 2000 53 4 312 314 10809422 \n24. Agras PI Kinik ST Cengiz N Baskin E Type 1 diabetes mellitus associated with nephrotic syndrome J Pediatr Endocrinol Metab 2006 19 8 1045 1048 16995591 \n25. Kari JA, El-Desoky SM, Mokhtar G, Jalalah SM. Simultaneous onset of steroid resistant nephrotic syndrome and IDDM in two young children. BMJ Case Rep. 2010:bcr0420102916. 10.1136/bcr.04.2010.2916.\n26. Peces R Riera JR Lopez Larrea C Alvarez J Steroid-responsive relapsing nephrotic syndrome associated with early diabetic glomerulopathy in a child Nephron. 1987 46 78 82 3600916 \n27. Kagiyama S Tsuruta H Tominaga M Morishita K Doi Y Onoyma K Minimal-change nephrotic syndrome and acute renal failure in a patient with aged onset insulin-dependent diabetes mellitus and autoimmune thyroiditis Am J Nephrol 1999 19 3 369 372 10393372 \n28. Kawasaki E Eguchi K Is type 1 diabetes in the Japanese population the same as among Caucasians? Ann N Y Acad Sci 2004 1037 96 103 15699499 \n29. Kawabata Y Ikegami H Kawaguchi Y Fujisawa T Shintani M Ono M Asian-specific HLA haplotypes reveal heterogeneity of the contribution of HLA-DR and -DQ haplotypes to susceptibility to type 1 diabetes Diabetes. 2002 51 2 545 551 11812768 \n30. Jia X Horinouchi T Hitomi Y Shono A Khor S Omae Y Strong association of the HLA-DR/DQ locus with childhood steroid-sensitive nephrotic syndrome in the Japanese population J Am Soc Nephrol 2018 29 8 2189 2199 30012571 \n31. Koyama A Fujisaki M Kobayashi M Igarashi M Narita M A glomerular permeability factor produced by human T cell hybridomas Kidney Int 1991 40 453 460 1787645 \n32. Pereira Wde F Brito-Melo GE Guimaraes FT Carvalho TG The role of the immune system in idiopathic nephrotic syndrome. A review of clinical and experimental studies Inflamm Res 2014 63 1 12 24121975 \n33. Araya CE Wasserfall CH Brusko TM Mu W Segal MS Johnson RJ Garin EH A case of unfulfilled expectations. Cytokines in idiopathic minimal lesion nephrotic syndrome Pediatr Nephrol 2006 21 603 610 16525836 \n34. Kanai T Shiraishi H Yamagata T Ito T Odaka J Saito T Aoyagi J Momoi MY Th2 cells predominate in idiopathic steroid-sensitive nephrotic syndrome Clin Exp Nephrol 2010 14 578 583 20686809 \n35. Azar ST Tamim H Beyhum HN Habbal MZ Almawi WY Type 1 (insulin-dependent) diabetes is a Th1- and Th2-mediated autoimmune disease Clin Diagn Lab Immunol 1999 6 3 306 310 10225827 \n36. Meadow SR Sarsfield JK Scott DG Rajah SM Steroid-responsive nephrotic syndrome and allergy: immunological studies Arch Dis Child 1981 56 517 524 7271285 \n37. Riley WJ Autoimmune polyglandular syndromes Horn Res 1992 38 Suppl 2 9 15 \n38. Almawi WY Tamim H Azar ST T helper type 1 and 2 cytokines mediate the onset and progression of type 1 (insulin-dependent) diabetes J Clin Endocrinol Metab 1999 84 1497 1502 10323367 \n39. Colucci M Corpetti G Emma F Vivarelli M Immunology of idiopathic nephrotic syndrome Pediatr Nephrol 2018 33 573 584 28451893 \n40. Viardot A Grey ST Mackay F Chisholm D Potential antiinflammatory role of insulin via the preferential polarization of effector T cells toward a T helper 2 phenotype Endocrinology 2007 148 1 346 353 17008395 \n41. Gladstone P Nepom GT The prevention of IDDM. Injecting insulin into the cytokine network Diabetes. 1995 44 7 859 862 7789655 \n42. Kretowski A Myśliwiec J Szelachowska M Kinalski M Kinalska I Insulin increases in vitro production of Th2 profile cytokines in peripheral blood cultures in subjects at high risk of diabetes type 1 and patients with newly diagnosed IDDM Horm Metab Res 1999 31 4 289 292 10333088\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2369",
"issue": "21(1)",
"journal": "BMC nephrology",
"keywords": "Genetic factors; Minimal change nephrotic syndrome; Steroid-sensitive nephrotic syndrome; Type 1 diabetes mellitus",
"medline_ta": "BMC Nephrol",
"mesh_terms": "D000328:Adult; D001706:Biopsy; D001774:Blood Chemical Analysis; D001781:Blood Component Removal; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007004:Hypoglycemic Agents; D007223:Infant; D007231:Infant, Newborn; D007328:Insulin; D007564:Japan; D007678:Kidney Glomerulus; D009402:Nephrosis, Lipoid; D011239:Prednisolone; D006435:Renal Dialysis",
"nlm_unique_id": "100967793",
"other_id": null,
"pages": "410",
"pmc": null,
"pmid": "32967631",
"pubdate": "2020-09-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "10323367;12042892;24121975;7271285;3600916;24296850;1292989;30728982;22798086;20686809;7789655;9370189;27639869;10225827;14685455;30012571;2968891;1787645;15699499;13742289;28451893;17008395;16525836;5790493;24026563;10393372;27252867;27148508;19940299;10809422;12037148;15972866;11812768;20225393;19443276;10333088;16995591;27590892;21719096;27925270",
"title": "Concurrent minimal change nephrotic syndrome and type 1 diabetes mellitus in an adult Japanese woman: a case report.",
"title_normalized": "concurrent minimal change nephrotic syndrome and type 1 diabetes mellitus in an adult japanese woman a case report"
} | [
{
"companynumb": "JP-SA-2020SA274076",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INSULIN LISPRO"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nThe potential risks related to drug exposure during pregnancy represent a vast chapter in modern obstetrics and data regarding the safety of antihypertensive drugs during pregnancy are relatively scarce.\n\n\nMETHODS\nA 37-year-old patient discovered her fifth pregnancy at our hospital after 26 weeks and 4 days of gestation. She reported a history of hypertension and was currently being treated with Losartan. Hospitalization was recommended for the patient and further evaluation of fetal vitality was performed. On the fourth day an ultrasound was performed, resulting in a severe oligohydramnios, fetal centralization and abnormal ductus venosus. After 36 hours, the newborn died. Pathologic evaluation: At autopsy, the skullcap had large fontanels and deficient ossification. The kidneys were slightly enlarged. A microscopic examination detected underdevelopment of the tubules and the presence of some dilated lumens. Immunohistochemical detection of epithelial membrane antigen was positive. Immunoreactivity of CD 15 was also assayed to characterize the proximal tubules, and lumen collapse was observed in some regions.\n\n\nCONCLUSIONS\nAngiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor antagonists (ARAs) are among the most widely prescribed drugs for hypertension. They are often used by hypertensive women who are considering become pregnant. While their fetal toxicity in the second or third trimesters has been documented, their teratogenic effect during the first trimester has only recently been demonstrated.\n\n\nCONCLUSIONS\nConstant awareness by physicians and patients should be encouraged, particularly in regard to the prescription of antihypertensive drugs in women of childbearing age who are or intend to become pregnant.",
"affiliations": "Universidade Federal de São Paulo.;Universidade Federal de São Paulo.;Maternidade Escola de Vila Nova Cachoeirinha.;Hospital Servidor Publico Estadual de São Paulo.;Maternidade Escola de Vila Nova Cachoeirinha.;Universidade de São Paulo.;Universidade Federal de São Paulo.",
"authors": "Korkes|Henri Augusto|HA|;de Oliveira|Leandro Gustavo|LG|;Berlinck|Livia|L|;Goes|Fernanda Sampaio|FS|;Borges|Antonio Fernando Allemand|AF|;Kirsztajn|Gianna Mastroianni|GM|;Sass|Nelson|N|",
"chemical_list": "D047228:Angiotensin II Type 1 Receptor Blockers; D019808:Losartan",
"country": "Brazil",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0101-2800",
"issue": "36(3)",
"journal": "Jornal brasileiro de nefrologia : 'orgao oficial de Sociedades Brasileira e Latino-Americana de Nefrologia",
"keywords": null,
"medline_ta": "J Bras Nefrol",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000328:Adult; D047228:Angiotensin II Type 1 Receptor Blockers; D005260:Female; D006801:Humans; D006973:Hypertension; D019808:Losartan; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D016216:Ultrasonography, Prenatal",
"nlm_unique_id": "9426946",
"other_id": null,
"pages": "410-3",
"pmc": null,
"pmid": "25317627",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Human fetal malformations associated with the use of an angiotensin II receptor antagonist: case report.",
"title_normalized": "human fetal malformations associated with the use of an angiotensin ii receptor antagonist case report"
} | [
{
"companynumb": "BR-ALEMBIC PHARMACUETICALS LIMITED-2017SCAL000590",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LOSARTAN POTASSIUM"
},
... |
{
"abstract": "BACKGROUND\nActive tuberculosis (TB) is commonly considered a contraindication for liver transplantation (LT). However, in patients with TB who develop acute liver failure (ALF) due to toxicity induced by anti-tubercular treatment (ATT), LT could be the only opportunity for treatment. The aim of this study was to evaluate the feasibility of LT in this scenario.\n\n\nMETHODS\nWe described 2 cases and comprehensively reviewed the literature finding 26 cases of LT performed in patients having a concomitant active TB and liver failure secondary to ATT toxicity.\n\n\nRESULTS\nTB was classified as pulmonary in 18/26 (69%), nodal in 3/26 (11%) TB cases, while the remaining 5/26 cases included disseminated, pleural, renal, ovarian, and vertebral TB localization (1 case each). ATT following LT consisted mainly of isoniazid or rifampin (RIF)-sparing regimens and included primarily fluoroquinolones and ethambutol. Rejection episodes and liver toxicity were reported in 19% and 8% of patients respectively. Graft rejection was more frequent among patients treated with RIF-containing regimens (P<.001). Mortality rate was 15% after a median follow up of 12 months. In only one case was death attributed to uncontrolled TB infection.\n\n\nCONCLUSIONS\nOur findings suggest that LT is an effective therapeutic option for patients with active TB developing ALF following ATT and should be considered for patients failing medical treatment.",
"affiliations": "Infectious Diseases Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy.;Infectious Diseases Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy.;Infectious Diseases Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy.;Internal Medicine Unit for the Treatment of Severe Organ Failure, Department of Medical and Surgical Sciences, Sant'Orsola Hospital, Alma Mater Studiorum University of Bologna, Bologna, Italy.;Liver and Multi-Organ Transplant Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy.;Infectious Diseases Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy.;Internal Medicine Unit for the Treatment of Severe Organ Failure, Department of Medical and Surgical Sciences, Sant'Orsola Hospital, Alma Mater Studiorum University of Bologna, Bologna, Italy.;Infectious Diseases Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy.;Infectious Diseases Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy.;Infectious Diseases Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy.;Liver and Multi-Organ Transplant Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy.;Infectious Diseases Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy.",
"authors": "Bartoletti|Michele|M|;Martelli|Giulia|G|;Tedeschi|Sara|S|;Morelli|Mariacristina|M|;Bertuzzo|Valentine|V|;Tadolini|Marina|M|;Pianta|Paolo|P|;Cristini|Francesco|F|;Giannella|Maddalena|M|;Lewis|Russell E|RE|;Pinna|Antonio D|AD|;Viale|Pierluigi|P|",
"chemical_list": "D000995:Antitubercular Agents; D024841:Fluoroquinolones; D004977:Ethambutol; D007538:Isoniazid; D012293:Rifampin",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12658",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "19(2)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "anti-tubercular treatment; liver failure; liver transplantation; tuberculosis",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000293:Adolescent; D000995:Antitubercular Agents; D001992:Bronchoalveolar Lavage Fluid; D004977:Ethambutol; D005240:Feasibility Studies; D005260:Female; D024841:Fluoroquinolones; D006084:Graft Rejection; D006801:Humans; D007538:Isoniazid; D017114:Liver Failure, Acute; D016031:Liver Transplantation; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009169:Mycobacterium tuberculosis; D011379:Prognosis; D012293:Rifampin; D016896:Treatment Outcome; D014376:Tuberculosis",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28054732",
"pubdate": "2017-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Liver transplantation is associated with good clinical outcome in patients with active tuberculosis and acute liver failure due to anti-tubercular treatment.",
"title_normalized": "liver transplantation is associated with good clinical outcome in patients with active tuberculosis and acute liver failure due to anti tubercular treatment"
} | [
{
"companynumb": "IT-MYLANLABS-2017M1021272",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MOXIFLOXACIN"
},
"drugadditional": "1",
... |
{
"abstract": "There are limited real-world mutational and virological outcomes data of treatment-experienced persons diagnosed with HIV-1 subtype C (HIV-1 C) who are failing Integrase Strand Transfer Inhibitor-based regimens. Requisition forms sent for HIV-1 genotypic resistance testing (GRT) between May 2015 and September 2019 were reviewed and participants experiencing virologic failure while on dolutegravir (DTG) or raltegravir (RAL) cART at sampling recruited. Sanger sequencing of the HIV-1 Pol gene was performed from residual plasma samples and drug resistance mutational (DRM) analysis performed using the Stanford University HIV drug resistance database. 40 HIV-1C integrase sequences were generated from 34 individuals, 24 of whom were on DTG cART, three on RAL cART and seven on an unknown (DTG or RAL)-anchored cART at time of GRT. 11/34 (32%) individuals had DRMs to DTG and other integrase inhibitors. 7/11 (64%) patients had exposure to a RAL-based cART at the time of sampling. Out of the 11 individuals with DRMs, one (9%) had 2-class, 6 (55%) had 3-class, and 4 (36%) had 4-class multidrug-resistant HIV-1C. 7/11 individuals (64%) are currently virologically suppressed. Of the four individuals not virologically suppressed, three had extensive DRMs involving 4-classes of ARV drugs and one individual has demised. Resistance to DTG occurs more often in patients exposed to RAL cART. Individuals with 4-class DRMs plus integrase T97 and E157Q mutations appear to have worse outcomes. There is a need for frequent VL monitoring and GRT amongst treatment-experienced HIV-1C diagnosed individuals.",
"affiliations": "Botswana Harvard AIDS Institute Partnership, Gaborone 0000, Botswana.;Botswana Harvard AIDS Institute Partnership, Gaborone 0000, Botswana.;Botswana Harvard AIDS Institute Partnership, Gaborone 0000, Botswana.;National Health Laboratory, Ministry of Health & Wellness, Gaborone 0000, Botswana.;Botswana Harvard AIDS Institute Partnership, Gaborone 0000, Botswana.;Botswana Harvard AIDS Institute Partnership, Gaborone 0000, Botswana.;Botswana Ministry of Health and Wellness, Gaborone 0000, Botswana.;Botswana Ministry of Health and Wellness, Gaborone 0000, Botswana.;Botswana Ministry of Health and Wellness, Gaborone 0000, Botswana.;Botswana Harvard AIDS Institute Partnership, Gaborone 0000, Botswana.;Botswana Harvard AIDS Institute Partnership, Gaborone 0000, Botswana.;National Health Laboratory, Ministry of Health & Wellness, Gaborone 0000, Botswana.;School of Allied Health Professions, Faculty of Health Sciences, University of Botswana, Gaborone 0000, Botswana.;Botswana Harvard AIDS Institute Partnership, Gaborone 0000, Botswana.;Botswana Harvard AIDS Institute Partnership, Gaborone 0000, Botswana.;Botswana Harvard AIDS Institute Partnership, Gaborone 0000, Botswana.",
"authors": "Seatla|Kaelo K|KK|0000-0002-2190-2842;Maruapula|Dorcas|D|;Choga|Wonderful T|WT|0000-0001-7606-0569;Ntsipe|Tshenolo|T|;Mathiba|Nametso|N|;Mogwele|Mompati|M|;Kapanda|Max|M|;Nkomo|Bornapate|B|;Ramaabya|Dinah|D|;Makhema|Joseph|J|;Mmalane|Mompati|M|;Mine|Madisa|M|;Kasvosve|Ishmael|I|0000-0002-2046-545X;Lockman|Shahin|S|;Moyo|Sikhulile|S|0000-0003-3821-4592;Gaseitsiwe|Simani|S|",
"chemical_list": "D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors",
"country": "Switzerland",
"delete": false,
"doi": "10.3390/v13040594",
"fulltext": "\n==== Front\nViruses\nViruses\nviruses\nViruses\n1999-4915\nMDPI\n\n33807382\n10.3390/v13040594\nviruses-13-00594\nArticle\nHIV-1 Subtype C Drug Resistance Mutations in Heavily Treated Patients Failing Integrase Strand Transfer Inhibitor-Based Regimens in Botswana †\nhttps://orcid.org/0000-0002-2190-2842\nSeatla Kaelo K. 12*\nMaruapula Dorcas 12\nhttps://orcid.org/0000-0001-7606-0569\nChoga Wonderful T. 13\nNtsipe Tshenolo 4\nMathiba Nametso 1\nMogwele Mompati 1\nKapanda Max 5\nNkomo Bornapate 5\nRamaabya Dinah 5\nMakhema Joseph 1\nMmalane Mompati 1\nMine Madisa 4\nhttps://orcid.org/0000-0002-2046-545X\nKasvosve Ishmael 2\nLockman Shahin 167\nhttps://orcid.org/0000-0003-3821-4592\nMoyo Sikhulile 17\nGaseitsiwe Simani 17\nGrevenynghe Julien Van Academic Editor\n1 Botswana Harvard AIDS Institute Partnership, Gaborone 0000, Botswana; dmaruapula@gmail.com (D.M.); wchoga@bhp.org.bw (W.T.C.); nmathiba@bhp.org.bw (N.M.); mogwelem@yahoo.com (M.M.); jmakhema@bhp.org.bw (J.M.); mmmalane@bhp.org.bw (M.M.); shahin.lockman@gmail.com (S.L.); smoyo@bhp.org.bw (S.M.); sgaseitsiwe@gmail.com (S.G.)\n2 School of Allied Health Professions, Faculty of Health Sciences, University of Botswana, Gaborone 0000, Botswana; kasvosvei@ub.ac.bw\n3 Division of Human Genetics, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa\n4 National Health Laboratory, Ministry of Health & Wellness, Gaborone 0000, Botswana; tntsipe@bhp.org.bw (T.N.); madisamine0@gmail.com (M.M.)\n5 Botswana Ministry of Health and Wellness, Gaborone 0000, Botswana; maxkapanda@gmail.com (M.K.); bnkomo@gov.bw (B.N.); dramaabya@gov.bw (D.R.)\n6 Division of Infectious Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA\n7 Department of Immunology & Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA\n* Correspondence: kseatla@bhp.org.bw; Tel.: +267-390-2671; Fax: +267-390-1284\n† Part of this work has been presented at the 22nd International AIDS Conference, Amsterdam, The Netherlands, 23–27 July 2018 (LBPEB019).\n\n31 3 2021\n4 2021\n13 4 59425 2 2021\n28 3 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nThere are limited real-world mutational and virological outcomes data of treatment-experienced persons diagnosed with HIV-1 subtype C (HIV-1 C) who are failing Integrase Strand Transfer Inhibitor-based regimens. Requisition forms sent for HIV-1 genotypic resistance testing (GRT) between May 2015 and September 2019 were reviewed and participants experiencing virologic failure while on dolutegravir (DTG) or raltegravir (RAL) cART at sampling recruited. Sanger sequencing of the HIV-1 Pol gene was performed from residual plasma samples and drug resistance mutational (DRM) analysis performed using the Stanford University HIV drug resistance database. 40 HIV-1C integrase sequences were generated from 34 individuals, 24 of whom were on DTG cART, three on RAL cART and seven on an unknown (DTG or RAL)-anchored cART at time of GRT. 11/34 (32%) individuals had DRMs to DTG and other integrase inhibitors. 7/11 (64%) patients had exposure to a RAL-based cART at the time of sampling. Out of the 11 individuals with DRMs, one (9%) had 2-class, 6 (55%) had 3-class, and 4 (36%) had 4-class multidrug-resistant HIV-1C. 7/11 individuals (64%) are currently virologically suppressed. Of the four individuals not virologically suppressed, three had extensive DRMs involving 4-classes of ARV drugs and one individual has demised. Resistance to DTG occurs more often in patients exposed to RAL cART. Individuals with 4-class DRMs plus integrase T97 and E157Q mutations appear to have worse outcomes. There is a need for frequent VL monitoring and GRT amongst treatment-experienced HIV-1C diagnosed individuals.\n\nBotswana\ndolutegravir\nresistance\nmutations\nHIV-1C\nintegrase inhibitors\n==== Body\n1. Introduction\n\nDolutegravir (DTG) is a second-generation integrase strand transfer inhibitor (INSTI) with superior efficacy, a higher genetic barrier to resistance, and a better safety profile than raltegravir (RAL), efavirenz, darunavir-ritonavir (DRV\\r) combination antiretroviral therapy’s (cART) [1,2]. It is recommended as part of the first-line cART by multiple HIV treatment guidelines [3,4,5,6]. However, the emergence of antiretroviral (ARV) resistant HIV-1 is a rising global health threat [7] due to risk of onward transmission of drug-resistant HIV-1 variants [8,9,10] in addition to failure to achieve virological suppression with subsequent increase in morbidity and mortality [11,12]. Globally about 38 million people are living with HIV (PLWH) [13]. Botswana, with a population of about 2.2 million, has an adult HIV prevalence of 20.7% and about 310,000 PLWH on ART [14,15]. HIV-1 subtype C (HIV-1C) predominates in Botswana and the region. Botswana was amongst the first low/middle income country (LMIC) to adopt INSTIs such as RAL and DTG to its mature free ART programme for highly treatment-experienced individuals, and also adopted DTG in first line-therapy in 2016 [4]. However, there is limited ‘real-life’ clinical and virologic outcomes programmatic data on PLWH diagnosed with HIV-1C failing DTG/RAL based regimens.\n\nHighly treatment-experienced PLWH previously failing a RAL-based cART regimen for prolonged periods are prone to develop virological failure (VF) when switched to DTG based cART due to cross-resistance and accumulation of more drug-resistant mutations (DRMs) that reduce DTG’s efficacy [16]. INSTI-naive highly treatment-experienced patients failing DTG cART have been found to have a virus with DRMs including G118R, D67N; H51H/Y, G118R, E138E/K, and less commonly R263R/K, V260I, R263R, N155H, G118R, and E138E [17]. These cases were mainly from clinical trials dominated by non-HIV-1C viruses [18,19,20,21]. However, there is limited information on the selection of INSTI DRMs and subsequent treatment outcomes on INSTI-based cART, especially amongst HIV-1C infected individuals.\n\nWe performed a comprehensive clinical and drug resistance genotypic characterization of HIV-1C from PLWH experiencing VF on DTG and/or RAL -based cART in Botswana.\n\n2. Materials and Methods\n\n2.1. Study Setting\n\nHIV care, including cART, is provided free of charge to all citizens diagnosed with HIV in Botswana. RAL and DTG have been available in the Botswana national HIV treatment program cART since late 2008 and early 2016 respectively [2].\n\n2.2. Selection of Study Population\n\nWe reviewed paper-based laboratory requisition forms sent for genotypic resistance testing on HIV-1 diagnosed adults (>18 years) who experienced virologic failure (generally two or more viral loads (VL) greater than 400 copies/mL while on cART, as per standard of care. These individuals were accessing public health facilities across Botswana as part of their routine HIV clinical care between May 2015 and September 2019.\n\nWe included participants whose laboratory requisition forms indicated that they were on DTG, RAL, or ‘INSTI’ cART at the time of the request. Laboratory requisition forms were accompanied by plasma biospecimens which were sent to a central laboratory, the Botswana Harvard HIV Reference Laboratory (BHHRL) which is SADCAS ISO 15189 accredited.\n\n2.3. Clinical and Laboratory Methods Description\n\n2.3.1. Clinical Data Extraction\n\nWe reviewed electronic and paper-based medical records to extract demographics, prior/current/subsequent ART regimens, HIV-1 RNA results, and documentation of poor adherence.\n\n2.3.2. Viral Load Quantification\n\nHIV-1 VL was quantified by either Abbott m2000sp/Abbott m2000rt platform (Wiesbaden, Germany), Cobas TaqMan/Cobas Ampliprep HIV-test (Roche Molecular Systems, Branchburg, NJ, USA) or Aptima HIV-1 Quant assay on Panther Systems (Hologic inc., San Diego, CA, USA) at BHHRL or district-based laboratories. VF was defined as two consecutive VL greater than 400 copies/mL and virologic suppression as a viral load < 400 copies/mL as per national ART guidelines. Because of the various VL detection platforms used and changes in the national VL reporting guidelines, some of the VL data was reported as <400, <50, <40 and <25 copies/mL.\n\n2.3.3. Genotypic Resistance Testing (GRT)\n\nUsing residual plasma samples from individuals undergoing routine genotypic resistance testing, we amplified and Sanger sequenced the integrase (IN) region and/or reverse transcriptase (RT) and protease (PR) genes. We included testing of multiple plasma specimens that were identified to come from one individual over time and which were reported as ‘unique’.\n\nReverse transcription-polymerase chain reactions (RT-PCR), and sequencing reactions were performed using a commercial assay, ViroSeqTM HIV-1 Integrase RUO Genotyping kit (VS-Int) (Celera Corporation, New Jersey, USA) as per manufacturer’s instructions and an ‘inhouse’ integrase assay (IH-Int) as previously described elsewhere [22]. Capillary electrophoresis was performed on an ABI 3130XL Applied Biosystems TM Genetic Analyzer.\n\nThe raw sequence data from the sequencer were then assembled and edited using Sequencher® version 5.0 DNA sequence analysis software (Gene Codes Corporation, Ann Arbor, MI, USA) and manually edited using BioEdit version 7.2.0 software [23]. Unique sequences covering the IN-codon positions 51–263 were included in the analysis.\n\nINSTI DRMs and accessory mutations were assessed using the Stanford University HIV drug resistance database algorithm version 8.7 (https://hivdb.stanford.edu/hivdb/by-sequences/ (accessed on 19 February 2021)). The mutations of interest included: T66A/I/K, E92Q, G118R, E138K/A/T, G140S/A/C, Y143R/C/H, S147G, Q148H/R/K, N155H and R263K [24]. Maximum-likelihood phylogenetic trees (bootstrap 1000) were generated using molecular evolutionary genetic analysis (MEGA) version X 10.1.6 [25] and included some duplicate sequences from the same individual collected over different time points (they cluster together with bootstrap values >95).\n\nDetermination of HIV-1 subtype was performed using Rega HIV subtyping tool v3.0 (http://dbpartners.stanford.edu:8080/RegaSubtyping/stanford-hiv/typingtool/ (accessed on 19 February 2021)) and the Stanford University HIV drug resistance database algorithm version 8.7 (https://hivdb.stanford.edu/hivdb/by-sequences/ (accessed on 19 February 2021)) [24,26].\n\nWe report reverse transcriptase (RT) and protease (PR) sequences for only the 11 patients found to have integrase DRMs. In instances where paired RT or PR sequences could not be performed, we looked for historical RT and PR results of the individuals and reported them. For one individual, we could not identify their paired or historic RT or PR sequences.\n\n3. Results\n\nWe retrieved 78 residual plasma samples from May 2015–September 2019, representing 65 unique individuals failing either a DTG or RAL-based cART regimen at the time of genotyping request. Of the 78 plasma samples, 40 (51%) (from 34 individuals) were successfully amplified and sequenced for HIV-1 Integrase by VS-Int and IH-Int assays Figure 1. Basic demographics and VL results of these individuals are shown in Table 1.\n\nAmongst the 34 individuals, we obtained cART initiation dates of 24: their mean duration on ART was 11 years (Q1, Q3:8, 13) at the time of sampling for GRT.\n\nAll generated viral sequences were HIV-1C. Among the 34 individuals, 24 were on DTG ART, three on RAL cART and seven on ‘unknown’ INSTI (either DTG or RAL) at the time of collection of the sample for GRT. INSTI DRMs were found in 11(32%) of the study participants; their mean age (Q1, Q3) at GRT was 43 (40, 44) years, 7 (64%) of the 11 were male, and their mean duration on ART (Q1, Q3) was 11.5 (10, 13) years. Seven (64%) of the 11 individuals had documentation showing they were previously on a RAL-based regimen. The remaining four individuals were on a DTG regimen at sampling for resistance testing and had no known history of RAL cART exposure. The HIV-1 reverse transcriptase (RT) and protease (PR) region of the 11 individuals were sequenced and/or their historical RT and PR DRMs retrieved Table 2. 10 (91%), 8 (73%) and 4 (36%) of these 11 individuals had nucleoside/nucleotide reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI) DRMs respectively.\n\nOne (9%), 6 (55%) and 4 (36%) had 2-class, 3-class and 4-class multidrug-resistant HIV. 7 (64%) of the individuals are currently virologically suppressed and 4 (36%) are not suppressed. Of the suppressed individuals, 6 (86%) have no PI DRMs and 1 (14%) has major PI DRMs. Six out of the 7 currently suppressed individuals are on a salvage regimen anchored by DTG and darunavir boosted by ritonavir (DRV\\r) Table 2. Three of the four individuals who were not suppressed had extensive DRMs involving 4-classes of ARV drugs. One of the individuals not suppressed has recently demised. The distribution of INSTI DRMs amongst the 11 individuals is shown in Figure 2 and Figure S1.\n\nAmongst the individuals previously exposed to RAL ART (seven out of eleven), DRMs selected whilst failing their current DTG based regimens were E138K, G140A, Q148R; and N155H Figure 3. The four individuals failing DTG cART but with no documented prior exposure to RAL, their selected DRMs were E138K, G140A, Q148K, A128T; G118R, E138K; N155ND and T66A, G118R, E138EAKT Figure 3.\n\n4. Discussion\n\nWe evaluated virological, clinical, and HIVDR mutational pathways from a national programmatic cohort of highly treatment-experienced PLWH failing a DTG/RAL based regimen in Botswana. We identified 11 (32%) individuals with INSTI DRMs (eight being on DTG and three on RAL based regimens at HIVDR testing). They had a longer mean duration of prior cART at the time of GRT (11.5 years), and seven of them were previously exposed to RAL based regimens. Longer duration of ART has been previously associated with the development of HIV-DR [27]. Despite having INSTI DRMs, two out of the 11 individuals were on DTG once a day dosing; the Viking trials demonstrated twice a day dosing to be effective amongst such individuals [28].\n\nA notable finding from our study was the identification of multi-drug resistance (MDR) HIV-1C variants; 2-class MDR 9.1%, 3-class MDR 54.5% and 4 class MDR 36.4%. We detected high rates of NRTI (90%), NNRTI (72.7%), and PI (36.4%) DRM’s. Another remarkable finding from our study was that despite this extensive MDR HIV-1C, nearly two-thirds of individuals (64%) are currently virologically suppressed. The Viking trial also showed 69% VL suppression despite extensive DRMs at 24 weeks [28]. The high VL suppression numbers despite multiclass DRMs could be explained by the inclusion of a potent PI-DRV\\r and lack of PI DRMs in the suppressed individuals (six out of seven). It could also not be ruled out that DTG retains some suppressive activity against variants with some INSTI resistance mutations. It was recently shown that it is only upon the development of the T97A mutation that variants harboring Q148H and G140S Integrase mutations started to have increased VLs [22,27].\n\nIn our study, E138K (n = 5), S147G (n = 4), Q148R (n = 4) and N155H (n = 4) where the most frequent INSTI DRMs identified. This is in contrast to Y143C/R/H (n = 12), N155H (n = 9) and T97A(n = 13) from a similar study in the region where HIV-1C also predominates [29]. The longer duration of cART treatment of our participants with subsequent accumulation of mutations could explain these differences. Comparable with others, amongst individuals with prior exposure to RAL, the most common mutations selected were N155H (n = 4), Q148R (n = 4), S147G (n = 4) and E138K (n = 3) as others have similarly found [30,31].\n\nAnother unique finding of our study was the lack of selection of the integrase codon 263 substitution amongst the four individuals with virological failure who had no previous exposure to RAL cART. Compared with a similar cohort of patients from clinical trials, the selection of major integrase DRM- R263K was common [17]. Perhaps, this could be explained by the different HIV-1 subtypes; our cohort was all subtype C viruses whilst the other one was predominantly subtype B viruses.\n\nLimitations of our study include the small sample size of participants; we managed to recruit 65 individuals and successfully genotyped the virus from 34 individuals. Although the study was heavily reliant on existing routine national programmatic clinical data, which often contains missing or unknown results, the results presented here represent ‘real-life’ events in HIV-1C diagnosed patients with prolonged cART treatment and DRMs.\n\nFor the 68% of participants with VF while on DTG/INSTI based regimens but devoid of INSTI DRMs, we did not assess for other mutations in nef, reverse transcriptase and protease genes that could contribute to VF [32,33].\n\nIn summary, there is a need for frequent VL testing and/or genotypic resistance testing amongst treatment-experienced PLWH experiencing VF while on DTG-based regimens. In Botswana and most low/middle-income countries, DTG-based regimens are preferred as first and second-line anchor drugs amongst PLWH initiating and failing non-DTG based cART respectively [4,6]. Constructing effective ART regimens amongst treatment-experienced individuals with over 3-class DRMs in resource-limited settings can be daunting considering the limited drug therapeutic options, need for regular training to ensure correct dosing of ARVs and lack of genotypic and phenotypic resistance testing. Similarly, to what others have found [34,35,36], we recommend that boosted darunavir should be included as part of a salvage regimen amongst treatment-experienced individuals identified to have multiclass HIV DRMs. For individuals with multi-class DRM who are not virologically suppressed, optimizing ART regimens to include newer ARVs such as the attachment inhibitor-fostemsavir and/or anti-CD-4 antibody-ibalizumab might suffice and avert death [37,38]. In the era of mass roll-out of DTG based regimens, there is a need for continued surveillance for INSTI DRMs and determining the clinical significance of these mutations in HIV-1C infections.\n\nAcknowledgments\n\nWe thank our patients and staff of all Infectious Disease Care Clinics (IDCC) that we visited throughout Botswana in particular; Phase II clinic-Kgomotso Sanani, Fortunate Puso; BTA clinic-Thato Moreri, Thomo Kgosithebe, Setshego Baakile, Israel Motsomi, Onneile Bakwena, Mosarwa Lentswe, Nelly Goitsemodimo, Refilwe Kelentse; Palapye Primary Hospital-Juliet Seaeye, Gracious Mhaka, Gasegamotho Sennamose, Tebogo Nthubatsang, Thato Maikano, Lorna Matengu, Onkemetse Rasesigo, Oratile Sekopane, Malebogo Basaakane, Tlholego Lesedi, G. Venson, Panko L. Franchising, Diana Keeenetswe, Emannuel Limbo; Nyangabwe Referral Hospital -Lebani Dema, Taita Morapedi, Nancy Modisaotsile, Vincent Santsoma, Pilot Samson, Seitlamo Kgalalelo, Sharon Mudonyo, Themba Bangu, Catherine Thapelo, Tyreman Moira; Sekgoma Memorial Hospital-Botho Keangobota, Poloko Kgari, Boitumelo Seane, Kefilwe Moloi, Gobuamang Lenkwetse, Annah Wale, Joyce Kaphepa, Leano Keobotse, Botho Keangobota; Masunga Hospital-Gaipone Bengani, Imil Muchapa, Balisi Tshuma, Gloria Makombo, Naledi Manase, Boikhutso Chaba, Mpho Mikoto, Mbati Basupi, Bethea Khumalo, Joyce Motlamaloba; Julia Molefhe clinic-Pretty Ntsheme; Extension 14 clinic-Joyce Khumanego, Neo Gareomane, Princes Marina Hospital- Dithapelo Medupe, Kelapile Dineo, Annah B. Pile, Tebogo Ngwanawamonno. We thank the Botswana Harvard HIV Reference Laboratory staff and Botswana Ministry of Health and Wellness in particular, the Department of HIV/AIDS Prevention for their collaboration. This study would not have been possible without the support of the leadership of the Botswana-Harvard AIDS Institute Partnership, including Ria Madison, Bernadette Kgake, Data management office, IT department, Regulatory Office in particular Tumalano Sekoto, Ngozana Seonyatseng and colleagues.\n\nSupplementary Materials\n\nThe following are available online at https://www.mdpi.com/article/10.3390/v13040594/s1, Figure S1: Phylogenetic tree of 40 HIV-1C Integrase sequences from treatment-experienced individuals whose plasma samples were sent for GRT while on DTG or INSTI based regimens. Analysis was performed using the Maximum Likelihood method and General Time Reversible model bootstrapped at 1000 replicates using MEGA X [25]. Diamond tagged sequences are those identified to have major INSTI DRMs. Letters, ‘a’, ‘b’, and ‘c’ at the end of some participants IDs indicate that the samples were collected over different time points but were from the same individual. GRT, genotypic resistance testing; DTG, dolutegravir; INSTI, integrase strand transfer inhibitors; DRM, drug resistance mutations.\n\nClick here for additional data file.\n\nAuthor Contributions\n\nWriting—original draft preparation, K.K.S.; writing—Review & Editing, K.K.S., D.M., W.T.C., T.N., N.M., M.M. (Mompati Mogwele), M.K., B.N., D.R., J.M., M.M. (Mompati Mmalane), M.M. (Madisa Mine), I.K., S.L., S.M., S.G.; Conceptualization, K.K.S., S.G.; Methodology, K.S., S.G., S.M.; Software, K.K.S., W.T.C., S.G.; Validation, K.K.S., S.G., S.M., W.T.C.; Investigation, K.K.S., D.M., W.T.C., T.N., N.M., M.M. (Mompati Mogwele); data curation, K.K.S., S.G., S.M.; formal analysis, K.K.S., W.T.C., S.G.,T.N., S.M.; Visualization, K.K.S., S.G.; Project administration, K.K.S., N.M., S.G.,S.M., J.M., M.M. (Madisa Mine); Supervision, M.M. (Madisa Mine), I.K., S.L., S.M., S.G.; funding acquisition, K.K.S., S.L., S.M., S.G.; Resources, K.K.S., S.L., S.M., S.G.; All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research was funded by Harvard University Center for AIDS Research (CFAR), an NIH funded program (P30 AI060354), which is supported by the following NIH Co-Funding and Participating Institutes and Centers: National Institute of Allergy and Infectious Diseases, National Cancer Institute, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Heart, Lung, and Blood Institute, National Institute on Drug Abuse, National Institute of Mental Health, National Institute on Aging, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of General Medical Sciences, National Institute on Minority Health and Health Disparities, National Institute of Dental and Craniofacial Research, Office of AIDS Research, and Fogarty International Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was supported through the Sub-Saharan African Network for TB/HIV Research Excellence (SANTHE), a DELTAS Africa Initiative [grant # DEL-15-006]. The DELTAS Africa Initiative is an independent funding scheme of the African Academy of Sciences (AAS)’s Alliance for Accelerating Excellence in Science in Africa (AESA) and supported by the New Partnership for Africa’s Development Planning and Coordinating Agency (NEPAD Agency) with funding from the Wellcome Trust [grant # 107752/Z/15/Z] and the UK government. The views expressed in this publication are those of the author(s) and not necessarily those of AAS, NEPAD Agency, Wellcome Trust or the UK government. The research reported in this publication was supported by the Fogarty International Center and National Institute of Mental Health, of the National Institutes of Health under Award Number D43 TW010543. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. SL was supported by the National Institutes of Health NIH/ National Institute of Allergy and Infectious Diseases K24 mentoring grant - NIH K24 AI131928. All funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n\nInstitutional Review Board Statement\n\nThe study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of the University of Botswana (UBR/RES/IRB/BIO/157) and the health research and development division (HPDME: 13/18/1) which serves as the Botswana Ministry of Health and Wellness Institutional Review Board (IRB). A waiver of informed consent to use existing stored routine clinical plasma samples and routine health data was granted.\n\nInformed Consent Statement\n\nPatient consent was waived as the blood samples were previously collected as part of routine patient care. Additional genotyping (for integrase inhibitor resistance) was performed on stored leftover plasma and combined with routinely collected demographic/clinical data.\n\nData Availability Statement\n\nIN sequences have been deposited into the national centre for biotechnology information (NCBI) GenBank and their accession numbers are MW690052-MW690089, MG989443.1, MG989444.1.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.\n\nFigure 1 Flow diagram revealing the number of plasma, sequences and patients on various cART regimens. Seqs, sequences; DTG, dolutegravir; RAL, raltegravir, cART, combination antiretroviral therapy; INSTI, integrase strand transfer inhibitors. VS-Int, ViroSeqTM HIV-1 Integrase RUO Genotyping kit Celera Corporation, USA; IH-Int, inhouse integrase assay. * Seqs clustering together with high bootstrap (>95) but being from different individuals.\n\nFigure 2 Prevalence of INSTI DRM in the 11 HIV-1C Integrase sequences from treatment-experienced individuals with virological failure whilst on dolutegravir/INSTI based therapy. INSTI, integrase strand transfer inhibitor, DRMs drug resistance mutations.\n\nFigure 3 Distribution of integrase drug resistance mutations according to prior exposure to raltegravir. DRM, drug resistance mutations, RAL, raltegravir.\n\nviruses-13-00594-t001_Table 1 Table 1 Basic demographics and viral load characteristics of individuals failing DTG/RAL cART.\n\nBasic Characteristics\tAll Participants\n(n = 65)\tParticipants with Sequences Generated (n = 34)\t\n* Age (years), median (Q1, Q3)\t40 (27, 49)\t41 (26, 45)\t\nGender\tFemale n (%)\t37 (57%)\t15 (44%)\t\nMale n (%)\t28 (43%)\t19 (56%)\t\nMedian log 10 HIV-1 VL (Q1, Q3) copies/mL\t† 3.78 (2.13, 4.49)\t± 4.53 (3.98, 5.10)\t\nN.B; VL was measured from all plasma samples sent for GRT before commencing testing as per standard of care. † VL written as <20, <400 or <40 or TND, we used 20, 400, 40 and 20 respectively for analysis. In this analysis they were nine out of 65. * 6 individuals did not have age written on the requisition and could not calculate their age.; they are not included in the analysis of age. †± VL was from 35 of the 40 plasma samples at the time of GRT as 5 had UNK VLs. cART, combination antiretroviral therapy; DTG, dolutegravir; RAL, raltegravir; VL, viral load, UNK, unknown; TND, target not detected.\n\nviruses-13-00594-t002_Table 2 Table 2 Demographics, viral loads, cART regimens and DRM’s of 11 individuals with multi-class drug resistance in Botswana.\n\nPatient #\tART Initiation Date\tDate Sample Collected\tAge at Sample Collection\tGender\tVL of Sample Collected for GRT (cps/mL)\tART Regimen at Time of Sampling of GRT\tPrior Exposure to RAL (Yes/No)\tMajor DRM’s Β\tCurrent ART Regimen\tCurrent VL (cps/mL)\tDate of Current VL\t\nRT(NRTI; NNRTI)\tPI\tINSTI\t\n1\n(139-0007-8)\t27-Apri-06\t31-May-17\t40\tM\t69,510\tTDF/FTC/DRV\\r/DTG\tNO\tD67N, K70R, M184V, T215I, K219E;\nA98G, V106I, Y188L\tNONE\tE138K, G140A, Q148K, (A128T)\tTDF/FTC/DRV\\r/DTG\n200/300 mg od/600\\100 mg bd/50 mg bd\t<400\t10-Sep-20\t\n2\n(139-0006-2)\t25-Nov-03\t21-Jun-17\t38\tF\t826\tTDF/FTC/DTG\tYES\tM184V;\nK101E, G190S\tNONE\tQ148R\tTDF/FTC/DTG\n200/300 mg OD/50 mg BD\t<50\t22-Jul-20\t\n3\n(139-0008-6)\t21-Sept-11\t± 10-Jan-18\t43\tM\t* <400\tAZT/3TC/DTG\tNO\tA62V, K65R, M184V;\nK103N, V106M\tNONE\tG118R, E138K\t3TC/DRV\\r/DTG\n(150 BD/600\\100 BD/50 OD)\t<25\t02-Sep-20\t\n∞ 4a\n(139-0009-5a)\t14-May-07\t19-Apr-17\t41\tF\t119,563\tABC/3TC/DTG\tYES\tM184V, T215Y;\nK103S, G190A\tNONE\tS147G, N155H, D232N\tTDF/FTC/DRV\\r/DTG\n(300/200 mg od/600\\100 mg bd/50 mg bd)\t<25\t11-Jun-20\t\n∞ 4b\n(139-0009-5b)\t\t± 18-May-18\t42\tF\t79,028\tABC/3TC/DTG\tYES\tM184V, T215Y;\nK103S, G190A\tNONE\tS147G, N155H, D232N\tTDF/FTC/DRV\\r/DTG\n(300/200 mg od/600\\100 mg bd/50 mg bd)\t<25\t11-Jun-20\t\n5\n(139-0147-0)\t27-Nov-06\t28-Jun-17\t21\tM\t815\tTDF/FTC/DTG\tNO\tND\tND\tN155ND\tTDF/FTC/DTG\n300/200/mg OD/50 mg BD\t12,304\t24-Jul-19\t\n6\n(139-0002-8)\t22-Sept-03\t01-Nov-17\t51\tM\t515\tTDF/FTC/DRV\\r/DTG\tYES\t*+ K70R, M184V;\nK219N/Y181C 20APRIL2009)\n\n* ¥ D67N, K70R, M184V/ NONE (18AUG2016)\t*+ V32I, I47V, I54L, I84V (20 APRIL2009)\n\n* ¥ V32I, I47V, I54L, I84V (18AUG2016)\tE138K, G140A, S147G, Q148R, (T97A)\tTDF/3TC/DRV\\r/DTG\n(300/300 mg OD/600\\100 BD/50 mg BD)\t22,690\t31-Aug-20\t\n7\n(139-0004-6)\t19-May-04\t06-Apr-18\t45\tM\t* 55,342\tAZT/3TC/DTG\tNO\tM41L, T69G, K70R, M184V, T215C, K219E;\nA98G, K101E\tM46I, I54V, L76V, V82A\tT66A, G118R, E138EAKT\tTDF/FTC/DRV\\r/DTG\n300/200 mg OD/600\\100 mg BD/50 mg OD\t992\t13-Oct-20\t\n8\n(139-0003-4)\t25-June-04\t11-Apr-18\t41\tF\t50,699\tTDF/FTC/RAL\tYES\tM184V, T215Y;\nNONE\tNONE\tE138K, G140A, Q148R\tTDF/3TC/DRV\\r/DTG\n300/300 mg OD/600\\100 mg BD/50 mg BD\t<25\t22-Jul-20\t\n9\n(139-0001-8)\t7-May-01\t06-Dec-18\t55\tM\t9775\tTDF/3TC/DTG\tYES\tM41L, D67N, K70KR, V75M, M184V, L210W, T215Y, K219E;\nA98G, Y181C, G190A\tM46I, I47V, I54L, L76V, I84V, Q58E, N83D\tE138K, S147G, Q148R, N155H, (E157Q)\tTDF/3TC/DTG\t177,268\t13-Feb-20\t\n10\n(139-0011-3)\t6-Feb-04\t13-May-15\t50\tF\t1300\tTDF/FTC/DRV\\r/RAL\tYES\t**+ D67N, K70R, K219E/K101Q, K103N (7DEC2009)\n** ¥ NONE/P225H (10FEB2012)\t**+ NONE(7DEC2009)\n** ¥ NONE (10FEB2012)\tN155H\tTDF/FTC/DRV\\r/DTG\n300/200 mg OD/600\\100 mg BD/50 mg BD\t<400\t10 Jan 2020\t\n11\n(139-0012-9)\t3-Oct-02\t18-May-15\t44\tM\t* 2300\tTDF/FTC/DRV\\r/RAL\tYES\tMajor; M184V, M41L, T215Y:\nNONE\tMajor; M46I, V82A\nAccessory; L24I\tN155NH (D232DN)\tAZT/3TC/DRV\\r/DTG\n450 mg BD/600\\100 mg BD/50 mg BD\t<50\t26-Aug-20\t\nΒ Major DRMs as determined by the Stanford HIV drug resistance database. ± Date sample collected not written on requisition forms, used date sample received in a testing laboratory and/or date samples testing started and/or results issued. * No VL results available for the sample, used last recorded VL before sampling for GRT obtained from IPMS. Historical DRMs denoted with a ’*’. Historical DRMs refers to GRT performed on plasma samples from the same individuals but at a different time point (date in appendix table). *+ from sample GRT performed on 20 April 2009. * ¥ from sample GRT performed on 18 Aug 2016. **+ from sample GRT performed on 7 DEC 2009. ** ¥ from sample GRT performed on 10 FEB 2012. ∞ 4a and 4b are the same individual but their specimens were collected at different time points. Major INSTI DRMS column, DRMs listed within brackets “()” are accessory INSTI resistance mutations. VL, viral load; ART, antiretroviral therapy; GRT, genotypic resistance testing; cps/ml, copies/mL; RT, reverse transcriptase; NRTI, nucleoside/nucleotide reverse transcriptase inhibitors; NNRTI, non-nucleoside reverse transcriptase inhibitors; PR, protease; PI, protease inhibitor; INSTI, integrase strand transfer inhibitors; DRMs, drug resistance mutations; VL, viral load; GRT, genotypic resistance test; RAL, raltegravir; 3TC, Lamivudine; DRV\\r, darunavir\\ritonavir; DTG, dolutegravir; FTC, emtricitabine; TDF, tenofovir disoproxil fumarate; BD, twice a day dosing; OD, once a day dosing; mg, milligrams; ND, not done; IPMS, integrated patient management software (a laboratory information systems software). Green colour depicts virological suppression and red colour non virological suppression.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Kandel C.E. Walmsley S.L. Dolutegravir—A review of the pharmacology, efficacy, and safety in the treatment of HIV Drug Des. Devel. Ther. 2015 9 3547 3555 10.2147/DDDT.S84850\n2. Molina J.M. Clotet B. Van Lunzen J. Lazzarin A. Cavassini M. Henry K. Kulagin V. Givens N. De Oliveira C.F. Brennan C. Once-daily dolutegravir versus darunavir plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a randomised, open-label, phase 3b study Lancet HIV 2015 2 e127 e136 10.1016/S2352-3018(15)00027-2 26424673\n3. EACS European AIDS Clinical Society (EACS) Guidelines Version 10.0 11 2019 English Available online: http://www.eacsociety.org/files/2018_guidelines-9.1-english.pdf (accessed on 22 April 2020)\n4. Botswana Ministry of Health Handbook of the Botswana 2016 Integrated HIV Clinical Care Guidelines Available online: https://www.moh.gov.bw/Publications/Handbook_HIV_treatment_guidelines.pdf (accessed on 15 April 2020)\n5. Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Available online: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf (accessed on 15 February 2020)\n6. WHO Update of Recommendations on First- and Second-Line Antiretroviral Regimens. (WHO/CDS/HIV/19.15) Licence: CC BY-NC-SA 3.0 IGO World Health Organization Geneva, Switzerland 2019\n7. WHO HIV Drug Resistance Report. (WHO/CDS/HIV/19.21) Licence: CC BY-NC-SA 3.0 IGO World Health Organization Geneva, Switzerland 2019\n8. McGee K.S. Okeke N.L. Hurt C.B. McKellar M.S. Canary in the Coal Mine? Transmitted Mutations Conferring Resistance to All Integrase Strand Transfer Inhibitors in a Treatment-Naive Patient Open Forum Infectious Diseases Oxford University Press Oxford, UK 2018\n9. Hurt C.B. Sebastian J. Hicks C.B. Eron J.J. Resistance to HIV integrase strand transfer inhibitors among clinical specimens in the United States, 2009–2012 Clin. Infect. Dis. 2014 58 423 431 10.1093/cid/cit697 24145878\n10. Boyd S.D. Maldarelli F. Sereti I. Ouedraogo G.L. Rehm C.A. Boltz V. Shoemaker D. Pau A.K. Transmitted raltegravir resistance in an HIV-1 CRF_AG-infected patient Antivir. Ther. 2011 16 257 261 10.3851/IMP1749 21447876\n11. Brien W.A. Hartigan P.M. Martin D. Esinhart J. Hill A. Benoit S. Rubin M. Simberkoff M.S. Hamilton J.D. Changes in plasma HIV-1 RNA and CD4+ lymphocyte counts and the risk of progression to AIDS. Veterans Affairs Cooperative Study Group on AIDS N. Engl. J. Med. 1996 334 426 431 10.1056/NEJM199602153340703 8552144\n12. Mellors J.W. Rinaldo C.R. Gupta P. White R.M. Todd J.A. Kingsley L.A. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma Science 1996 272 1167 1170 10.1126/science.272.5265.1167 8638160\n13. UNAIDS Global HIV & AIDS statistics—2020 Fact Sheet Available online: https://www.unaids.org/en/resources/fact-sheet (accessed on 23 December 2020)\n14. Hemelaar J. Elangovan R. Yun J. Dickson-Tetteh L. Fleminger I. Kirtley S. Williams B. Gouws-Williams E. Ghys P.D. Alash’le G A. Global and regional molecular epidemiology of HIV-1, 1990–2015: A systematic review, global survey, and trend analysis Lancet Infect. Dis. 2019 19 143 155 10.1016/S1473-3099(18)30647-9 30509777\n15. UNAIDS Country Factsheets Botswana 2019 Available online: https://www.unaids.org/en/regionscountries/countries/botswana (accessed on 23 December 2020)\n16. Lombardi F. Giacomelli A. Armenia D. Lai A. Dusina A. Bezenchek A. Timelli L. Saladini F. Vichi F. Corsi P. Prevalence and factors associated with HIV-1 multi-drug resistance over the past two decades in the Italian ARCA database Int. J. Antimicrob. Agents 2021 57 106252 10.1016/j.ijantimicag.2020.106252 33259914\n17. Cevik M. Orkin C. Sax P.E. Emergent Resistance to Dolutegravir Among INSTI-Naive Patients on First-line or Second-line Antiretroviral Therapy: A Review of Published Cases Open Forum Infect. Dis. 2020 7 ofaa202 10.1093/ofid/ofaa202 32587877\n18. Aboud M. Kaplan R. Lombaard J. Zhang F. Hidalgo J.A. Mamedova E. Losso M.H. Chetchotisakd P. Brites C. Sievers J. Dolutegravir versus ritonavir-boosted lopinavir both with dual nucleoside reverse transcriptase inhibitor therapy in adults with HIV-1 infection in whom first-line therapy has failed (DAWNING): An open-label, non-inferiority, phase 3b trial Lancet Infect. Dis. 2019 19 253 264 10.1016/S1473-3099(19)30036-2 30732940\n19. Cahn P. Pozniak A.L. Mingrone H. Shuldyakov A. Brites C. Andrade-Villanueva J.F. Richmond G. Buendia C.B. Fourie J. Ramgopal M. Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: Week 48 results from the randomised, double-blind, non-inferiority SAILING study Lancet 2013 382 700 708 10.1016/S0140-6736(13)61221-0 23830355\n20. Lepik K.J. Harrigan P.R. Yip B. Wang L. Robbins M.A. Zhang W.W. Toy J. Akagi L. Lima V.D. Guillemi S. Emergent drug resistance with integrase strand transfer inhibitor-based regimens AIDS 2017 31 1425 1434 10.1097/QAD.0000000000001494 28375875\n21. Viani R.M. Ruel T. Alvero C. Fenton T. Acosta E.P. Hazra R. Townley E. Palumbo P. Buchanan A.M. Vavro C. Long-Term Safety and Efficacy of Dolutegravir in Treatment-Experienced Adolescents With Human Immunodeficiency Virus Infection: Results of the IMPAACT P1093 Study J. Pediatric. Infect. Dis. Soc. 2020 9 159 165 10.1093/jpids/piy139 30951600\n22. Seatla K.K. Avalos A. Moyo S. Mine M. Diphoko T. Mosepele M. Gaolatlhe T. Rowley C.F. Ramaabya D. Jarvis J.N. Four-class drug-resistant HIV-1 subtype C in a treatment experienced individual on dolutegravir-based antiretroviral therapy in Botswana AIDS 2018 32 1899 1902 10.1097/QAD.0000000000001920 29894383\n23. Hall T.A. BioEdit: A user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT Nucleic Acids Symposium Series Information Retrieval Ltd. London, UK 1999 c1979 c2000\n24. Liu T.F. Shafer R.W. Web resources for HIV type 1 genotypic-resistance test interpretation Clin. Infect. Dis. 2006 42 1608 1618 10.1086/503914 16652319\n25. Kumar S. Stecher G. Li M. Knyaz C. Tamura K. MEGA X: Molecular Evolutionary Genetics Analysis across Computing Platforms Mol. Biol. Evol. 2018 35 1547 1549 10.1093/molbev/msy096 29722887\n26. Pineda-Peña A.C. Faria N.R. Imbrechts S. Libin P. Abecasis A.B. Deforche K. Gómez-López A. Camacho R.J. De Oliveira T. Vandamme A.M. Automated subtyping of HIV-1 genetic sequences for clinical and surveillance purposes: Performance evaluation of the new REGA version 3 and seven other tools Infect. Genet. Evol. 2013 19 337 348 10.1016/j.meegid.2013.04.032 23660484\n27. George J.M. Kuriakose S.S. Dee N. Stoll P. Lalani T. Dewar R. Khan M.A. Rehman M.T. Grossman Z. Maldarelli F. Rapid development of high-level resistance to dolutegravir with emergence of T97A mutation in 2 treatment-experienced individuals with baseline partial sensitivity to dolutegravir Open Forum Infect. Dis. 2018 10.1093/ofid/ofy221\n28. Castagna A. Maggiolo F. Penco G. Wright D. Mills A. Grossberg R. Molina J.M. Chas J. Durant J. Moreno S. Dolutegravir in antiretroviral-experienced patients with raltegravir- and/or elvitegravir-resistant HIV-1: 24-week results of the phase III VIKING-3 study J. Infect. Dis. 2014 210 354 362 10.1093/infdis/jiu051 24446523\n29. Steegen K. Van Zyl G. Letsoalo E. Claassen M. Hans L. Carmona S. Resistance in patients failing integrase strand transfer inhibitors: A call to replace raltegravir with dolutegravir in third-line treatment in South Africa Open Forum Infect. Dis. 2019 6 ofz377 10.1093/ofid/ofz377\n30. Gallien S. Delaugerre C. Charreau I. Braun J. Boulet T. Barrail-Tran A. De Castro N. Molina J.M. Kuritzkes D.R. Emerging integrase inhibitor resistance mutations in raltegravir-treated HIV-1-infected patients with low-level viremia AIDS 2011 25 665 669 10.1097/QAD.0b013e3283445834 21326075\n31. Chang S.Y. Lin P.H. Cheng C.L. Chen M.Y. Sun H.Y. Hsieh S.M. Sheng W.H. Su Y.C. Su L.H. Chang S.F. Prevalence of Integrase Strand Transfer Inhibitors (INSTI) Resistance Mutations in Taiwan Sci. Rep. 2016 6 35779 10.1038/srep35779 27779200\n32. Siedner M.J. Moorhouse M.A. Simmons B. De Oliveira T. Lessells R. Giandhari J. Kemp S.A. Chimukangara B. Akpomiemie G. Serenata C.M. Reduced efficacy of HIV-1 integrase inhibitors in patients with drug resistance mutations in reverse transcriptase Nat. Commun. 2020 11 1 10 10.1038/s41467-020-19801-x 31911652\n33. Malet I. Subra F. Charpentier C. Collin G. Descamps D. Calvez V. Marcelin A.G. Delelis O. Mutations Located outside the Integrase Gene Can. Confer Resistance to HIV-1 Integrase Strand Transfer Inhibitors mBio 2017 10.1128/mBio.00922-17 28951475\n34. Huhn G.D. Tebas P. Gallant J. Wilkin T. Cheng A. Yan M. Zhong L. Callebaut C. Custodio J.M. Fordyce M.W. A Randomized, Open-Label Trial to Evaluate Switching to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Plus Darunavir in Treatment-Experienced HIV-1-Infected Adults J. Acquir. Immune Defic. Syndr. 2017 74 193 200 10.1097/QAI.0000000000001193 27753684\n35. Madruga J.V. Berger D. McMurchie M. Suter F. Banhegyi D. Ruxrungtham K. Norris D. Lefebvre E. De Béthune M.-P. Tomaka F. Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: A randomised controlled phase III trial Lancet 2007 370 49 58 10.1016/S0140-6736(07)61049-6 17617272\n36. Armenia D. Bouba Y. Gagliardini R. Fabeni L. Borghi V. Berno G. Vergori A. Cicalini S. Mussini C. Antinori A. Virological response and resistance profile in highly treatment-experienced HIV-1-infected patients switching to dolutegravir plus boosted darunavir in clinical practice HIV Med. 2021 10.1111/hiv.13062\n37. Seval N. Frank C. Kozal M. Fostemsavir for the treatment of HIV Expert Rev. Anti Infect. Ther. 2021 10.1080/14787210.2021.1865801\n38. Chahine E.B. Durham S.H. Ibalizumab: The First Monoclonal Antibody for the Treatment of HIV-1 Infection Ann. Pharmacother. 2021 55 230 239 10.1177/1060028020942218 32659101\n\n",
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"keywords": "Botswana; HIV-1C; dolutegravir; integrase inhibitors; mutations; resistance",
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"title": "HIV-1 Subtype C Drug Resistance Mutations in Heavily Treated Patients Failing Integrase Strand Transfer Inhibitor-Based Regimens in Botswana.",
"title_normalized": "hiv 1 subtype c drug resistance mutations in heavily treated patients failing integrase strand transfer inhibitor based regimens in botswana"
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"abstract": "Multiple myeloma is characterised by monoclonal paraprotein production and osteolytic lesions, commonly leading to skeletal-related events (spinal cord compression, pathological fracture, or surgery or radiotherapy to affected bone). Denosumab, a monoclonal antibody targeting RANKL, reduces skeletal-related events associated with bone lesions or metastases in patients with advanced solid tumours. This study aimed to assess the efficacy and safety of denosumab compared with zoledronic acid for the prevention of skeletal-related events in patients with newly diagnosed multiple myeloma.\n\n\n\nIn this international, double-blind, double-dummy, randomised, active-controlled, phase 3 study, patients in 259 centres and 29 countries aged 18 years or older with symptomatic newly diagnosed multiple myeloma who had at least one documented lytic bone lesion were randomly assigned (1:1; centrally, by interactive voice response system using a fixed stratified permuted block randomisation list with a block size of four) to subcutaneous denosumab 120 mg plus intravenous placebo every 4 weeks or intravenous zoledronic acid 4 mg plus subcutaneous placebo every 4 weeks (both groups also received investigators' choice of first-line antimyeloma therapy). Stratification was by intent to undergo autologous transplantation, antimyeloma therapy, International Staging System stage, previous skeletal-related events, and region. The clinical study team and patients were masked to treatment assignments. The primary endpoint was non-inferiority of denosumab to zoledronic acid with respect to time to first skeletal-related event in the full analysis set (all randomly assigned patients). All safety endpoints were analysed in the safety analysis set, which includes all randomly assigned patients who received at least one dose of active study drug. This study is registered with ClinicalTrials.gov, number NCT01345019.\n\n\n\nFrom May 17, 2012, to March 29, 2016, we enrolled 1718 patients and randomly assigned 859 to each treatment group. The study met the primary endpoint; denosumab was non-inferior to zoledronic acid for time to first skeletal-related event (hazard ratio 0·98, 95% CI 0·85-1·14; pnon-inferiority=0·010). 1702 patients received at least one dose of the investigational drug and were included in the safety analysis (850 patients receiving denosumab and 852 receiving zoledronic acid). The most common grade 3 or worse treatment-emergent adverse events for denosumab and zoledronic acid were neutropenia (126 [15%] vs 125 [15%]), thrombocytopenia (120 [14%] vs 103 [12%]), anaemia (100 [12%] vs 85 [10%]), febrile neutropenia (96 [11%] vs 87 [10%]), and pneumonia (65 [8%] vs 70 [8%]). Renal toxicity was reported in 85 (10%) patients in the denosumab group versus 146 (17%) in the zoledronic acid group; hypocalcaemia adverse events were reported in 144 (17%) versus 106 (12%). Incidence of osteonecrosis of the jaw was not significantly different between the denosumab and zoledronic acid groups (35 [4%] vs 24 [3%]; p=0·147). The most common serious adverse event for both treatment groups was pneumonia (71 [8%] vs 69 [8%]). One patient in the zoledronic acid group died of cardiac arrest that was deemed treatment-related.\n\n\n\nIn patients with newly diagnosed multiple myeloma, denosumab was non-inferior to zoledronic acid for time to skeletal-related events. The results from this study suggest denosumab could be an additional option for the standard of care for patients with multiple myeloma with bone disease.\n\n\n\nAmgen.",
"affiliations": "Center for Multiple Myeloma, Massachusetts General Hospital Cancer Center, Boston, MA, USA. Electronic address: NRAJE@mgh.harvard.edu.;National and Kapodistrian University of Athens, School of Medicine, Alexandra General Hospital, Athens, Greece.;Innsbruck University Hospital & OncoTyrol, Center of Personalized Cancer Medicine, Innsbruck, Austria.;National Hospital Organization Higashi Nagoya National Hospital, Nagoya, Japan.;Hospital Universitario de Salamanca, Salamanca, Spain.;Cedars-Sinai Medical Center, Los Angeles, CA, USA.;Medical University of Lublin, Lublin, Poland.;University Hospital Brno, Department of Internal Medicine, Hematology and Oncology, Brno, Czech Republic.;Department of Hematology, Centre Hospitalier Le Mans, Le Mans, France.;Amgen, Thousand Oaks, CA, USA.;Amgen, Thousand Oaks, CA, USA.;Amgen, Thousand Oaks, CA, USA.;Indiana University School of Medicine, Indianapolis, IN, USA.",
"authors": "Raje|Noopur|N|;Terpos|Evangelos|E|;Willenbacher|Wolfgang|W|;Shimizu|Kazuyuki|K|;García-Sanz|Ramón|R|;Durie|Brian|B|;Legieć|Wojciech|W|;Krejčí|Marta|M|;Laribi|Kamel|K|;Zhu|Li|L|;Cheng|Paul|P|;Warner|Douglas|D|;Roodman|G David|GD|",
"chemical_list": "D000970:Antineoplastic Agents; D050071:Bone Density Conservation Agents; D000069448:Denosumab; D000077211:Zoledronic Acid",
"country": "England",
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"doi": "10.1016/S1470-2045(18)30072-X",
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"issn_linking": "1470-2045",
"issue": "19(3)",
"journal": "The Lancet. Oncology",
"keywords": null,
"medline_ta": "Lancet Oncol",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D050071:Bone Density Conservation Agents; D001859:Bone Neoplasms; D000069448:Denosumab; D004311:Double-Blind Method; D005260:Female; D005598:Fractures, Spontaneous; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D000077982:Progression-Free Survival; D012307:Risk Factors; D013117:Spinal Cord Compression; D013997:Time Factors; D016896:Treatment Outcome; D000077211:Zoledronic Acid",
"nlm_unique_id": "100957246",
"other_id": null,
"pages": "370-381",
"pmc": null,
"pmid": "29429912",
"pubdate": "2018-03",
"publication_types": "D017428:Clinical Trial, Phase III; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study.",
"title_normalized": "denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma an international double blind double dummy randomised controlled phase 3 study"
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"abstract": "Laparoscopic transabdominal preperitoneal inguinal hernia repair is a safe and effective technique. In this study we tested the hypothesis that self-gripping mesh used with the laparoscopic approach is comparable to polypropylene mesh in terms of perioperative complications, against a lower overall cost of the procedure. We carried out a prospective randomized trial comparing a group of 30 patients who underwent laparoscopic inguinal hernia repair with self-gripping mesh versus a group of 30 patients who received polypropylene mesh with fibrin glue fixation. There were no statistically significant differences between the two groups with regard to intraoperative variables, early or late intraoperative complications, chronic pain or recurrence. Self-gripping mesh in transabdominal hernia repair was found to be a valid alternative to polypropylene mesh in terms of complications, recurrence and postoperative pain. The cost analysis and comparability of outcomes support the preferential use of self-gripping mesh.",
"affiliations": "University of Turin, Section of General Surgery, San Luigi Gonzaga Teaching Hospital, Regione Gonzole 10, 10043 Orbassano, Turin, Italy.;University of Turin, Department of Oncology, School of Medicine, Teaching Hospital \"San Luigi Gonzaga\", Section of General Surgery, Orbassano, Turin, Italy.;University of Turin, Department of Oncology, School of Medicine, Teaching Hospital \"San Luigi Gonzaga\", Section of General Surgery, Orbassano, Turin, Italy.;University of Turin, Department of Oncology, School of Medicine, Teaching Hospital \"San Luigi Gonzaga\", Section of General Surgery, Orbassano, Turin, Italy.;University of Turin, Department of Oncology, School of Medicine, Teaching Hospital \"San Luigi Gonzaga\", Section of General Surgery, Orbassano, Turin, Italy.;University of Turin, Department of Oncology, School of Medicine, Teaching Hospital \"San Luigi Gonzaga\", Section of General Surgery, Orbassano, Turin, Italy.",
"authors": "Ferrarese|Alessia|A|;Bindi|Marco|M|;Rivelli|Matteo|M|;Solej|Mario|M|;Enrico|Stefano|S|;Martino|Valter|V|",
"chemical_list": null,
"country": "Poland",
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"doi": "10.1515/med-2016-0087",
"fulltext": "\n==== Front\nOpen Med (Wars)Open Med (Wars)medmedOpen Medicine2391-5463De Gruyter Open med-2016-008710.1515/med-2016-0087Research ArticleSelf-gripping mesh versus fibrin glue fixation in laparoscopic inguinal hernia repair: a randomized prospective clinical trial in young and elderly patients Ferrarese Alessia alessia.ferrarese@gmail.com1Bindi Marco 2Rivelli Matteo 2Solej Mario 2Enrico Stefano 2Martino Valter 21University of Turin, Section of General Surgery, San Luigi Gonzaga Teaching Hospital, Regione Gonzole 10, 10043 Orbassano, Turin, Italy2University of Turin, Department of Oncology, School of Medicine, Teaching Hospital “San Luigi Gonzaga”, Section of General Surgery, Orbassano, Turin, Italy2016 26 11 2016 11 1 497 508 12 8 2016 19 8 2016 © 2016 Alessia Ferrarese et al.2016This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.Abstract\nLaparoscopic transabdominal preperitoneal inguinal hernia repair is a safe and effective technique. In this study we tested the hypothesis that self-gripping mesh used with the laparoscopic approach is comparable to polypropylene mesh in terms of perioperative complications, against a lower overall cost of the procedure.\n\nWe carried out a prospective randomized trial comparing a group of 30 patients who underwent laparoscopic inguinal hernia repair with self-gripping mesh versus a group of 30 patients who received polypropylene mesh with fibrin glue fixation.\n\nThere were no statistically significant differences between the two groups with regard to intraoperative variables, early or late intraoperative complications, chronic pain or recurrence.\n\nSelf-gripping mesh in transabdominal hernia repair was found to be a valid alternative to polypropylene mesh in terms of complications, recurrence and postoperative pain. The cost analysis and comparability of outcomes support the preferential use of self-gripping mesh.\n\nKeywords\nInguinal herniaLaparoscopic repairTransabdominal hernia repair\n==== Body\n1 Introduction\nInguinal hernia is one of the most common diseases, with an incidence of 700,000 cases each year in the United States and a male-to-female preponderance of 9 to 1 [1, 2].\n\nHernia repair is one of the most frequently performed general surgical procedures in the world [1].\n\nLaparoscopic transabdominal hernia repair was first performed in the early 1990s by F. Ger, in Germany [3–6], and consisted of nickel clips to close the defect through an intra-abdominal approach. The first laparoscopic transabdominal preperitoneal hernia repair (TAPP) was performed in 1992 in France by Arregui and Doin, who fixed a mesh in the peritoneal space after making an incision through the parietal peritoneum [7, 8].\n\nThe advantages of laparoscopic over open mesh repair in terms of improved intraoperative diagnosis, better aesthetic result and reduced postoperative pain have been demonstrated in literature [9–13].\n\nLaparoscopic inguinal hernia repair through a transabdominal preperitoneal approach has been described in literature as a difficult procedure; this difficulty is linked to the intrinsic complexity of the anatomical area to be dissected and also to the patient’s habitus and the characteristics of the abdominal wall defect [14].\n\nLaparoscopy is always performed under general anesthesia and, according to some authors, carries a higher risk of intraoperative complications.\n\nCurrent indications for laparoscopic repair are bilateral inguinal hernias and recurrent hernias following a previous anterior repair (grade B of recommendation) [15–22].\n\nDespite developments in prosthetic materials and improvements to methods of fixation, polypropylene mesh with fibrin glue fixation still sets the standard for laparoscopic repair [21, 23–38].\n\nThe use of fibrin glue to fix the mesh in hernia repair was first described in 2001 by Katkhouda et al. using a pig model [39].\n\nNumerous new meshes have been developed in recent years; however, none of these have been able to match polypropylene mesh for ease of handling and efficacy, nor can they replace it as the new gold standard [40–42].\n\nOne of the most recent meshes to have come onto the market features a self-gripping technology. According to the literature, these self-gripping meshes have excellent properties of fixation and efficacy [43]; self-gripping mesh is composed of a layer of large-pore polyester coated with a layer of polylactic acid self-gripping micro hooks. The mesh exhibits intrinsic and atraumatic fixation so to close the hernia safely and effectively, considerably reducing the level of chronic pain.\n\nIn 2006 Chastan was the first to describe a new hernia repair procedure through the inguinal approach using a Velcro®-like self-gripping mesh without tacking systems [44].\n\nInadequate mesh fixation has been reported to be the main cause of recurrences following laparoscopic hernia repair.\n\nChronic pain is an infrequent, but serious, potential complication of mesh fixation with tacks [49–51].\n\nTekit et al. described two instances in which further surgery was required due to debilitating pain following TAPP repair [46].\n\nThe International Endohernia Society (IEHS) guide-lines of 2011 and European Hernia Society guidelines of 2009 defined endoscopic inguinal hernia techniques as safe, providing specific technical steps are followed [21, 22]; in 2012 a randomized prospective study comparing TAPP versus totally extraperitoneal laparoscopic hernia repair defined the two methods as similar in terms of overall perioperative outcome and found the totally extraperitoneal approach to be significantly advantageous in terms of postoperative pain.\n\nAt the time of preparing the guidelines and conducting the study cited above, there was no standardized technique for applying self-gripping mesh in laparoscopic procedures [52].\n\nIn 2012, Fumagalli et al. conducted a study to compare the TAPP approach with self-gripping mesh versus fixation with clips, and the authors concluded, within the limits of a retrospective study, that the use of self-gripping mesh could be a valid alternative to the other techniques [53].\n\nIn a retrospective study of 2012, Birk et al. concluded that laparoscopic hernia repair using self-gripping mesh was a rapid, effective and safe technique, with fewer cases of recurrence and reduced incidence of chronic pain; they reported that the costs of fixation systems required with other non-self-gripping meshes were superfluous [54].\n\nThe aim of this study was to compare laparoscopic surgical procedure using self-gripping mesh versus the procedure using polypropylene mesh with fibrin glue fixation.\n\nThe end point of the trial was to test the hypothesis that self-gripping mesh is comparable to polypropylene mesh in terms of perioperative complications against a lower overall cost of the procedure in young and elderly (> 65 years old).\n\n2 Methods\n2.1 Study design\nThis non-stratified, monocentric study with balanced randomization (1:1) used a parallel group design to compare the TAPP approach with self-gripping mesh to the TAPP repair with polypropylene mesh with biological fibrin glue fixation.\n\n2.2 Eligibility criteria\nPatients eligible for inclusion were men with primary or recurrent unilateral inguinal hernia, aged 25 to 70 years, with a BMI (body mass index) of < 18 and ASA (American Society of Anesthesiology) class < = 3. The purpose of recruiting a male-only cohort was to standardize the surgical setting as far as possible in terms of anatomy and technical problems encountered in performing the inguinal dissection.\n\nExclusion criteria were glaucoma, previous retinal detachment or relevant cardiovascular co-morbidity.\n\n2.3 Setting\nThe study was conducted at the General Surgery Unit, Department of Oncology, San Luigi Gonzaga School of Medicine, University of Turin in Orbassano, Italy, between 1 January 2014 and 1 January 2015.\n\n2.4 Surgical procedures\nPatients were randomized to receive laparoscopic inguinal hernia repair with either self-gripping mesh or polypropylene mesh with glue fixation.\n\nSelf-gripping mesh was a lightweight, monofilament, two-dimensional mesh with an upper layer of resorbable polylactic acid micro hooks on the adhesive side. This was compared with a medium-weight, large-pore polypropylene mesh fixed by means of 1-2 cc of biological fibrin glue.\n\nThe procedures were performed by two surgeons, both of whom were specialists in laparoscopy, having performed at least 500 cholecystectomies and a further 300 laparoscopic surgical procedures (including at least 70 TAPP procedures).\n\nThe mean at follow-up is currently 11 months. Eligible patients were recruited between March 2013 and December 2013. All participants underwent a surgical and anesthesiological evaluation at the time of randomization into the study. They also underwent a postoperative evaluation at one day, seven days and three months after surgical procedure.\n\nAll the operations were performed as day surgery procedures: patients were admitted to hospital on the morning of the operation and discharged the first or second day after surgery, following a physical examination of the abdomen and monitoring of gas canalization.\n\nEthical approval: The research related to human use has been complied with all the relevant national regulations, institutional policies and in accordance the tenets of the Helsinki Declaration, and has been approved by the authors’ institutional review board or equivalent committee.\n\nInformed consent: Informed consent has been obtained from all individuals included in this study.\n\n2.5 Details of the surgical technique\nThe same laparoscopic technique was used for both groups, with access by umbilical incision, Veress assisted, and two operating trocars. A preperitoneal pocket was created by performing medial, lateral and midline dissection with reduction of the hernial sac. In all cases, the funicular elements were parietalized, and hemostasis was secured.\n\nIn all cases the mesh was cut to a size of 10 x 12 x 8 cm with incision of the funicular portion. Self-gripping mesh was inserted rolled up, and the polypropylene mesh was inserted flat; the latter was fixed using 1-2 cc of biological fibrin glue prepared by diluting the thrombin component in a ratio of 1:10 with respect to the fibrin after appropriate thawing.\n\n2.6 Variables evaluated\nFor both groups, we evaluated perioperative variables (operating time and postoperative length of hospital stay), intraoperative complications (vascular lesions, deferential lesions), early postoperative complications (hematoma, seroma, orchitis, wound infection, neuralgia, difficulty with urination), and late postoperative complications (testicular phlogosis, testicular atrophy, deferential lesions, chronic local pain, mesh infection, recurrence).\n\nPost-operative pain was evaluated with a visual analogue scale (VAS) one-dimensional numerical rating scale (NRS) graded from 0 to 10 [55]. The evaluation was performed at one day, seven days and three months in both groups (Table 4); we used the definition coined by other authors and proposed in the guidelines for the prevention of chronic postoperative pain [56]. These authors defined chronic pain as pain that persists for more than six months after the operation and that is due to synthetic material used to repair the defect [57, 58].\n\n2.7 Outcomes\nThe primary end point of this study was a comparison of the two techniques based on analysis of the previously defined parameters, given the known reduction in the overall cost of the implantable systems (reduction in the total cost of the operation).\n\nFor the equivalence study, to establish the similarity of the perioperative complications of recurrence and chronic pain associated with two surgical procedures, we calculated a sample size of 30 patients per group, given an incidence of recurrence of approximately 5% with a TAPP procedure [59], a fixed chronic pain rate of 28.7 % [10] and a formal estimated power of the study of 80%. After that, we studied surgery-related variables in the subgroup of elderly patients, and we commented on its incidence.\n\n2.8 Method of randomization\nParticipants were assigned to one of the two treatment groups by simple randomization generated with the on-line software available at www.randomization.com.\n\nAfter we obtained patients’ informed consent, they were allocated to the groups by a researcher who was not clinically involved in the trial, and randomization was concealed by use of sealed envelopes held in a specific part of the Department. The researcher informed the surgeon which prosthesis was to be used only when the envelope was opened. The patients were told which mesh had been used at the end of the study.\n\n2.9 Statistical methodology\nStatistical proportions of dichotomic variables (classification and type of hernia, number of complications) were compared with the Chi-square test and Fisher’s exact test.\n\nContinuous variables (age distribution, BMI distribution, mean operative time, postoperative length of hospital stay, operating time, American Society of Anesthesiologists [ASA] evaluation) were expressed as the average (range) and analyzed with the Mann-Whitney U test. Patient distribution according to the two teams was verified. All statistical analyses were performed with R software (vers. 2.6.2); a P value of < 0.01 was considered statistically significant.\n\n3 Results\nDuring the study period, hernioplasty was indicated for 142 patients. Eighty-two patients were excluded from the study: 65 because they did not meet eligibility criteria, 13 because they did not give their consent to take part in the trial and 4 for other reasons (refusal of general anesthesia) (Figure 1).\n\nFigure 1 Flowchart\n\nSixty patients were randomized: 30 were assigned to surgical treatment with polypropylene mesh with fibrin glue fixation (PM group) and 30 to surgical treatment with self-gripping mesh (SGM group).\n\nNone of the patients recruited into the study was excluded, withdrew from or died during the course of the trial, and thus all patients were included in the analysis.\n\nTable 1 summarizes the participants’ basic characteristics; study groups were compared on demographic and clinical characteristics. Primary outcome variables are shown in Tables 2a and 2b in the total group and in the elderly.\n\nTable 1 Patient Baseline Characteristics\n\nPatient Baseline Characteristics\tPM Group\tSGM Group\tP\t\nTotal\t\t\t\t\nMale [no. (%)]\t30\t30\t-\t\nFemale [no. (%)]\t0\t0\t-\t\nMean age (yr), mean (± SD)\t53,3 (± 10,9)\t53 ( 11,0)\t0,906\t\nHernia type\t\t\t\t\n Indirect [no. (%)]\t27 (90%)\t26 (86,6%)\t0,687\t\n Direct [no. (%)]\t3 (10%)\t4 (13,3%)\t0,687\t\nRecurrence\t\t\t\t\n Recurrence [no. (%)]\t4 (13.3%)\t5 (16.6%)\t0,717\t\n Primitive [no. (%)]\t28 (86.6%)\t25 (83.3%)\t0,717\t\nASA\t\t\t\t\n I [no. (%)]\t5 (16,6%)\t5 (16,6%)\t1\t\n II[no. (%)]\t24 (80%)\t23 (76,6%)\t0,754\t\n III [no. (%)]\t1 (3,3%)\t2 (6,6%)\t0,553\t\nBMI (Kg/m2), mean (± SD)\t24,5 (± 1,2)\t24,1 (± 1,6)\t0,315\t\nPM Group: Polypropylene Mesh Group\n\nSGM Group: Self-Gripping Mesh Group\n\nASA: American Society of Anesthesiologists’ physical status score\n\nBMI: Body Mass Index\n\nTable 2a Surgery-Related Variables\n\nSugery-Related Variables\tPM Group\tSGM Group\tP\t\nOperative time (min), mean (± SD)\t74,4 (± 12,8)\t74,9 (± 14,8)\t0,882\t\nMean Postoperative Hospitalisation Stay (day), mean (± SD)\t1,1 (± 0,2)\t1,0 (± 0,2)\t0,647\t\nPM Group: Polypropylene Mesh Group\n\nSGM Group: Self-Gripping Mesh Group\n\nTable 2b Surgery-Related Variables in elderly\n\nSugery-Related Variables\tPM Group\tSGM Group\tP\t\nOperative time (min), mean (± SD)\t72,4 (± 10,8)\t77,9 (± 13)\t0,782\t\nMean Postoperative Hospitalisation Stay (day), mean (± SD)\t1,0 (± 0,2)\t1,0 (± 0,2)\t0,777\t\nPM Group: Polypropylene Mesh Group\n\nSGM Group: Self-Gripping Mesh Group\n\nIntention-to-treat analysis revealed an average operating time of 74.4 minutes for the PM group and 74.9 minutes for SGM group. Analysis of surgery-related variables revealed no statistically significant differences between the two groups (Table 2a) and in the elderly (Table 2b).\n\nIn terms of complications, Table 3 shows the data of intention-to-treat analysis. No surgical wound infection, mesh superinfection, urogenital or other complications occurred.\n\nTable 3 Complications\n\nComplications\tPM Group\tSGM Group\tP\tRR (95% CI)\t\nIntraoperative complications\t\t\t\t\t\nVascular lesions\t0\t1\t0,313\t0 (nv)\t\nDeferential lesions\t0\t0\t-\t-\t\nEarly postoperative complications\t\t\t\t\t\nHematoma\t1\t0\t0,313\t0 (nv)\t\nSeroma\t0\t0\t-\t-\t\nOrchitis\t0\t0\t-\t-\t\nWound infections\t0\t0\t-\t-\t\nNeuralgia\t0\t0\t-\t-\t\nUrinary problems\t0\t0\t-\t-\t\nLate postoperative complications\t\t\t\t\t\nTesticular problems\t0\t0\t-\t-\t\nChronic pain\t0\t0\t-\t-\t\nMesh infection\t0\t0\t-\t-\t\nRecurrence\t1\t0\t0,313\t0 (Nv)\t\n\t\nTotale\t2\t1\t\t\t\nPM Group: Polypropylene Mesh Group\n\nSGM Group: Self-Gripping Mesh Group\n\nNv: not evaluable\n\nTable 4a VAS Scale evaluation\n\nTiming of valutation [Vas scale (cm)]\tPM Group\tSGM Group\tP\t\nDay 1 mean (± SD)\t2,5 (± 0,8)\t2,4 (± 0,8)\t0,881\t\nDay 2 mean (± SD)\t1,1 (± 0,9)\t1,0 (± 1,0)\t0,701\t\nDay 3 mean (± SD)\t0,2 (± 0,6)\t0,6 (± 0,9)\t0,121\t\nPM Group: Polypropylene Mesh Group\n\nSGM Group: Self-Gripping Mesh Group\n\nSD: standard deviation\n\nTable 4b VAS Scale evaluation in elderly\n\nTiming of valutation [Vas scale (cm)]\tPM Group\tSGM Group\tP\t\nDay 1 mean (± SD)\t2,2 (± 0,7)\t2,5 (± 0,6)\t0,671\t\nDay 2 mean (± SD)\t1,1 (± 0,6)\t1,0 (± 0,9)\t0,698\t\nDay 3 mean (± SD)\t0,1 (± 0,6)\t0,3 (± 0,9)\t0,211\t\nPM Group: Polypropylene Mesh Group\n\nSGM Group: Self-Gripping Mesh Group\n\nSD: standard deviation\n\nThe assessment of chronic pain, using the VAS, showed no statistically significant differences at one day, seven days and three months in either group (Table3a) (Figure 2); there were no differences in the elderly (Table 3b).\n\nFigure 2 VAS Scale valutation\n\nThe comparison between complications did not reveal any statistically significant differences between two groups.\n\nCost analysis of the implantable systems found that the total cost of hernia repair with self-gripping mesh was € 123 (the cost of the mesh alone), whereas the cost of hernioplasty with polypropylene mesh was € 272 (€ 22 for mesh and € 259 for 5 cc of glue).\n\n4 Discussion\nWe believe that laparoscopic transabdominal hernia repair is an effective procedure that can achieve excellent results in terms of aesthetics, morbidity and postoperative pain [9–13, 60–61].\n\nThese are fundamental aspects, since the incidence of chronic pain and disability following inguinal hernia repair through open or laparoscopic procedures is not negligible [62–66].\n\nIn agreement with Bittner et al., we are convinced that the application of a strictly standardized technique is an essential precondition for reducing the risk of intraoperative complications to a minimum [14].\n\nThe procedure must be performed by a laparoscopic surgeon with extensive experience of open abdominal-wall surgery and an excellent knowledge of abdominal-wall anatomy.\n\nThe results achieved with the self-gripping mesh and the polypropylene mesh were comparable, as both are working prostheses and both methods of fixation are valid and effective.\n\nOperating times were comparable, despite the surgeons initially finding it more difficult to position the self-gripping mesh; however, both surgeons confirmed that they found the mesh easy to handle after first ten procedures. Moreover, for the SGM group, there was no need to consider the time required to prepare and apply the fibrin glue.\n\nThe postoperative length of hospital stay was comparable for both procedures; both were performed as day surgery with one night in hospital and only a very small number of patients (3 in the PM group, 2 in the SGM group) had to stay two nights. Analytical comparison of post-operative length of hospital stay revealed no statistically significant differences between two groups. The analysis of elderly group showed no significant difference.\n\nA review of the Food and Drug Administration sets the incidence of hematoma after laparoscopic repair of inguinal hernia at < 1%, seroma at 4% and infection at 42%.\n\nThe incidence of intraoperative complications reported in our study was in line with those reported in the literature (Table 3).\n\nThe most worrying complication is infection of the mesh. In some cases treatment with antibiotics is not sufficient to solve the problem and another operation may be needed to remove the mesh; this complication is made worse by a high rate of sepsis and mortality [72–76].\n\nIn our study there were no cases of mesh superinfection in either group.\n\nAnother serious complication that has been reported in the literature associated, above all, with open inguinal hernia repair is erectile dysfunction and subsequent inability to procreate [77–78].\n\nNone of the patients in either of our two groups reported sexual dysfunction or urological complications.\n\nOne typical complication of inguinal hernia repair is recurrence. In the literature, the recurrence rate following hernia repair has been reported from 8 to 17% of cases [17, 79].\n\nA meta-analysis to compare inguinal hernia repair with open and laparoscopic techniques revealed an incidence of recurrence of 2.7% with an open approach versus 5.5% with laparoscopy (transabdominal or totally extraperitoneal approach) with an average follow-up of 28 months [61].\n\nIn our study, there was one case of recurrence in the PM group; this occurred on the fifteenth day after surgery and was thus attributable to an erroneous technique with incorrect positioning of the mesh or inaccurate dilution of the glue.\n\nChronic postoperative pain was measured according to the modified definition of the International Association for the Study of Pain (IASP) [56].\n\nComparison of postoperative pain in the two study groups (assessed on the VAS) did not reveal any statistically significant differences during the hospital stay or at follow-up after seven days and three months; we believe this reflects the atraumatic nature of both fixation methods.\n\nCost analysis found the polypropylene mesh to be less cost-effective, owing to the high cost of the biological glue used for fixation. The cost of this system could be reduced by using smaller quantities of fibrin glue or alternative products such as cyanoacrylate [41], which has been found to guarantee good fixation even when only very small amounts are used; however, further prospective studies are needed to compare the different methods of fixation to test their actual efficacy and benefits.\n\nThis study has some limitations. First, the sample includes only male patients within a given age range.\n\nSince it is reasonable to assume that hernia defects in females are similar, and possibly also easier to repair, women might also benefit from this type of procedure. Provided there are no co-pathologies that are contraindications for laparoscopic surgery, this technique could also be used equally effectively on patients aged more than 75 years.\n\nMoreover, our sample included patients with just one primary or recurring defect; these findings cannot thus be applied with certainty to patients with a bilateral defect.\n\nThe study was limited to a small sample with an average follow-up of just 11 months. An average time of 11 months is reasonable for detecting early recurrences but prevents us from evaluating late recurrences.\n\nAnother limitation regards the use of two different surgeons, albeit from the same school and with similar experience; both surgeons used the same verified standard technique, although the evaluation of their similarity was based on their own self-assessment and was therefore not objective. Hopefully, the presence of specialized surgical tutors will make it possible for this operation to be performed by a large number of surgeons in different surgical settings, even during training [14, 80–84].\n\nSurgery seems to be more difficult in elderly patients [85], but we consider laparoscopy as feasible in emergency [86–89]. It is a secure technique in both young and elderly patients [90–96] and in repair of wound defects. The constant improvement of open and laparoscopic surgical procedures [97–104] and diagnostic techniques [105–118] have allowed a significant development in the field of wall defects.\n\nIn conclusion, the laparoscopic approach for inguinal hernia repair is a safe and effective procedure. The TAPP technique with self-gripping mesh has been found to be a valid alternative to TAPP repair with polypropylene mesh with fibrin glue fixation in terms of the incidence of recurrence, complications and chronic pain.\n\nThe lower cost of the procedure using self-gripping mesh also weighs in favor of this type of mesh.\n\nConflict of interest statement: Authors state no conflict of interest.\n\nAbbreviations and acronyms\nTAPPTransabdominal Pre-Peritoneal\n\nASAAmerican Society of Anesthesiology\n\nBMIBody Max Index\n\nPM GroupPolypropylene-Mesh Group\n\nSGM GroupSelf-Gripping Mesh Group\n\nSDStandard Deviation\n==== Refs\nReferences\n[1] Bax T Sheppard BC Crass RA Surgical Options in the Management of Groin Hernias, Oregon Health Sciences University, Portland Oregon. Am Fam Physician 1999 59 143 156 9917580 \n[2] Rutkow IM Robbins AW Demographic, classificatory, and socioeconomic aspects of hernia repair in the United States Surg Clin North Am 1993 73 413 426 8497793 \n[3] Ger R. 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The tension-free hernioplasty in a randomized trial Am J Surg 1996 172 315 319 8873520 \n[64] Cunningham J Temple WJ Mitchell P et al. Cooperative hernia study: pain in the postrepair patient Ann Surg 1996 224 598 602 8916874 \n[65] Kumar S Wilson RG Nixon SJ Macintyre IM. Chronic pain after laparoscopic and open mesh repair of groin hernia Br J Surg 2002 89 1476 1479 12390395 \n[66] Rowntree LG. National program for physical fitness: revealed and developed on the basis of 13,000,000 physical examina-tions of Selective Service registrants JAMA 1944 125 821 827 \n[67] Robinson TN Clarke JH Schoen J Walsh MD. Major mesh-related complications following hernia repair. Events reported to the Food and Drug Administration Surg Endosc 2005 19 1556 1560 16211441 \n[68] Taylor SG O’Dwyer PJ Chronic groin sepsis following tension-free inguinal hernioplasty Br J Surg 1999 86 562 565 10215837 \n[69] Ismail W Agrawal A Zia MI. 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Perforated Duodenal Diverticulum: Case Report and Short Review of the Literature Chirurgia 2014 27 129 131 \n[86] Solej M Martino V Mao P Enrico S Rosa R Fornari M Destefano I Ferrarese AG Gibin E Bindi F Falcone A Ala U Nano M Early versus delayed laparoscopic cholecystectomy for acute cholecystitis Minerva Chir 2012 67 381 387 23232475 \n[87] Gentile V Ferrarese AG Marola S Surace A Borello A Ferrara Y Enrico S Martino V Nano M Solej M. Perioperative and postoperative outcomes of perforated diverticulitis Hinchey II and III: Open Hartmann’s procedure vs laparoscopic lavage and drainage in the elderly International Journal of Surgery 2014 12 suppl 2 86 89 \n[88] Surace A Marola S Benvenga S Borello A Gentile V Ferrarese AG Enrico S Martino V Nano M Solej M. 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"journal": "Open medicine (Warsaw, Poland)",
"keywords": "Inguinal hernia; Laparoscopic repair; Transabdominal hernia repair",
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"title": "Self-gripping mesh versus fibrin glue fixation in laparoscopic inguinal hernia repair: a randomized prospective clinical trial in young and elderly patients.",
"title_normalized": "self gripping mesh versus fibrin glue fixation in laparoscopic inguinal hernia repair a randomized prospective clinical trial in young and elderly patients"
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"abstract": "To describe our experience with concurrent chemoradiotherapy using three-dimensional conformal radiotherapy (3D-CRT) and high-dose-rate intracavitary brachytherapy with weekly cisplatin in the treatment of patients with locally advanced cervical cancer.\nForty-three patients were identified between January 2009 and December 2015. Their medical records were retrospectively reviewed, and data on patient characteristics, tumour, treatment and toxicities were collected and analysed.\nThe median age was 45 years (interquartile range (IQR): 26) The median tumour size was 45 mm (IQR: 20). Thirty-eight patients (88%) had a cervical tumour with a size of ≥ 40 mm. The median cervical tumour size evaluated by magnetic resonance imaging (MRI) was 52 mm (IQR: 17). Twenty-two patients (51%) had enlarged lymph nodes on MRI (≥ 10 mm). MRI demonstrated the involvement of the parametrium in 29 patients (67%). Fifteen patients had positive para-aortic nodes (36%). The median total treatment time was 58 days (IQR: 20). Sixteen patients (39%) received extended-field radiotherapy. Cisplatin was administered simultaneously for a median of five courses. The median follow-up period was 32 months (IQR: 28 months). Grade 3 acute toxicity was observed at the gastrointestinal level in seven patients (16%). Late grade 3/4 toxicity was observed in 14 patients (33%). Seven patients (16%) persisted with the disease and five died. The local relapse rate was 9%. Eleven patients underwent a hysterectomy after treatment. The disease-free interval was 24.2 months. The 2-year global survival rate was 82.9%.\nConcurrent chemo-radiotherapy appears to be an effective regimen, with acceptable toxicity, for patients with locally advanced cervical cancer.",
"affiliations": "Department of Gynaecology, Hospital Italiano of Buenos Aires, Buenos Aires C1199 ABH, Argentina.;Department of Radiation Oncology, Hospital Italiano of Buenos Aires, Buenos Aires C1199 ABH, Argentina.;Department of Gynaecology, Hospital Italiano of Buenos Aires, Buenos Aires C1199 ABH, Argentina.;Department of Radiation Oncology, Hospital Italiano of Buenos Aires, Buenos Aires C1199 ABH, Argentina.;Department of Radiation Oncology, Hospital Italiano of Buenos Aires, Buenos Aires C1199 ABH, Argentina.;Department of Gynaecology, Hospital Italiano of Buenos Aires, Buenos Aires C1199 ABH, Argentina.",
"authors": "Giavedoni|María Eugenia|ME|;Staringer|Lucas|L|;Garrido|Rosa|R|;Bertoncini|Cintia|C|;Sardi|Mabel|M|;Perrotta|Myriam|M|",
"chemical_list": null,
"country": "England",
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"doi": "10.3332/ecancer.2019.919",
"fulltext": "\n==== Front\nEcancermedicalscienceEcancermedicalscienceecancermedicalscienceecancermedicalscience1754-6605Cancer Intelligence 10.3332/ecancer.2019.919can-13-919ResearchExperience with concurrent chemoradiotherapy treatment in advanced cervical cancer: results from a hospital in Argentina Giavedoni María Eugenia 1Staringer Lucas 2Garrido Rosa 1Bertoncini Cintia 2Sardi Mabel 2Perrotta Myriam 1\n1 Department of Gynaecology, Hospital Italiano of Buenos Aires, Buenos Aires C1199 ABH, Argentina\n2 Department of Radiation Oncology, Hospital Italiano of Buenos Aires, Buenos Aires C1199 ABH, ArgentinaCorrespondence to: Maria Eugenia Giavedoni maria.giavedoni@hospitalitaliano.org.ar2019 02 4 2019 13 91919 12 2018 © the authors; licensee ecancermedicalscience.2019This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Objective\nTo describe our experience with concurrent chemoradiotherapy using three-dimensional conformal radiotherapy (3D-CRT) and high-dose-rate intracavitary brachytherapy with weekly cisplatin in the treatment of patients with locally advanced cervical cancer.\n\nMethods\nForty-three patients were identified between January 2009 and December 2015. Their medical records were retrospectively reviewed, and data on patient characteristics, tumour, treatment and toxicities were collected and analysed.\n\nResults\nThe median age was 45 years (interquartile range (IQR): 26) The median tumour size was 45 mm (IQR: 20). Thirty-eight patients (88%) had a cervical tumour with a size of ≥ 40 mm. The median cervical tumour size evaluated by magnetic resonance imaging (MRI) was 52 mm (IQR: 17). Twenty-two patients (51%) had enlarged lymph nodes on MRI (≥ 10 mm). MRI demonstrated the involvement of the parametrium in 29 patients (67%). Fifteen patients had positive para-aortic nodes (36%). The median total treatment time was 58 days (IQR: 20). Sixteen patients (39%) received extended-field radiotherapy. Cisplatin was administered simultaneously for a median of five courses. The median follow-up period was 32 months (IQR: 28 months). Grade 3 acute toxicity was observed at the gastrointestinal level in seven patients (16%). Late grade 3/4 toxicity was observed in 14 patients (33%). Seven patients (16%) persisted with the disease and five died. The local relapse rate was 9%. Eleven patients underwent a hysterectomy after treatment. The disease-free interval was 24.2 months. The 2-year global survival rate was 82.9%.\n\nConclusion\nConcurrent chemo-radiotherapy appears to be an effective regimen, with acceptable toxicity, for patients with locally advanced cervical cancer.\n\ncarcinoma of the cervixradiotherapyconcurrent chemotherapybrachytherapy\n==== Body\nIntroduction\nIn 2012, 528,000 new cases of women with cervical cancer were diagnosed worldwide [1]. In Argentina, 4,956 women are diagnosed each year with the same disease and 2,127 die each year. Cervical cancer is the third most frequent cancer in Argentina among women (after breast and colorectal cancer) and the second most frequent among women aged 14–44 years old [2].\n\nCervical cancer is staged by clinical gynaecological examination. In 2009, the most up-to-date version of cervical cancer staging was published by the Committee of the International Federation of Gynecology and Obstetrics (FIGO) [3]. Since 2009, FIGO has recommended, whenever possible, an assessment with magnetic nuclear resonance since it is the best diagnostic method for locoregional staging of this cancer. This was confirmed in the recent FIGO staging published in 2018, where the imaging and pathological findings are incorporated into the staging [4].\n\nStage IB2 is considered to be locally advanced cervical cancer [5]. Local, regional and distant relapses are more likely in this group of patients.\n\nIn the treatment of locally advanced cervical cancer, five randomised Phase III clinical studies [6–10] and two meta-analyses [11, 12] showed significant improvement in overall survival and progression-free survival with radio-chemo-concurrence with platinum, with respect to exclusive radiotherapy, or with hydroxyurea. Because of these studies, in 1999, the National Cancer Institute (NCI) issued the recommendation for use, thus making radio-chemo-concurrence the standard treatment for cervical cancer in locally advanced stages [13]. In spite of the development and improvement in radiotherapy techniques, it is not possible to reach the dose of radiation required by the pathology without the use of brachytherapy. Although the different forms of delivery produce the same global survival rates, high-rate brachytherapy incorporated in the last decades improves the use option, facilitating the practice for the operator and improving tolerance for patients and shortening treatment time [14]. Radiotherapy is curative for locally advanced cervical cancer for approximately 65%–75% of patients in Stage IIB, for 30%–50% of patients in Stage IIIB and for 10%–15% of patients in Stage IVA. However, radiation treatment for gynaecological cancers brings to light questions about the quality of life for patients, due to its toxicity.\n\nThere is very little communication about this type of treatment in South America [15], the majority of the literature coming from other regions, [16–22] and which examine the benefits and morbidity of the treatment. Therefore, this research would provide greater knowledge regarding the treatment of cervical cancer in our region and encourage the prospective registration and dissemination of its results in Latin America. In this paper, we aim to describe the experience of the Hospital Italiano de Buenos Aires in the treatment of concurrent chemo-radiation and high-rate brachytherapy in locally advanced stages of cervical cancer through the analysis of a retrospective cohort from 2009 to 2015.\n\nObjectives and methods\nA descriptive and observational study was carried out in the Gynecology and Radiation Oncology Department (Mevaterapia) of the Hospital Italiano de Buenos Aires.\n\nThe study population consisted of patients in the registries during the period 2009–2015 with a diagnosis of cervical cancer of epithelial origin in locally advanced stages who had received external pelvic radiotherapy with three-dimensional shaped technique (3D) plus high-rate brachytherapy and concurrence with cisplatin as primary treatment. Patients with previous pelvic radiotherapy, presence of another type of concomitant cancer, history of partial or total hysterectomy, patients who had begun their treatment in another healthcare centre and patients with a histological diagnosis of neuroendocrine carcinoma were excluded.\n\nField work\nThe clinical histories corresponding to the selected patients were reviewed and the information was collected in a database constructed for that purpose. The following variables were evaluated for each patient: age, performance status, body mass index, previous surgeries, last pretreatment haemoglobin value, pretreatment creatinine clearance, histological tumour type, tumour size, FIGO stage, tumour characteristics in the MRI, lymph node staging by images or surgery, characteristics of the radiant treatment, characteristics of concurrent chemotherapy, variables in terms of oncological follow-up, toxicities, persistence, recurrence (with histological confirmation) and death.\n\nWe reviewed the images of the MRI performed on the patients in the context of pretreatment staging to evaluate prognostic factors, such as tumour size, involvement and location of lymph nodes, involvement of parametria, involvement of septums and invasion of other adjacent organs. The following were considered to be (1) signs of lymph node involvement: diameter greater than 1 cm on the minor axis, changes in lymph node morphology, altered signal at T2 or heterogeneous image and restricted diffusion, (2) signs of parametrial involvement: interruption in the paracervical fibrous ring or parametrium-tumour irregularity and (3) signs of septum involvement: anterior or posterior fatty infiltration.\n\nAlthough there are different criteria for classifying acute [23] or chronic [24] toxicity, in this study, we defined the limit as 90 days from the beginning of treatment.\n\nMajor toxicity was reported as Grades 3, 4 and 5. Acceptable toxicity was classified as Grades 1 and 2.\n\nAcute haematological toxicities were classified according to the NCI Common Terminology Criteria for Adverse Events, version 3.0 [25] Score, and non-haematological acute toxicities and chronic toxicities were classified using the Toxicity Criteria of the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer (EORTC) [26] scores. However, this last scale may be considered to be inadequate to classify some of the more common complications of radiation treatment for cervical cancer; therefore, more variables in this category were identified using the description published in Eifel’s study [27].\n\nOncological monitoring data were obtained from medical visits stored in the hospital’s electronic clinical history or from telephone calls that the investigators made to patients whose last control was not carried out at the institution.\n\nStandard evaluation and treatment\nAll patients were regularly examined by gynecologists, oncologists and radiant oncologists. Pretreatment evaluation consisted of taking the clinical history, a physical evaluation and pelvic examination, a biopsy of the uterine cervix and an MRI of the abdomen and pelvis.\n\nStaging of the lumbar aortic area to define the radiation treatment was performed in two ways: through positron emission tomography (PET) CT or through lumbar aortic laparoscopic staging surgery. The latter began at our institution under a research protocol starting in 2012.\n\nExternal radiation was administered using 3D. A pelvic scan was performed with oral contrast in the institutional scanner (Philips Brilliance CT 16-slice). The images were imported into the planning system (Blue Frame Shell, Version 14.05.00). Planning was organised using anterior, posterior and both lateral fields known as the four-field box technique in the pelvic area and with anterior, posterior and lateral fields in the lumbar aortic area. Photon energy of 6, 10 and 15 MV were used. Patients received a dose of 50–50.4 Gy in 25–28 fractions in the pelvic area and 45 Gy in 25 fractions in the lumbar aortic region. Some patients received a parametrial boost of 5.4 Gy in three additional fractions. Regarding brachytherapy—until July 2015, iridium 192 was used as a radioactive source using 2D, following the international guidelines (International Commission on Radiation Units and Measurements (ICRU) 38) [28]. Then, it was replaced by cobalt 60 using 3D and applicators compatible with computed axial tomography. The volumes to be treated were delineated according to the consensus of the Groupe Européen de Curietherapie and the European Society for Radiotherapy and Oncology [29]. In both 2D and 3D, a 6-Gy design per fraction was used for a total dose of 24 Gy. Two fractions per week were given, making a total of four fractions.\n\nPatients received indications for concurrent chemotherapy with cisplatin at a dose of 40 mg/m2 (maximum dose of 70 mg) once a week for five cycles during the period of radiation therapy. Our scheme is coincident with what is described in the current literature [7, 9, 30, 31]. The causes for suspension of chemotherapy were as follows: (1) fever over 38°C, (2) neutropenia under 1,500/mm3, (3) thrombocytopenia under 75,000/mm3, (4) vomiting, (5) diarrhoea, (6) creatinine clearance dropping to under 50 mL/minute and (7) performance status 2 or more. Chemotherapy was resumed when toxicity became Grade 1. In premedication, patients received hydration with saline solution, mannitol solution, ranitidine 50 mg IV, dexamethasone 8 mg IV and ondansetron 8 mg IV.\n\nLaboratory tests with blood count, liver function tests, electrolytes and creatinine clearance were requested at the initial evaluation and repeated at 3 weeks. A weekly clinical check-up was performed during treatment. Then, patients were monitored every 3 months for the first 2 years and every 6 months until the end of the 5 years. After treatment, a control study with images was requested. The negative, positive and doubtful findings in the images were described. We consider doubtful findings to be inflammatory changes that could not be classified and that required a new control after a prudent period of time (more than 3 months).\n\nStatistical analysis\nIn the descriptive statistical analysis, the continuous variables were expressed as median and interquartile range (IQR), and the categorical variables were summarised as absolute and relative frequencies.\n\nIn the follow-up analysis, the follow-up time was calculated as the difference between the date of diagnosis and the date of the final control or death. Three patient conditions were analysed: death by illness, persistence (patients who remained actively ill with cancer in spite of treatment) and relapse (reappearance of the illness in patients who responded to treatment).\n\nFor the death event, the fatality rate was estimated as the number of deceased patients per 100 persons with cancer and overall survival at 2 years as a percentage of living patients per 100 patients with cervical cancer, with their respective confidence intervals of 95%. Patients followed for less than 2 years were excluded from the analysis (n = 35).\n\nFor relapse, the rate was estimated to be the number of relapsed cases per 100 person-years, with a confidence interval of 95%, and the period free of illness as the time from diagnosis of the illness until the date of the first relapse, last medical control or death, expressed as median in months and interquartile range. Patients with less than 2 years of follow-up were excluded from the calculation (n = 32).\n\nThe percentage of tumour persistence and death was calculated for the total cohort.\n\nStatistical analysis was performed using the STATA 13 program.\n\nThe clinical study was approved by the Ethics Committee of the Hospital Italiano de Buenos Aires, Argentina.\n\nResults\nA total of 43 patients were included. The patients’ characteristics are listed in Table 1. Six patients (14%) began treatment with a haemoglobin level of less than 10 g/dL. Of the total, five patients (11%) required a blood transfusion prior to treatment. Seven (16%) patients began with creatinine clearance under 70 mL/minute.\n\nTable 2 shows the tumour details. Thirty-eight patients (88.4%) had a cervical tumour size of ≥ 4 cm. Twelve patients (28%) had a tumour size of ≥ 6 cm. Images showed lymph node involvement in the pelvic area in 19 patients and in the lumbar aortic area in only one patient. Lymph node involvement was shown in both areas in only two patients. Parametrial involvement was detected by MRI in 24 patients in stages II and III and five patients in stages IB and IIA; in these cases, the parametrial involvement was not detected in the physical examination. Septum involvement was observed in 12 patients (28%) by MRI. Lumbar aortic lymph node staging was accomplished through laparoscopic surgery in 23 patients (23/43), nine of which showed involvement (9/23), and through PET in 20 patients (20/43), of which six were positive (6/20). In all, only two patients did not have lumbar aortic staging.\n\nTable 3 shows the radiation treatment details. Regarding the duration of radiation treatment (external and brachytherapy), the median was 58 days (interquartile range: 20 days). A total of 29 patients (67.4%) completed concurrent radiochemotherapy in ≤ 63 days. For most patients (95%), treatment was sequential. One patient required hemostatic flash as part of the treatment due to anaemia at the time of presentation, and three patients had a boost in parametrium. Seventeen patients had extended-field radiation: 15 for lymph node involvement (surgery and PET) and two patients for massive pelvic lymph node involvement. The median duration of extended-field radiation was 41 days (interquartile range: 6 days). Regarding the chemotherapy, the median for cycles completed was five cycles. Only seven (16%) patients had to suspend chemotherapy. The principal causes were diarrhoea, decreased creatinine clearance and vomiting.\n\nTable 4 lists the frequency of acute and chronic toxicities selected for this study, according to the highest grade reached. Although most patients experienced acute gastrointestinal or urinary toxicity, only 16% experienced severe toxicity (Grade 3) in the digestive tract. Only two patients experienced Grade 4 acute toxicity: one patient with debilitating sensitive neuropathy and one patient with septic shock secondary to pyometra. In addition to the toxicities reported in the table, 12 patients (28%) experienced some acute toxicity: pelvic pain (n = 1), vaginal disorders (n = 3), hot flashes (n = 3), bone fractures (n = 1) and hydroelectrolyte changes (n = 4). Of the total, only five patients required hospitalisation.\n\nWhen we group toxicities by patient, we see that 14 patients (33%) experienced some Grade 3/4 chronic toxicity. Of these, most had symptoms in the rectosigmoid area with pain and urgency. Intestinal and urinary toxicities appeared with a median time from the end of treatment of 10.8 (IQR: 4.9) and 10.8 (IQR: 14.7) months, respectively. Of the total, only 11 patients required hospitalisation. There were other chronic toxicities not reported in Table 4: bone fracture (n = 1), menopause (n = 8), thrombosis (n = 2), bone marrow depression, pyometra/hematometrea, pelvic pain and edema.\n\nFour patients experienced fistulas: two rectovaginal and two vesicovaginorectal. Median time to onset of the fistula was 9.5 months (IQR: 1.6). In two patients, the fistula was due to tumour persistence.\n\nThe median time to the first control with images was 2.7 months. Forty-one patients had MRIs (95%) and negative findings were seen in 51%, positive findings in 23% and doubtful findings in 26%.\n\nAfter treatment, ten patients (23%) received a cervical biopsy for suspected persistence of the disease (clinical or MRI), of which four were positive for the disease. Eleven patients (26%) had a rescue hysterectomy with the following indications: pyometra, persistent metrorrhagia, probable or clearly clinically persistence, persistence confirmed by pathology. Of the hysterectomies performed, three were positive for cancer (3/11).\n\nThe oncological results are shown in Table 5. Of the total, 29 patients (67%) had a follow-up time of > 2 years, with a minimum of 6 months (due to death from the disease) and a maximum of 78 months.\n\nDiscussion\nIn this paper, we report the experience of 43 patients with pelvic 3D-CRT and high-rate brachytherapy with concurrent chemotherapy in advanced cervical cancer. At 2 years, the global survival rate was 82.9%, with a tumour persistence rate of 16% and local recurrence of 9%. With a median follow-up time of 32 months, grade 3 acute gastrointestinal toxicity was observed in 16% and grade 3/4 chronic toxicity in 33%.\n\nTable 6 is a comparison with other studies available from the current literature. There were wide differences in treatment, recording, definition and evaluation of toxicities which hinder the comparative analysis.\n\nIt is well known that the total time of treatment is one of the most important prognostic factors in patients with cervical cancer treated with radiotherapy. In this sense, two studies have shown a significant decrease in pelvic control and the overall survival rate when the treatment exceeds 6 weeks [21, 32]. In this study, although all the patients completed the proposed radiant treatment, 14 of them did it in a longer time than recommended. This was probably due to the availability of brachytherapy equipment, to delays due to non-working days and to special situations on the part of patients, such as non-medical situations and patients residing long distances from the radiation centre.\n\nOn the other hand, in July 2015, the radiotherapy department acquired a brachytherapy device with 3D planner, which improved the combination of the two radiant treatments, improving therapeutic times. This practice provided a reduction in the toxicity observed in patients treated after this date. Modulated Intensity Radiotherapy and Modulated Intensity Volumetric Arcotherapy are currently being incorporated into the treatment of cervical cancer. It will be interesting to know in the future how this technology influences the survival and toxicity of the patients treated.\n\nRegarding acute toxicity, Toita observed that grade 3/4 leukopenia was the most frequent adverse effect and found a 25% incidence in grade 3/4 toxicity in platelets. [21] Potter found 4% grade 3 anaemia, 23% grade 3/4 leukopenia and 10% grade 3 thrombocytopenia [33]. Al Asiri reported 5% grade 3/4 leukopenia [22]. Unlike previously published results, our work showed less acute haematological toxicity, the majority being grade 1/2 and only 9% grade 3 leukopenia. Toita reported 28% grade 3/4 nausea and vomiting and 15% grade 3/4 diarrhoea [21]. Al Asiri observed 5% grade 3/4 nausea and vomiting [22]. Our work yields almost zero toxicity at the level of nausea and vomiting and 16% grade 3/4 diarrhoea; this coincides with what has been reported.\n\nAs for chronic toxicity, gastrointestinal symptoms are the most commonly observed adverse effects after pelvic radiotherapy. More than 50% of patients experienced some form of this. The average time of presentation is 8–10 months after treatment [24]. Ogino reported a late rectal complication rate for grades 1, 2, 3 and 4 of 5.6%, 31.7%, 6.8% and 8.1%, respectively [34]. Our study yields similar results: 4.7%, 25.6%, 11.6% and 9.3%, respectively. Likewise, Souhami reported severe toxicity after treatment: rectal ulcer (n = 10), obstruction of the small intestine (n = 2) and recto-vaginal fistula (n = 2) [17]. Other authors reported less chronic intestinal toxicity. Toita observed eight patients (20%) with gastrointestinal complications (all grades) [21]. Potter did not report any late toxicity at the gastrointestinal level grade 3/4 [33]. On the other hand, Nakano conducted a long-term follow-up (22 years) and reported major colorectal complications at 5, 10 and 20 years at a rate of 3.8%, 4.4% and 5.3%, respectively [35]. These results warn of the possibility of long-term toxicity.\n\nThe urological effects are mild; the most common are the narrowing of the urethra and actinic cystitis [24]. However, they increase in frequency over time. Nakano reported major urological complications at 5, 10 and 20 years at rates of 0.8%, 0.9% and 1.3%, respectively [35]. In our study, chronic toxicity at the urinary level was 16% and only two patients had severe toxicity (grade 4), in the same proportion as reported by Potter [33].\n\nThe impact of the radiation therapy on bones is recognised and can manifest itself in different ways. The most common event is a pelvic fracture, which may be asymptomatic and can be diagnosed with images. The mean time to the event is 6–20 months after radiation ends [24]. We found two asymptomatic cases in our series, the first was an L4 vertebral fracture that required vertebroplasty. The second was osteonecrosis of the symphysis pubis and a sacral fracture that improved with medical treatment.\n\nPelvic radiotherapy is especially toxic for the ovaries in premenopausal patients and can lead them to experience early menopause. It has been reported that vasomotor and genitourinary symptoms (atrophy and dysfunction) of menopause affect 80% of patients and worsen their quality of life [24]. Eleven patients in our study reported hot flashes and vaginal dryness and nine presented dyspareunia or vaginal shortening. These conditions are related to treatment and to the resulting hormonal disorder. We believe that these values are underrepresented because this toxicity is very difficult to evaluate and requires systematization, with a direct interrogation to achieve adequate understanding. This is not yet incorporated into our usual practice. Due to the importance it has for patient quality of life, we consider the search of symptoms and the interrogation of the patient very important in the follow-up and treatment.\n\nIn the context of toxicities, it is notable that 39% of patients had extended-field radiation and 26% has post-radiation surgery. Both factors consistently influence toxicity rates, causing them to rise.\n\nThe frequency of delayed toxicity observed in our study was higher than in other studies. This finding could result from careful, systematic follow-up of patients after radiotherapy to detect possible sequelae, including uncommon adverse effects.\n\nFollow-up time was short, but this study found a high overall early survival rate and a low local relapse rate. This finding is likely due to several factors: rigorous patient selection in an interdisciplinary context, the firm belief of the medical team in the treatment, following guidelines that limited treatment volume, and careful planning of clinical monitoring between treatments. These factors all contribute to treatment compliance and good adherence by patients.\n\nFor study treatments, dose prescription and planning were adjusted based on the aforementioned principles. Last, it is notable that a considerable percentage of patients were in stages 1B or 2 (N = 12). This fact contributed to better oncological results and a lower possibility of treatment-associated adverse effects.\n\nSome surgeons complete hysterectomies after radiotherapy in selected patients (large initial tumour size, residual post-treatment disease). Results of the GYNECO 02 study suggest that performing a post-radiation hysterectomy has no therapeutic impact on patients with a complete clinical and radiological response [36]. In our study, 11 patients had surgery after treatment, which involves greater surgery-associated morbidity for patients. Reducing the number of post-radiation surgeries is thus desirable.\n\nExamining histological tumour type, our study found that most were epidermoid (N = 37), and very few were of other histological types. It was therefore not possible to know and document if there are differences in radiotherapy treatment results.\n\nThis study has several limitations. It describes results in a single, private centre with a small number of patients, making it difficult to extrapolate those results to other centres. However, it would be interesting to conduct a national, multi-centre study. Conversely, complications and grade 1 and 2 toxicities may have been underreported in this study. Underreporting may have resulted from problems following and recognising related post-treatment symptoms. Moreover, delayed toxicities may not be represented as some patients did not survive long enough to experience delayed complications of radiation. Another limitation of this study is that it was retrospective and patient case histories may have contained incomplete records. Finally, the follow-up time in the study was short for evaluating oncological results and delayed toxicities.\n\nHowever, we can also highlight the strengths of this study. They include a homogeneous population with a reasonable number of patients from a single institution in Argentina. That facility used modern radiation technology and collected information by telephone, not losing any patients to follow-up.\n\nConclusion\nThis study provides us with us an initial updated approach of primary radiotherapy in in cervical cancer patients with locally advanced stages at Hospital Italiano de Buenos Aires.\n\nThe delayed adverse effects most commonly observed in our population were gastrointestinal symptoms. The rate of acute toxicity was lower than expected, while the rate of chronic toxicity was higher due to a correct and adequate follow-up of our patients and knowledge on the part of the patients, with the purpose of an accurate diagnosis and precise handling of the sequela of radiant treatment. It would be interesting to compare these findings with the results of other studies in Latin America. This study contributes to our understanding of the current situation of patients and available treatments in the region.\n\nWith our follow up period, the overall early survival rate is higher than what is reported in other internationally published studies.\n\nIn conclusion, we report favourable results regarding radiochemotherapy concurrent with high rate brachytherapy in cervical cancer in locally advanced stages. This concurrent treatment showed good local control, was well tolerated, and had an acceptable percentage of complications.\n\nWe believe that we will benefit from new advances and treat cancer more effectively using multi-modal treatments, molecular therapies and fewer radical surgeries, with lower morbidity.\n\nConflict of interest\nThe authors do not have any conflicts to disclose.\n\nFunding statement\nNo financial funding was provided to support this project.\n\nAcknowledgments\nThe authors would like to thank Dr Vicens Jimena, Research Department; Dr Díaz Federico and Dr Krakobsky Vanesa, Radiation Oncology Department; Dr Chacon Carolina, Diagnostic Imaging Department; and Dr María Guadalupe Patrono, Gynaecology Department; Hospital Italiano de Buenos Aires.\n\nTable 1. Baseline characteristics of cervical cancer patients (n = 43).\nDetails\tMeasurement\t\nPatients (n)\t43\t\nAge (years), median (IQR)▵\t45 (26)\t\nPerformance status (n/%)\t\n0\t32/74.4\t\n1\t10/23.3\t\n2\t1/2.3\t\nBody Mass Index in kg/m2, median (IQR)▵\t23.8 (7.5)\t\nPatient with history of prior surgeries (n/%)\t\nNo\t30/69.8\t\nYes\t13/30.2\t\nHaemoglobin pretreatment in g/dL, median (IQR)▵\t12 (2.1)\t\nCreatinine clearance in mL/min, median (IQR)▵\t97 (47.7)\t\n▵ Interquartile range\n\nTable 2. Tumour characteristics of cervical cancer patients (n = 43).\nDetails\tMeasurement\t\nHistological type (n/%)\t\nSquamous\t37/86\t\nAdenocarcinoma\t4/9.3\t\nOther\t2/4.7\t\nTumour size in cm, median (IQR)▵\t45 (20)\t\nTumour stage (FIGO) (n/%)\t\nIB2\t12/27.9\t\nIIA2\t6/14.0\t\nIIB\t15/34.9\t\nIIIB\t10/23.3\t\nTumour size in images (MRI) in cm, median (IQR)▵\t52 (17)\t\nLymph node involvement in images (MRI) (n/%)\t\nNegative\t21/48.8\t\nPositive\t22/51.2\t\nParametrial infiltration in images (MRI) (n/%)\t\nNegative\t14/32.6\t\nPositive\t29/67.4\t\nPretreatment lumbar aortic staging (surgery) (n/%)\t\nNo\t20/46.5\t\nYes\t23/53.5\t\nLumbar aortic lymph node involvement (PET/surgery) (n/%)\t15/36\t\n▵ Interquartile range\n\nTable 3. Characteristics of concurrent radiochemotherapy in cervical cancer patients (n = 43).\nDetails\tMeasurements\t\nRadiation treatment (n/%)\t\nExternal RT and BT\t26/60.5\t\nExternal RT + BT + lumbar aortic field (group 2)\t17/39.5\t\nRadiotherapy dose (cGy) (n/%)\t\nExternal\t\n46\t1/2.3\t\n48.6\t2/4.7\t\n50\t20/46.5\t\n50.4\t17/39.5\t\n55.8\t3/7.0\t\nExternal radiotherapy dose fraction (cGy) (n/%)\t\n1.8\t22/51.2\t\n2\t21/48.8\t\nRadiotherapy energy (n/%)\t\nExternal\t\nF6Mv\t23/53.5\t\nF10Mv\t10/23.3\t\nF15Mv\t10/23.3\t\nLumbar aortic field\t\nF6Mv\t8/47.1\t\nF10Mv\t5/29.4\t\nF15Mv\t4/23.5\t\nBrachytherapy source (n/%)\t\nIr192\t33/76.7\t\nCo60\t10/23.3\t\nTotal treatment time (days)\t\nExternal RT, median (IQR)▵\t40 (7)\t\nExternal RT + BT, median (IQR)▵\t58 (20)\t\nExternal RT + BT + lumbar aortic field, median (IQR)▵\t84 (19)\t\nPatient with total treatment time (<63 days) (n/%)\t29/67.4\t\nPatients receiving ≥ four cycles of chemotherapy (n/%)\t39/90.6\t\nRT: radiotherapy, BT: brachytherapy,\n\n▵ Interquartile range\n\nTable 4. Acute and chronic toxicities profile in cervical cancer patients (n = 43).\nAcute adverse effect\tGrades (n)\t\n0\t1\t2\t3\t4\t\nLower gastrointestinal\t1\t5\t30\t7\t—\t\nUrinary\t1\t17\t25\t—\t—\t\nAsthenia\t1\t21\t20\t1\t—\t\nDermatological\t18\t23\t2\t—\t—\t\nVomiting\t39\t3\t1\t—\t—\t\nAnaemia (haemoglobin)\t13\t19\t11\t—\t—\t\nLeukopenia\t14\t19\t6\t4\t—\t\nNeutropenia\t33\t4\t6\t—\t—\t\nThrombocytopenia\t39\t4\t—\t—\t—\t\nInfectious\t39\t—\t3\t—\t1\t\nMotor neuropathy\t42\t—\t—\t1\t—\t\nSensory neuropathy\t39\t—\t2\t1\t1\t\nAbnormal transaminases\t40\t1\t2\t—\t—\t\nAbnormal bilirubin\t43\t—\t—\t—\t—\t\nHyponatremia\t36\t4\t—\t3\t—\t\nAbnormal creatinine clearance\t30\t6\t7\t—\t—\t\nChronic adverse effect\tGrades (n)\t\n0\t1\t2\t3\t4\t\nExtremities/Neuromuscular\t39\t1\t2\t—\t1\t\nHematochezia\t21\t5\t12\t4\t1\t\nRectosigmoid abnormalities\t21\t2\t11\t5\t4\t\nDiarrhoea\t29\t4\t7\t3\t—\t\nVaginal abnormalities\t28\t6\t9\t—\t—\t\nUrinary abnormalities\t36\t2\t3\t—\t2\t\nTable 5. Results of oncological follow-up of cervical cancer patients (n = 43).\nFollow-up\tMeasurement\t\nFollow-up time in months, median (IQR)▵\t32 (28)\t\nFatality rate (person-years)\t5/100\t\nGlobal survival at 2 years (%)\t82.9\t\nRelapse rate (person-years)\t5.7/100\t\nRecurrence (n)\t6/35\t\nLocal recurrence rate (%)\t9\t\nTime to relapse in months, median (IQR)▵\t20.9 (9.26)\t\nDisease-free interval in months, median (IQR)▵\t24,2(24,2)\t\nPersistence (n/ total)\t7/43\t\nDeaths (n/ total)\t6/43\t\n▵ Interquartile range\n\nTable 6. Comparison of studies available in current literature.\nStudy, year\tSouhami et al [17], 1993\tToita et al [21], 2005\tPötter et al [33], 2006\tAtahan et al [16], 2007\tParker et al [18], 2009\tKato et al [20], 2010\tAl Asiri et al [22], 2013\tGiavedoni, 2016\t\nQT/RT concurrency (n)\t50\t40\t48\t89/183\t92\t120\t74\t43\t\nCountry\tCanada\tJapan\tAustria\tTurkey\tUK\tSouth-east Asia\tSaudi Arabia\tArgentina\t\nFIGO stage (I, II, III, IV) (%)\t0, 40, 54, 6\t2, 33, 65, 0\t4, 50, 42, 4\t10, 64, 26, 0\t8, 63, 26, 3\t0, 0, 50, 50\t0, 66, 26, 8\t28, 49, 23, 0\t\nRadiant treatment used\tTechnique\tConventional (2D)\tConventional (2D) with 18 MV\tCT based 3D conformal\tConventional (2D)\tConventional (2D)\tConventional (2D) ALE/60 CO\tCT based 3D conformal\tCT based 3D conformal\t\nEBRT (DT) Gy\t46\t50\t50\t50\t45\t50\t45–50.4\t50\t\nFields\tfour-field box\tAPPA\tfour-field box\tfour-field box o APPA\tfour-field box\tfour-field box or APPA\tAPPA\tfour- field box\t\nBoost\t—\tyes\t—\t—\t—\tyes\t—\tyes\t\nDose Boost (Gy)\t—\t6–10\t—\t—\t—\t10-15\t—\t5.4\t\nBrachytherapy (BT)\tHDR-BT 30 Gy (3 × 10 Gy)\tHDR-BT 18 Gy (3 × 6 Gy)\tMRI- based 3D HDR-BT\n(5–6 o 7 ×7 Gy)\tHDR-BT 28 Gy (4 × 7 Gy)\tHDR-BT 24 Gy (4 × 6 Gy)\tLDR-BT or HDR-BT\tHDR-BT 28 Gy (4–6 ×7 Gy)\tHDR-BT/ TAC- based 3D 24 Gy (4 × 6 Gy)\t\nFollow-up\tSurvival rate Early global (months)\t65% to 44\t79% to 36\t61% to 36\t—\t72% to 24\t79.6% to 24\t—\t82.9% to 24\t\nRate of SG to 5 years (%)\t—\t—\t—\t55\t55\t—\t64.5\t—\t\nMedian of Follow-up (months)\t27\t37\t33\t45\t26\t27.3\t60\t32\t\nRate of Local relapse (%)\t7 (16%)\t3 (7%)\t10 (21%)\t48 (26%)\t—\t14 (12%)\t8 (11%)\t3 (9%)\t\nToxicity\tClassification of toxicity (acute// chronic)\tRTOG// Pilepich%\tNCI-CTC version 2.0// RTOG/EORTG\tNCI// LENT SOMA score\tRTOG/ EORTG// RTOG/ EORTG\t// NCI-CTC version 3.0\tNCI-CTC version 3.0// RTOG/ EORTG\tNCI-CTC version 2.0// RTOG/ EORTG\tNCI-CTC version 3.0 y RTOG/ EORTG// RTOG/ EORTG\t\nLate toxicity G3 or G4 (%)\t13/50 (26)\t1/40 (2.5)\t2 (4)\t8/183 (8)\t4/92 (4)\t3/120 (4)\t3 (4)\t14/43 (32.5)\t\nAreas evaluated - Chronic toxicity\tbladder, bowel\tbladder, bowel\tvagina, bladder, bowel\tbladder, bowel\tvagina, bladder, bowel, neuromusc/ ext\tbladder, bowel\turinary tract, bowel, neuropathy, hearing loss\tvagina, bladder, bowel, neuromusc/ ext\t\nQT/RT: chemoradioconcurrence, FIGO: International Federation of Gynecologists and Obstetrics, CT: computed tomography, 3D: three dimensional, ALE: linear accelerator, 60CO: cobalt 60, Gy: grey, APPA: anterior-posterior, HDR- BT: high rate brachytherapy, LDR- BT: low rate brachytherapy, MRI: magnetic resonance imaging, SG: global survival, RTOG: Radiation Therapy Oncology Group, NCI-CTC: Common Toxicity Criteria of the National Cancer Institute, RTOG/EORTG: European Organization for Research and Treatment of Cancer, LENT SOMA: Late Effects Normal Tissue Task Force- Subjective, Objective, Management, Analytic scales, Neuromuscular/ext: neuromuscular/extremities % Pilepich, M. International Journal of Radiation Oncology, Biology, Physics. 1987; 13 (3):351–357, EBRT: External Beam Radiation Therapy, DT: Total dose, TAC/TC/CT: computed axial tomography\n==== Refs\nReferences\n1. Globocan I World Health Organization 2012 23/6/16 [http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx ] \n2. Bruni L Barrionuevo-Rosas L Serrano B Human papillomavirus and related diseases in Argentina. Summary report 2014 ICO Information Centre on HPV and Cancer (HPV Information Centre) \n3. Pecorelli S Zigliani L Odicino F FIGO staging for carcinoma of the cervix Int J Gynecol Obstet 2009 105 2 107 108 10.1016/j.ijgo.2009.02.009 \n4. Bhatla N Aoki D Nand D Cancer of the cervix uteri Int J Gynecol Obs 2018 143 22 36 10.1002/ijgo.12611 \n5. Rojas-Espaillat LA Rose PG Management of locally advanced cervical cancer Curr Opin Oncol 2005 17 5 485 492 10.1097/01.cco.0000174049.14515.8d 16093801 \n6. Keys HM Bundy BN Stehman FB Radiation and adjuvant hysterectomy for bulky stage Ib cervical carcinoma N Engl J Med 1999 340 15 1154 1161 10.1056/NEJM199904153401503 10202166 \n7. Rose PG Bundy BN Watkins EB Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer N Engl J Med 1999 340 15 1144 1153 10.1056/NEJM199904153401502 10202165 \n8. Whitney CW Sause W Bundy BN Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjuvant to radiation therapy in stages IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes. A Gynecologic Oncology Group and Southwest Oncology Group Study J Clin Oncol 1999 17 5 1339 1348 10.1200/JCO.1999.17.5.1339 10334517 \n9. Morris M Eifel PJ Lu J Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer N Engl J Med 1999 340 15 1137 1143 10.1056/NEJM199904153401501 10202164 \n10. Peters WA Liu PY Barrett RJ Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early stage cancer of the cervix J Clin Oncol 2000 18 8 1606 1613 10.1200/JCO.2000.18.8.1606 10764420 \n11. Green JA Kirwan JM Tierney JF Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: a systematic review and meta-analysis Lancet 2001 358 9284 781 786 10.1016/S0140-6736(01)05965-7 11564482 \n12. Lukka H Hirte H Fyles A Concurrent cisplatin-based chemotherapy plus radiotherapy for cervical cancer - a meta-analysis Clin Oncol 2002 14 3 203 212 10.1053/clon.2002.0076 \n13. American College of Obstetricians and Gynecologists ACOG practice bulletin. Diagnosis and treatment of cervical carcinomas. Number 35, May 2002. American College of Obstetricians and Gynecologists Int J Gynaecol Obstet 2002 78 1 79 91 12197489 \n14. High dose rate brachytherapy for carcinoma of the cervix NICE National Institute for Health and Care Excellence 2006 27/6/16 [https://www.nice.org.uk/guidance/ipg160 ] \n15. San Martín T Suárez P Olfos G Cancer cervicouterino en estadio IB2: tratamiento con radioquimioterapia concomitante y cirugia Rev Chil Obstet Ginecol 2003 68 6 447 457 10.4067/S0717-75262003000600001 \n16. Atahan IL Onal C Ozyar E Long-term outcome and prognostic factors in patients with cervical carcinoma: a retrospective study Int J Gynecol Cancer 2007 17 4 833 842 10.1111/j.1525-1438.2007.00895.x 17367320 \n17. Souhami L Seymour R Roman TN Weekly cisplatin plus external beam radiotherapy and high dose rate brachytherapy in patients with locally advanced carcinoma of the cervix Int J Radiat Oncol 1993 27 4 871 878 8244817 \n18. Parker K Gallop-Evans E Hanna L Five years’ experience treating locally advanced cervical cancer with concurrent chemoradiotherapy and high-dose-rate brachytherapy: results from a single institution Int J Radiat Oncol Biol Phys 2009 74 1 140 146 10.1016/j.ijrobp.2008.06.1920 18922646 \n19. Nakano T Kato S Cao J Cervical cancer a regional cooperative clinical study of radiotherapy for cervical cancer in east and south-east Asian countries Radiot Oncol 2007 84 314 319 10.1016/j.radonc.2007.05.012 \n20. Kato S Ohno T Thephamongkhol K Multi-institutional phase ii clinical study of concurrent chemoradiotherapy for locally advanced cervical cancer in east and southeast Asia Int J Radiat Oncol Biol Phys 2010 77 3 751 757 \n21. Toita T Moromizato H Ogawa K Concurrent chemoradiotherapy using high-dose-rate intracavitary brachytherapy for uterine cervical cancer Gynecol Oncol 2005 96 3 665 670 10.1016/j.ygyno.2004.11.046 15721409 \n22. Al Asiri M Tunio M Al AH Five-year outcome of concurrent radiotherapy and chemotherapy in Saudi women with locally advanced cervical cancer: Single-institution experience Ann Saudi Med 2013 33 4 327 333 10.5144/0256-4947.2013.327 24060709 \n23. Toita T Kitagawa R Hamano T Feasibility and acute toxicity of concurrent chemoradiotherapy (CCRT) with high Y dose rate intracavitary brachytherapy (HDR-ICBT) and 40-mg/m2 weekly cisplatin for Japanese patients with cervical cancer Int J Gynecol Cancer 2012 22 8 1420 1426 10.1097/IGC.0b013e3182647265 22932262 \n24. Van Le L Mccormack M Enhancing care of the survivor of gynecologic cancer Am Soc Clin Oncol Educ Book 2016 35 270 275 10.1200/EDBK_158676 \n25. National Cancer Institute Common Terminology Criteria for adverse Events, version 3.0 (CTCAE) 2003 Bethesda, MD National Cancer Institute \n26. Cox JD Stetz J Pajak TF Toxicity criteria of the radiation therapy oncology group (RTOG) and the European organization for research and treatment of cancer (EORTC) Int J Radiat Oncol Biol Phys 1995 31 5 1341 1346 10.1016/0360-3016(95)00060-C 7713792 \n27. Eifel PJ Levenback C Wharton JT Time course and incidence of late complications in patients treated with radiation therapy for FIGO stage IB carcinoma of the uterine cervix Int J Radiat Oncol Biol Phys 1995 32 5 1289 1300 10.1016/0360-3016(95)00118-I 7635768 \n28. Bethesda M ICRU report 38. Dose and volumen specification for reporting intracavitary therapy in gynecology International Commission on Radiation Units and Measurements 1985 38 1 20 \n29. Pötter R Tanderup K Kirisits C Clinical and translational radiation oncology the EMBRACE II study: the outcome and prospect of two decades of evolution within the GEC-ESTRO GYN working group and the EMBRACE studies Clin Transl Radiat Oncol 2018 9 48 60 10.1016/j.ctro.2018.01.001 29594251 \n30. Monk BJ Tewari KS Koh WJ Multimodality therapy for locally advanced cervical carcinoma: state of the art and future directions J Clin Oncol 2007 25 20 2952 2965 10.1200/JCO.2007.10.8324 17617527 \n31. Thomas G Improved treatment for cervical cancer- concurrent chemotherapy and radiotherary N Engl J Med 1999 1198 1206 10.1056/NEJM199904153401509 \n32. Nugent EK Case AS Hoff JT Chemoradiation in locally advanced cervical carcinoma: an analysis of cisplatin dosing and other clinical prognostic factors Gynecol Oncol 2010 116 3 438 441 10.1016/j.ygyno.2009.09.045 19896180 \n33. Pötter R Dimopoulos J Bachtiary B 3D conformal HDR-brachy- and external beam therapy plus simultaneous cisplatin for high-risk cervical cancer: clinical experience with 3 year follow-up Radiother Oncol 2006 79 1 80 86 10.1016/j.radonc.2006.01.007 16516316 \n34. Ogino I Kitamura T Okamoto N Late rectal complication following high dose rate intracavitary brachytherapy in cancer of the cervix Int J Radiat Oncol Biol Phys 1995 31 4 725 734 10.1016/0360-3016(94)00547-8 7860383 \n35. Nakano T Kato S Ohno T Long-term results of high-dose rate intracavitary brachytherapy for squamous cell carcinoma of the uterine cervix Cancer 2005 103 1 92 101 10.1002/cncr.20734 15540233 \n36. Morice P Rouanet P Rey A Results of the GYNECO 02 study, an FNCLCC phase III trial comparing hysterectomy with no hysterectomy in patients with a (Clinical and Radiological) complete response after chemoradiation therapy for stage IB2 or II cervical cancer Oncologist 2012 17 64 71 10.1634/theoncologist.2011-0276 22234626\n\n",
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"abstract": "The present report describes a case of a 68-year-old male patient with epidermal growth factor receptor (EGFR)-mutant non-small cell lung carcinoma (NSCLC). After cytotoxic chemotherapy of three regimens following 22 months of treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKIs), including osimertinib, the patient underwent S-1 treatment. Despite a decrease in carcinoembryonic antigen 1 month after initiating S-1 treatment, the patient developed cardiac tamponade. The evaluation of pericardial effusion confirmed small-cell lung carcinoma (SCLC) transformation. Subsequently, a combination therapy of carboplatin and etoposide was administered, which led to a marked improvement in imaging. In patients with NSCLC who develop pericardial effusion after long-term EGFR-TKI therapy, including osimertinib treatment, it is important to investigate whether SCLC transformation occurs or not as a treatable entity.",
"affiliations": "Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Yokohama, Kanagawa 236-0051, Japan.;Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Yokohama, Kanagawa 236-0051, Japan.;Department of Pathology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0027, Japan.;Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Yokohama, Kanagawa 236-0051, Japan.;Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Yokohama, Kanagawa 236-0051, Japan.;Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Yokohama, Kanagawa 236-0051, Japan.;Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Yokohama, Kanagawa 236-0051, Japan.;Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Yokohama, Kanagawa 236-0051, Japan.;Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Yokohama, Kanagawa 236-0051, Japan.;Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Yokohama, Kanagawa 236-0051, Japan.",
"authors": "Otoshi|Ryota|R|;Sekine|Akimasa|A|;Okudela|Koji|K|;Asaoka|Masato|M|;Sato|Yozo|Y|;Ikeda|Satoshi|S|;Baba|Tomohisa|T|;Komatsu|Shigeru|S|;Hagiwara|Eri|E|;Ogura|Takashi|T|",
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"fulltext": "\n==== Front\nMol Clin Oncol\nMol Clin Oncol\nMCO\nMolecular and Clinical Oncology\n2049-9450 2049-9469 D.A. Spandidos \n\nMCO-0-0-2059\n10.3892/mco.2020.2059\nArticles\nSmall-cell lung carcinoma transformation of lung adenocarcinoma diagnosed by pericardial effusion: A case report\nOtoshi Ryota 1 Sekine Akimasa 1 Okudela Koji 2 Asaoka Masato 1 Sato Yozo 1 Ikeda Satoshi 1 Baba Tomohisa 1 Komatsu Shigeru 1 Hagiwara Eri 1 Ogura Takashi 1 1 Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Yokohama, Kanagawa 236-0051, Japan\n2 Department of Pathology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0027, Japan\nCorrespondence to: Dr Akimasa Sekine, Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, 6-16-1 Tomioka-higashi, Kanazawa-ku, Yokohama, Kanagawa 236-0051, Japan akimasa.sekine@gmail.com\n8 2020 \n03 6 2020 \n03 6 2020 \n13 2 129 132\n22 8 2019 30 4 2020 Copyright: © Otoshi et al.2020This 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.The present report describes a case of a 68-year-old male patient with epidermal growth factor receptor (EGFR)-mutant non-small cell lung carcinoma (NSCLC). After cytotoxic chemotherapy of three regimens following 22 months of treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKIs), including osimertinib, the patient underwent S-1 treatment. Despite a decrease in carcinoembryonic antigen 1 month after initiating S-1 treatment, the patient developed cardiac tamponade. The evaluation of pericardial effusion confirmed small-cell lung carcinoma (SCLC) transformation. Subsequently, a combination therapy of carboplatin and etoposide was administered, which led to a marked improvement in imaging. In patients with NSCLC who develop pericardial effusion after long-term EGFR-TKI therapy, including osimertinib treatment, it is important to investigate whether SCLC transformation occurs or not as a treatable entity.\n\nsmall-cell lung carcinoma transformationepidermal growth factor receptorosimertinibadenocarcinomapericardial effusion\n==== Body\nIntroduction\nNon-small-cell lung carcinoma (NSCLC) with epidermal growth factor receptor (EGFR) mutations responds well to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). However, most patients acquire resistance to EGFR-TKIs and experience disease progression (1). Although several resistance mechanisms to EGFR-TKIs have been recently reported, small-cell lung carcinoma (SCLC) transformation is a relatively rare resistance mechanism and mostly develops in NSCLC patients with 1st and 2nd generation EGFR-TKIs such as gefitinib, erlotinib, and afatinib (2,3). To date, only a few cases of SCLC transformation during or after treatment with osimertinib have been reported (4-8). However, all previously reported cases of SCLC transformation have been diagnosed by pathological tissues of primary lesion or metastatic lesions, not pericardial effusion. Here, we report the case of malignant pericarditis developed in SCLC transformed NSCLC patient with a history of osimertinib treatment.\n\nCase report\nA 68-year-old man with a smoking history of 40 packs per year was admitted to our hospital due to relapse of stage IA lung adenocarcinoma in December 2014, which was previously surgically resected in December 2012. Computed tomography (CT) revealed mediastinal lymphadenopathy and multiple lung nodules (Fig. 1). In addition, serum carcinoembryonic antigen (CEA) level had increased to 16.0 ng/ml. The specimen obtained by endobronchial ultrasound-guided transbronchial needle aspiration to mediastinal lymph node (#4R) confirmed lung adenocarcinoma with an EGFR mutation (exon 19 deletion) by therascreen® EGFR RGQ PCR Kit (Qiagen, Hilden, Germany). Then, he was enrolled in a clinical trial (FLAURA trial) comparing osimertinib and gefitinib (or erlotinib) as the 1st line chemotherapy and treated with osimertinib in March 2015(9). Although this treatment had a significant response lasting 11 months and CEA fell to the normal level, routine-follow-up CT in February 2016 showed slight ground-glass attenuation (GGA) in the right lower lobe. The treatment was discontinued on suspicion of drug-induced pneumonitis. Although GGA was spontaneously regressed, mediastinal lymphadenopathy and multiple lung nodules aggravated. Therefore, erlotinib treatment as 2nd line chemotherapy was initiated with a careful observation in May 2016. After 8 months treatment with erlotinib, follow-up CT in January 2017 demonstrated re-progression of the mediastinal lymph node and appearance of minor amounts of pericardial effusion. With a re-biopsy of the lymph node (#4R), lung adenocarcinoma was found the EGFR T790M mutation in addition to the EGFR exon 19 deletion although liquid biopsy, a blood test that detects evidence of cancer cells or tumor DNA, showed only exon 19 deletion by cobas EGFR Mutation test v2 (Roche Molecular Systems, Pleasanton, CA, USA). Thus, re-challenge with osimertinib as 3rd line treatment was initiated, and three month later, despite a tentative response, enlargement of mediastinal tumors with an elevated CEA level of 24.3 ng/ml was observed. Next, the patient was treated with carboplatin in combination with paclitaxel, docetaxel, and pemetrexed as 4th-6th line treatment, respectively, which did not present a desired effect and CEA level remained elevated. Thus, S-1 monotherapy was initiated in August 2018 as 7th line treatment (Fig. 2A). One month after this treatment was initiated, an apparent decrease in CEA level from 100.5 ng/ml to 30 ng/ml was observed. However, dyspnea gradually appeared, and CT showed apparent enlargement of mediastinal tumors and increase of pericardial effusion, which ultimately resulted in cardiac tamponade due to disease progression (Fig. 2B). Then, a pericardial paracentesis was performed, and the specimens obtained from pericardial fluid showed poorly differentiated cells with a high nuclear-to-cytoplasmic ratio. With the immunohistochemical staining, neuroendocrine markers such as synaptophysin, NCAM and chromogranin were positive (Fig. 3). Besides, the additional blood tests indicated that neuron specific enolase (NSE) was 39.4 ng/ml. Based on these results, SCLC transformation was confirmed. Additionally, the molecular analysis of the obtained specimens showed that the exon 19 deletion was still positive despite negative T790M mutation by cobas EGFR Mutation test v2. After pericardial paracentesis (Fig. 2C), a combination therapy of carboplatin and etoposide was administered in September 2018. After the 1st course of this regimen, mediastinal tumor and pericardial effusion were dramatically improved with a substantial decrease of NSE level, and therefore 4 cycles of this regimen were completed (Fig. 2D). The disease related SCLC transformation was considered to remain stable with normal level of NSE in March 2019.\n\nDiscussion\nWe herein report the case of SCLC transformation diagnosed by pericardial effusion after a long-term treatment with EGFR-TKIs including osimertinib. All previously reported cases of SCLC transformation have been diagnosed by pathological tissues of primary lesion or metastatic lesions, not pericardial effusion. Our results could provide the following two clinical implications.\n\nFirst, SCLC transformation would occur after treatment with osimertinib. Among several mechanisms of acquired resistance to EGFR-TKIs, SCLC transformation reportedly accounts for 3-14% and mostly developed as the acquired resistance to 1st- or 2nd-generation EGFR-TKIs (2,3). To date, there are limited cases of SCLC transformation after osimertinib treatment (4-8). Marcoux et al (10) reported that median total time of treatment with EGFR-TKIs at the diagnosis of SCLC transformation was 15.8 months. In our case, the duration of total osimertinib treatment was 14 months and the total interval of EGFR-TKI treatment was 22 months. Taking those reports together with the present case, SCLC transformation would occur after long-term use of EGFR-TKIs regardless of the generation of EGFR-TKIs. With regard to mechanism of SCLC transformation, there have been the following two hypotheses (11). Firstly, lung cancer consists of combined SCLC and NSCLC histology at first diagnosis, and EGFR-TKI treatment would cause a component of SCLC dominant. Secondary, type II alveolar cells, the origin of some EGFR-mutant adenocarcinomas, also have the potential to become SCLC. Lung adenocarcinoma arising from these alveolar type II cells and harboring EGFR mutations might transform to SCLC under the selective pressure of TKI therapy. In our case, we did not detect a component of SCLC histologically at first diagnosis. Of note, the molecular analysis of the cell block from pericardial effusion showed that the exon 19 deletion was still positive despite negative T790M mutation, as seen in some reports (4-6). Based on those findings, we consider that this transformed SCLC developed from a common precursor of adenocarcinoma.\n\nSecond, physicians should investigate whether SCLC transformation occurs or not, especially in NSCLC patients who develop pericardial effusion after long-term EGFR-TKI treatment. Generally, malignant pericardial effusion develops in 2.5% of lung cancer patients and is correlated with a poor prognosis with median survival of 74.5 days (12,13). Of note, even minimal pericardial effusion is reported as an independent prognostic factor for those patients (14). Generally, EGFR-mutant NSCLC patients who develop pericardial effusion after the treatment failure with EGFR-TKIs therapy present very poor prognosis due to lack of therapeutic options. On the other hand, the median survival in patients with SCLC transformation reportedly reached 10.9 months (10). Therefore, it is crucial not to overlook SCLC transformation as a treatable entity. Importantly, in our case, despite the decrease of CEA level from 100.5 to 30.0 ng/ml during S-1 treatment, his disease paradoxically progressed with high level of NSE. In fact, some previous reports about SCLC transformation revealed that pro-gastrin releasing peptide (pro-GRP) and NSE are reported to be likely to increase (5,6). Therefore, it would be extremely important to measure tumor markers of pro-GRP and NSE in NSCLC patient with pericardial effusion after long-term EGFR-TKI treatment.\n\nIn conclusion, we presented the case of SCLC transformation diagnosed by pericardial effusion after long-term EGFR-TKI treatment including osimertinib. In NSCLC patients who develop pericardial effusion after long-term EGFR-TKI therapy including osimertinib, it is important to investigate whether SCLC transformation occurs or not, and measuring tumor markers.\n\nAcknowledgements\nNot applicable.\n\nFunding\nNo funding was received.\n\nAvailability of data and materials\nThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\n\nAuthors' contributions\nRO and AS analysed and interpreted the data and wrote the manuscript. RO, AS, MA, YS, SI, TB, SK, EH and TO evaluated the patient and participated in the therapy. KO evaluated the pathological specimens. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nPatient consent for publication\nThe patient provided written informed consent for the publication of the case details and any associated images.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nFigure 1 Chest computed tomography revealed multiple lung nodules (arrow) and mediastinal lymphadenopathy, including right lower paratrachel lymph node, at relapse.\n\nFigure 2 Changes in imaging of the patient over time. (A) Before treatment with S-1, a chest radiograph revealed mild enlargement of the cardiac silhouette. Chest computed tomography demonstrated mediastinal tumor and minor amount of pericardial effusion. (B) Chest radiograph showing apparent enlargement of the cardiac silhouette and pleural effusion. Chest computed tomography revealed apparent enlargement of mediastinal tumors and an increase in pericardial effusion. (C) After drainage, pericardial effusion decreased but was still present. (D) Mediastinal tumor and pericardial effusion markedly decreased after combination therapy of carboplatin and etoposide was initiated.\n\nFigure 3 Histological findings of the cell block from pericardial effusion. The specimens showed poorly differentiated cells with a high nuclear-to-cytoplasmic ratio. (A) Hematoxylin and eosin staining. Magnification, x400. Immunostaining revealed that (B) synaptophysin, (C) NCAM and (D) chromogranin were positive. Magnification, x400.\n==== Refs\nReferences\n1 Mok TS Wu YL Thongprasert S Yang CH Chu DT Saijo N Sunpaweravong P Han B Margono B Ichinose Y Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma N Engl J Med 361 947 957 2009 10.1056/NEJMoa0810699 19692680 \n2 Yu HA Arcila ME Rekhtman N Sima CS Zakowski MF Pao W Kris MG Miller VA Ladanyi M Riely GJ Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers Clin Cancer Res 19 2240 2247 2013 10.1158/1078-0432.CCR-12-2246 23470965 \n3 Sequist LV Waltman BA Dias-Santagata D Digumarthy S Turke AB Fidias P Bergethon K Shaw AT Gettinger S Cosper AK Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors Sci Transl Med 3 75ra26 2011 10.1126/scitranslmed.3002003 21430269 \n4 Minari R Bordi P Del Re M Facchinetti F Mazzoni F Barbieri F Camerini A Comin CE Gnetti L Azzoni C Primary resistance to osimertinib due to SCLC transformation: Issue of T790M determination on liquid re-biopsy Lung Cancer 115 21 27 2018 10.1016/j.lungcan.2017.11.011 29290257 \n5 Iijima Y Hirotsu Y Mochizuki H Amemiya K Oyama T Uchida Y Kobayashi Y Tsutsui T Kakizaki Y Miyashita Y Omata M Dynamic changes and drug-induced selection of resistant clones in a patient with EGFR-mutated adenocarcinoma that acquired T790M mutation and transformed to small-cell lung cancer Clin Lung Cancer 19 e843 e847 2018 10.1016/j.cllc.2018.07.002 30122430 \n6 Taniguchi Y Horiuchi H Morikawa T Usui K Small-cell carcinoma transformation of pulmonary adenocarcinoma after osimertinib treatment: A case report Case Rep Oncol 11 323 329 2018 10.1159/000489603 29928211 \n7 Kim TM Song A Kim DW Kim S Ahn YO Keam B Jeon YK Lee SH Chung DH Heo DS Mechanisms of acquired resistance to AZD9291: A mutation-selective, irreversible EGFR inhibitor J Thorac Oncol 10 1736 1744 2015 10.1097/JTO.0000000000000688 26473643 \n8 Ham JS Kim S Kim HK Byeon S Sun JM Lee SH Ahn JS Park K Choi YL Han J Two cases of small cell lung cancer transformation from EGFR mutant adenocarcinoma during AZD9291 treatment J Thorac Oncol 11 e1 e4 2016 10.1016/j.jtho.2015.09.013 26762749 \n9 Soria JC Ohe Y Vansteenkiste J Reungwetwattana T Chewaskulyong B Lee KH Dechaphunkul A Imamura F Nogami N Kurata T Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer N Engl J Med 378 113 125 2018 10.1056/NEJMoa1713137 29151359 \n10 Marcoux N Gettinger SN O'Kane G Arbour KC Neal JW Husain H Evans TL Brahmer JR Muzikansky A Bonomi PD EGFR-mutant adenocarcinomas that transform to small-cell lung cancer and other neuroendocrine carcinomas: Clinical outcomes J Clin Oncol 37 278 285 2019 10.1200/JCO.18.01585 30550363 \n11 Oser MG Niederst MJ Sequist LV Engelman JA Transformation from non-small-cell lung cancer to small-cell lung cancer: Molecular drivers and cells of origin Lancet Oncol 16 e165 e172 2015 10.1016/S1470-2045(14)71180-5 25846096 \n12 Hayano M Hokamura Y Kimura Y Kimura T Tokube K Clinical studies of 16 cases of carcinomatous pericarditis Kokyu To Junkan 39 683 686 1991 (In Japanese) 1896661 \n13 Wang PC Yang KY Chao JY Liu JM Perng RP Yen SH Prognostic role of pericardial fluid cytology in cardiac tamponade associated with non-small cell lung cancer Chest 118 744 749 2000 10.1378/chest.118.3.744 10988197 \n14 Kato R Hayashi H Chiba Y Tanaka K Takeda M Nakagawa K Prognostic impact of minimal pericardial effusion in patients with advanced non-small-cell lung cancer Clin Lung Cancer 18 e449 e455 2017 10.1016/j.cllc.2017.05.011 28576595\n\n",
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"abstract": "OBJECTIVE\nOral mucositis (OM) and prolonged wound healing are common side-effects of cancer treatments. Photobiomodulation (PBM), previously called low-level laser, is currently part of the official guideline for OM prevention. However, all the PBM protocols relate to office-based devices, operated by professional health caregivers, requiring frequent applications. In the following case series, we present our experience with a self-applied consumer home-use PBM device for supportive care.\n\n\nMETHODS\nFive patients receiving cancer treatment presented at the clinic (female:male 3:2, 55-76 years old) with OM grade 3/4 (n=2), post-surgical non-healing wounds (n=3), and dermatitis (n=1). The PBM treatment (808 nm, 250 mW peak power, 15KHz, 5 J/min, ray size 4.5×1.0cm2) was self-applied by the patients. The protocol included extra/intra-oral applications, over the wound bed/margins and adjacent lymph nodes.\n\n\nRESULTS\nThe treatment was found effective for resolving OM with rapid pain relief and accelerated healing in post-operative wounds and dermatitis, without reported adverse events. Patients found routine easy to follow and painless, and the protocol was easily integrated as an adjuvant treatment to standard care at the clinic or home while not requiring additional time from the staff.\n\n\nCONCLUSIONS\nSide-effects induced by cancer therapy have a detrimental effect on the patient's well-being and may delay or even prevent the patients from completing treatment regimens. PBM is already an established tool for supportive treatment in cancer patients. The advent of a self-applied personal PBM treatment with easy-to-apply protocols for a variety of side-effects makes this technology an important accessible and safe supportive care option.",
"affiliations": "Institute for Research in Military Medicine (IRMM), Faculty of Medicine, The Hebrew University of Jerusalem, POB 12272, 9112001, Jerusalem, Israel. lilachg@ekmd.huji.ac.il.;Institute for Research in Military Medicine (IRMM), Faculty of Medicine, The Hebrew University of Jerusalem, POB 12272, 9112001, Jerusalem, Israel.;Department of Professional Practice, Scarborough Health Network, Centenary Hospital, Toronto, Canada.",
"authors": "Gavish|Lilach|L|http://orcid.org/0000-0003-0392-8958;Zadik|Yehuda|Y|;Raizman|Rose|R|",
"chemical_list": null,
"country": "Germany",
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"doi": "10.1007/s00520-021-06027-w",
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"issn_linking": "0941-4355",
"issue": "29(8)",
"journal": "Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer",
"keywords": "Case report; Dehiscence, Oral mucositis; Home-use; Low-level laser; Photobiomodulation; Supportive care",
"medline_ta": "Support Care Cancer",
"mesh_terms": "D000368:Aged; D005260:Female; D006801:Humans; D028022:Low-Level Light Therapy; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D010166:Palliative Care; D013280:Stomatitis",
"nlm_unique_id": "9302957",
"other_id": null,
"pages": "4743-4749",
"pmc": null,
"pmid": "33517481",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "32888351",
"title": "Supportive care of cancer patients with a self-applied photobiomodulation device: a case series.",
"title_normalized": "supportive care of cancer patients with a self applied photobiomodulation device a case series"
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"abstract": "The severe acute respiratory syndrome coronavirus 2 (SARs-CoV-2) has resulted in a global pandemic. Hydroxychloroquine±azithromycin have been widely used to treat coronavirus disease 2019 (COVID-19) despite a paucity of evidence regarding efficacy. The incidence of torsade de pointes remains unknown. Widespread use of these medications forced overwhelmed health care systems to search for ways to effectively monitor these patients while simultaneously trying to minimize health care provider exposure and use of personal protective equipment.\n\n\n\nPatients with COVID-19 positive who received hydroxychloroquine±azithromycin across 13 hospitals between March 1 and April 15 were included in this study. A comprehensive search of the electronic medical records was performed using a proprietary python script to identify any mention of QT prolongation, ventricular tachy-arrhythmias and cardiac arrest.\n\n\n\nThe primary outcome of torsade de pointes was observed in 1 (0.015%) out of 6476 hospitalized patients with COVID-19 receiving hydroxychloroquine±azithromycin. Sixty-seven (1.03%) had hydroxychloroquine±azithromycin held or discontinued due to an average QT prolongation of 60.5±40.5 ms from a baseline QTc of 473.7±35.9 ms to a peak QTc of 532.6±31.6 ms. Of these patients, hydroxychloroquine±azithromycin were discontinued in 58 patients (86.6%), while one or more doses of therapy were held in the remaining nine (13.4%). A simplified approach to monitoring for QT prolongation and arrythmia was implemented on April 5. There were no deaths related to the medications with the simplified monitoring approach and health care provider exposure was reduced.\n\n\n\nThe risk of torsade de pointes is low in hospitalized patients with COVID-19 receiving hydroxychloroquine±azithromycin therapy.",
"affiliations": "Department of Cardiology (M.S., J.G., D.C., S.E.M., L.M.E.), The Feinstein Institutes for Medical Research, Northwell Health, NY.;Department of Cardiology (M.S., J.G., D.C., S.E.M., L.M.E.), The Feinstein Institutes for Medical Research, Northwell Health, NY.;Department of Cardiology (M.S., J.G., D.C., S.E.M., L.M.E.), The Feinstein Institutes for Medical Research, Northwell Health, NY.;Biostatistics Unit (J.F.), The Feinstein Institutes for Medical Research, Northwell Health, NY.;Institute of Health Innovations and Outcomes Research & Center for Research Informatics & Innovation (M.Q.), The Feinstein Institutes for Medical Research, Northwell Health, NY.;Department of Cardiology (M.S., J.G., D.C., S.E.M., L.M.E.), The Feinstein Institutes for Medical Research, Northwell Health, NY.;Department of Cardiology (M.S., J.G., D.C., S.E.M., L.M.E.), The Feinstein Institutes for Medical Research, Northwell Health, NY.",
"authors": "Saleh|Moussa|M|;Gabriels|James|J|;Chang|David|D|;Fishbein|Joanna|J|;Qiu|Michael|M|;Mountantonakis|Stavros E|SE|;Epstein|Laurence M|LM|;|||",
"chemical_list": "D000998:Antiviral Agents; D006886:Hydroxychloroquine; D017963:Azithromycin",
"country": "United States",
"delete": false,
"doi": "10.1161/CIRCEP.120.008937",
"fulltext": null,
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"issn_linking": "1941-3084",
"issue": "13(11)",
"journal": "Circulation. Arrhythmia and electrophysiology",
"keywords": "COVID-19; azithromycin; hydroxychloroquine; pandemic; torsade de pointes",
"medline_ta": "Circ Arrhythm Electrophysiol",
"mesh_terms": "D000200:Action Potentials; D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents; D017963:Azithromycin; D000086382:COVID-19; D066126:Cardiotoxicity; D003695:Delivery of Health Care; D005260:Female; D006329:Heart Conduction System; D006339:Heart Rate; D006760:Hospitalization; D006801:Humans; D006886:Hydroxychloroquine; D008297:Male; D008875:Middle Aged; D009518:New York; D061214:Patient Safety; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016171:Torsades de Pointes; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101474365",
"other_id": null,
"pages": "e008937",
"pmc": null,
"pmid": "33003964",
"pubdate": "2020-11",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": "32407884;26660066;15549175;32150618;32330546;32347743;31996437;32330277;32838355;32450107;16115318;30514889;32936252",
"title": "Safely Administering Potential QTc Prolonging Therapy Across a Large Health Care System in the COVID-19 Era.",
"title_normalized": "safely administering potential qtc prolonging therapy across a large health care system in the covid 19 era"
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"abstract": "We describe the case of a 34 year-old man with diagnosis of migraine with and without aura that developed myopia and acute glaucoma after 7 days of treatment with topiramate. The patient had also been taking citalopram daily for two months. Both topiramate and citalopram have been related to the increase of intraocular pressure and the development of glaucoma. We can't exclude that in this patient citalopram caused an increase of the ocular pressure in dose-dependent manner, facilitating topiramate-induced glaucoma. We recommend to pay particular attention in prescribing of topiramate in migraine patients who are already under treatment with citalopram or other antidepressants with a similar mechanisms of action.",
"affiliations": "Headache Centre, Division of Toxicology and Clinical Pharmacology, University of Modena and Reggio Emilia, Modena, Italy. lukespacca@hotmail.com.",
"authors": "Spaccapelo|Luca|L|;Leschiutta|Silvia|S|;Aurea|Claudio|C|;Ferrari|Anna|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/1757-1626-2-87",
"fulltext": "\n==== Front\nCases JCases Journal1757-1626BioMed Central 1757-1626-2-871917105810.1186/1757-1626-2-87Case ReportTopiramate-associated acute glaucoma in a migraine patient receiving concomitant citalopram therapy: a case-report Spaccapelo Luca 1lukespacca@hotmail.comLeschiutta Silvia 2silvialeschiutta@hotmail.comAurea Claudio 1farmacologia.clinica@hotmail.itFerrari Anna 1annaf@unimore.it1 Headache Centre, Division of Toxicology and Clinical Pharmacology, University of Modena and Reggio Emilia, Modena, Italy2 Postgraduate school of Pharmacology, University of Modena and Reggio Emilia, Modena, Italy2009 26 1 2009 2 87 87 4 11 2008 26 1 2009 Copyright ©2009 Spaccapelo et al; licensee BioMed Central Ltd.2009Spaccapelo et al; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.We describe the case of a 34 year-old man with diagnosis of migraine with and without aura that developed myopia and acute glaucoma after 7 days of treatment with topiramate. The patient had also been taking citalopram daily for two months. Both topiramate and citalopram have been related to the increase of intraocular pressure and the development of glaucoma. We can't exclude that in this patient citalopram caused an increase of the ocular pressure in dose-dependent manner, facilitating topiramate-induced glaucoma. We recommend to pay particular attention in prescribing of topiramate in migraine patients who are already under treatment with citalopram or other antidepressants with a similar mechanisms of action.\n==== Body\nIntroduction\nTopiramate is approved as first or second choice in antiepileptic therapy, as an additional therapy for the syndrome of Lennox-Gastaut, and for the prophylaxis of migraine with or without aura in adult patients that have not responded or are intolerant to the other standard therapies [1]. Topiramate has also been prescribed for a variety of \"off-label\" conditions, such as affective disorders, postherpetic neuralgias, peripheral neuropathies, post-traumatic stress disorder, loss of weight, and insomnia [2].\n\nThe most common adverse events related to topiramate are represented by fatigue, paresthesia, alterations of taste, loss of weight, and drowsiness. In patients treated with topiramate, a rare but severe adverse event is represented by acute myopia with secondary closed-angle glaucoma.\n\nIn the reported cases of glaucoma, the dose of topiramate varied from 50 mgs or less (47% of cases), to 50–75 mg (33% of cases), and 100 mg (13%) to more than 100 mg (7%) and this adverse event already manifested in the 85% of cases in the first 2 weeks of treatment or at the increase of the dose [3].\n\nAlso selective inhibitors of the reuptake of serotonin (SSRI) have been related to angle-closed glaucoma [4], even if less frequently than tricyclic antidepressants. Their agonists activity at noradrenergic receptors (when present), together with passive mydriasis induced by the increase of serotonin levels, could favour the closing of the irido-corneal angle. Two cases of glaucoma have recently been reported in patients treated with citalopram, the most selective among SSRIs in the reuptake of serotonin [5,6].\n\nWe describe here the case of a patient in treatment with citalopram that developed myopia and acute glaucoma 7 days after the beginning of the therapy with topiramate.\n\nCase presentation\nA 34 year-old man with diagnosis of migraine with and without aura, particularly worsened both for duration and for intensity in the last 3 years, was under treatment at our Headache Centre of the University Hospital of Modena. We prescribed topiramate 25 mg/day as treatment of prophylaxis. According to the prescription, the patient would have had to increase the dosing of the drug of 25 mg/day every 15 days, up to the dose of 100 mg/day, and then to return then to our centre for a checkup.\n\nThe patient had also been taking citalopram 20 mg (1 tablet/day) for two months for the treatment of an anxious-depressive syndrome. Neurological examination resulted in the normality, with symmetrical deep tendon reflexes, uninjured sensibility, absent nystagmus, and well performed vestibulo-ocular reflexes. The fundus oculi was in the limits for age, with preserved visual field. A magnetic resonance imaging (MRI), performed one month before to exclude possible organic causes of the worsening of headache, didn't detect any pathological alteration.\n\nSeven days after the start of the treatment with topiramate, the patient complained of blurred vision and ocular pain as an intense compression. The trouble persisted during the evening, until the following morning, of unchanged intensity. For these symptoms, the patient applied to a nearby oculistic clinic, where a pressure of 40 mmHg in both eyes was found, compatible with diagnosis of acute glaucoma. The patient also presented a reduction of depth of the anterior chamber, hyperaemia of the sclera and light corneal edema. The fundus oculi showed however a rosy, not excoriated pupilla, with clean borders. The opthalmologist confirmed a severe acute myopia (right eye = -5,5 diopters, left eye = -5 diopters).\n\nThe therapy with topiramate was immediately stopped and the patient started the following antiglaucoma therapy: acetazolamide 250 mg for twice a day in tablets, latanoprost, timolol 0,50% 1 drop 3 times/day and pilocarpine 2% 1 drop for 3 times/day in eyewash. The same day, a blood sample was taken for the determination of topiramate levels by means of Fluorescence Polarized Immuno Assay (FPIA). The plasma concentration was 1,7 μg/ml, therefore below the therapeutic range (2–25 μg/ml).\n\nAlready 2 days later, ocular pressure was reduced to 14 mmHg in the right eye and to 17 mmHg in the left eye at the ophthalmological checkup. After 4 days, the depth of the anterior ocular chamber returned to normal and ocular tone subsequently reduced to 10 mmHgs in both eyes, while an important loss of the visus remained (right eye = -10,0 diopters, left eye = -6,5 diopters). The complete resolution of the symptomatology was atteined after 8 days of antiglaucoma therapy and from the suspension of topiramate: the patient eventually had a visus equal to 10/10 bilaterally, and fundus oculi and ocular pressure within the normal limits.\n\nDiscussion\nThe first clinical symptoms of glaucoma (blurred vision and ocular pain) seem to be caused by an uveal effusion and by an anterior rotation of the ciliary body. The consequent ocular configuration would shallow the anterior chamber and would close the irido-corneal angle, eventually precipitating the glaucomatous crisis [7].\n\nThe molecular mechanism of this serious side effect is not clear yet, but the most shared hypothesis currently remains the idiosyncratic reaction. It seems indeed difficult to relate the mechanisms of action of topiramate (specifically within the central nervous system) to the increase of ocular pressure and the onset of angle closed glaucoma. Furthermore, it is reported that topiramate modulates voltage-dependent Na+ channels, thus reducing the firing of cerebellar granule cells, and it seems contemporarily to strengthen the activity of GABA (increasing post-synaptic currents of GABAA receptors); finally, it would reduce the effects of the activation of glutamatergic of AMPA-kainate [8] subtype.\n\nTopiramate is also a weak inhibitor of carbonic anhydrase (particularly of subtypes II and IV), like other sulphonamides, and acetazolamide, a drug of the same class and specific inhibitor of carbonic anhydrase, is paradoxically an effective antiglaucoma drug, also used by our patient for its activity of reduction of aqueous humor production. In particular, it is hypothesized that the antiglaucomatous activity of the sulphonamides depends on the inhibition of the isoenzyme 12 (hCA XII) of the carbonic anhydrase. Topiramate presents good affinity for this isoenzyme (KIs of 3.8 NM), while it does not show significant selectivity[9]: this observation would confirm a possible antiglaucoma mechanism of topiramate under normal conditions. Furthermore, an overexpression of the gene that codifies for this isoenzyme (hCA XII) of carbonic anhydrase has been observed in glaucomatous patients [10].\n\nThe ability to cause glaucoma seems therefore independent of the pharmacodynamic well-known effect of topiramate; the individual characteristics of the patient can probably have had a decisive role.\n\nA peculiar element of this case is that our patient assumed daily citalopram, a selective serotonin reuptake inhibitor, as antidepressive therapy. Indeed, this drug is also implicated in the development of angle-closed glaucoma [11].\n\nSerotoninergic receptors have been identified in the ciliary body in both animals and humans [12], suggesting that serotonin has an important role of modulation of ocular pressure. In experimental models, it has been observed that serotonin, binding to serotoninergic intraocular receptors 5-HT2 and 5-HT3, facilitates the contraction of bovine ciliary muscle, with diminution of ocular pressure [13]; but topical application of serotonin increases intraocular pressure in dose-dependent manner in the rabbit [14]. The overall effect of an increase of serotonin on intraocular pressure is not completely clarified yet. A case of acute glaucoma has been reported in a patient after an overdose of citalopram, similarly to that observed with fluoxetine [15].\n\nOn the basis of experimental and clinical data, we can hypothesize that the mechanism of action of citalopram contributes to the increasing of intraocular pressure in dose-dependent manner. Remarkable clinical consequences have not however been reported, because of changes in plasmatic levels of citalopram, caused by concomitant assumption of other drugs [16]. It is therefore unlikely that glaucoma was caused in our patient by an increase of plasmatic concentrations of citalopram, caused by topiramate-related inhibition of its elimination.\n\nTopiramate is poorly metabolized by liver and it is a weak inducer, not a pharmaco-metabolic inhibitor. The only meaningful pharmacodynamic interaction from the clinical point of view seems to be the reduction of plasmatic concentration of estrogens in oral contraceptives, with reduction of their efficacy [17]. About 85% of unmetabolized topiramate is finally eliminated by urine; more than 16 hours after the start of symptomatology, plasmatic levels of topiramate were even lower than therapeutic range, excluding a possible dose-dependent adverse reaction to this drug.\n\nConclusion\nIn conclusion, topiramate and citalopram were connected both with the increasing of intraocular pressure and the development of glaucoma. So far, no evidences have emerged showing that a contemporary assumption of both these drugs within therapeutic doses can increase the risk of acute glaucoma, but it has been hypothesized that selective serotonin reuptake inhibitors are able to strengthen the uveal effusion of topiramate [18].\n\nWe cannot exclude that citalopram increases ocular pressure in dose-dependent manner, through intraocular accumulation of serotonin, consequently increasing the risk of topiramate-induced glaucoma in a patient with a predisposed genetic substratum.\n\nWe therefore recommend to pay particular attention to the prescription of topiramate in patients in therapy with citalopram or other antidepressants with similar mechanisms of action.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors' contributions\nLS drafted this manuscript and analized the patient data, SL and CA reviewed the current literature and helped to draft the manuscript, AF critically revised the manuscript. All authors read and approved the final manuscript.\n==== Refs\nPascual J Sánchez del Rio M Mateos V Láinez JM Hernández-Gallego J Leira R Topiramate for patients with refractory migraine: an observational, multicentre study in Spain Neurology 2003 18 364 367 \nSpina E Perugi G Antiepileptic drugs: indications other than epilepsy Epileptic Disord 2004 6 57 75 15246950 \nFraunfelder FW Fraunfelder FT Keates EU Acute Topiramate-associated, bilateral, secondary angle-closure glaucoma Ophthalmology 2004 111 109 111 10.1016/j.ophtha.2003.04.004 14711721 \nHauben M Reich L Reports of acute angle closure glaucoma-related adverse events with SSRIs: results of to disproportionality analysis CNS Drugs 2006 20 327 329 10.2165/00023210-200620040-00006 16599650 \nMassaoutis P Goh D Foster PJ Bilateral symptomatic angle closure associated with to regular dose of citalopram, an SSRI antidepressant Br J Ophthalmol 2007 91 1086 1087 10.1136/bjo.2006.107185 17638821 \nCroos R Thirumalai S Hassan S Davis Jda R Citalopram associated with acute angle-closure glaucoma: case report BMC Ophthalmol 2005 5 23 16202173 10.1186/1471-2415-5-23 \nCongdon NG Friedman DS Angle-closure glaucoma: impact, etiology, diagnosis, and treatment Curr Opin Ophthalmol 2003 14 70 73 10.1097/00055735-200304000-00002 12698044 \nCraig JE Ong TJ Louis DL Wells JM Mechanism of topiramate-induced acute-onset myopia and angle closure glaucoma Am J Ophthalmol 2004 137 193 195 10.1016/S0002-9394(03)00774-8 14700673 \nVullo D Innocent T Nishimori I Carbonic anhydrase inhibitors. Inhibition of the transmembrane isozyme XII with sulfonamides-to new target for the design of antitumor and antiglaucoma drugs? Bioorg Med Chem Lett 2005 15 963 969 10.1016/j.bmcl.2004.12.053 15686894 \nLiao SY Ivanov S Ivanova A Ghosh S Cote MA Keefe K Expression of cell surface transmembrane carbonic anhydrase genes CA9 and CA12 in the human eye: overexpression of CA12 (CAXII) in glaucoma J Med Genet 2003 40 257 261 12676895 10.1136/jmg.40.4.257 \nMassaoutis P Goh D Foster PJ Bilateral symptomatic angle closure associated with regular dose of citalopram, an SSRI antidepressant Br J Ophtamology 2007 91 1086 1087 10.1136/bjo.2006.107185 \nMartin XD Malina HZ Brennan MC Hendrickson PH Lichter PR The ciliary body – the third organ found to synthesize indoleamines in humans Eur J Ophthalmol 1992 2 67 72 1379862 \nLograno MD Romano MR Pharmacological characterization of the 5-HT1A, 5-HT2 and 5-HT3 receptors in bovine ciliary muscle Eur J Pharmacol 2003 464 69 74 10.1016/S0014-2999(03)01320-7 12600697 \nMeyer-Bothling U Bron AJ Osborne NN Topical application of serotonin or the 5-HT1-agonist 5-CT intraocular pressure in rabbits Invest Ophthalmol Vis Ski 1993 34 3035 3042 \nCostagliola C Mastropasqua L Streado L Fluoxetine oral administration increases intraocular pressure Br J Opthalmol 1996 80 678 10.1136/bjo.80.7.678 \nBrosen K Naranjo CA Review of pharmacokinetic and pharmacodynamic interaction studies with citalopram European Neuropsychopharmacology 2001 11 275 283 10.1016/S0924-977X(01)00101-8 11532381 \nSabers A Pharmacokinetic interactions between contraceptives and antiepileptic drugs Seizure 2008 17 141 144 10.1016/j.seizure.2007.11.012 18206393 \nCostagliola C Parmeggiani F Sebastiani A SSRIs and intraocular pressure modifications: evidence, therapeutic implications and possible mechanisms CNS Drugs 2004 18 475 484 10.2165/00023210-200418080-00001 15182218\n\n",
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"title": "Topiramate-associated acute glaucoma in a migraine patient receiving concomitant citalopram therapy: a case-report.",
"title_normalized": "topiramate associated acute glaucoma in a migraine patient receiving concomitant citalopram therapy a case report"
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"abstract": "BACKGROUND\nParaneoplastic movement disorders in prostate cancer are rare, and to our knowledge paraneoplastic myoclonus has not previously been reported.\n\n\nMETHODS\nWe report two men with adenocarcinoma of the prostate who developed isolated alcohol-responsive action myoclonus of one leg. Myoclonus was absent at rest but triggered by movement, standing, or walking. Evaluations excluded malignant invasion of the nervous system, and testing for commercial paraneoplastic antibodies in serum and cerebrospinal fluid were unrevealing. Both patients experienced significant improvement with alcohol, and sodium oxybate was used in one patient with good initial benefit.\n\n\nCONCLUSIONS\nAlcohol-responsive leg myoclonus might be a novel paraneoplastic syndrome associated with prostate cancer. The nature of the syndrome and the source of the myoclonus are currently unknown.",
"affiliations": "Movement Disorder Division, Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Neurology Division, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.;Movement Disorder Division, Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.",
"authors": "Termsarasab|Pichet|P|;Frucht|Steven J|SJ|",
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"fulltext": "\n==== Front\nTremor Other Hyperkinet Mov (N Y)Tremor Other Hyperkinet Mov (N Y)TOHMTremor and Other Hyperkinetic Movements2160-8288Columbia University Libraries/Information Services 10.7916/D80G3JSXCase ReportsAlcohol-responsive Action Myoclonus of the Leg in Prostate Cancer: A Novel Paraneoplastic Syndrome? Alcohol-responsive Action Myoclonus of the Leg in Prostate CancerTermsarasab Pichet 12*Frucht Steven J. 11 Movement Disorder Division, Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA2 Neurology Division, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, ThailandLouis Elan D. Yale University, USA*To whom correspondence should be addressed. E-mail: pichetterm@gmail.com2015 22 12 2015 5 35714 10 2015 16 11 2015 2015Termsarasab et al.This is an open-access article distributed under the terms of the Creative Commons Attribution–Noncommerical–No Derivatives License, which permits the user to copy, distribute, and transmit the work provided that the original author and source are credited; that no commercial use is made of the work; and that the work is not altered or transformed.Background\nParaneoplastic movement disorders in prostate cancer are rare, and to our knowledge paraneoplastic myoclonus has not previously been reported.\n\nCase Report\nWe report two men with adenocarcinoma of the prostate who developed isolated alcohol-responsive action myoclonus of one leg. Myoclonus was absent at rest but triggered by movement, standing, or walking. Evaluations excluded malignant invasion of the nervous system, and testing for commercial paraneoplastic antibodies in serum and cerebrospinal fluid were unrevealing. Both patients experienced significant improvement with alcohol, and sodium oxybate was used in one patient with good initial benefit.\n\nDiscussion\nAlcohol-responsive leg myoclonus might be a novel paraneoplastic syndrome associated with prostate cancer. The nature of the syndrome and the source of the myoclonus are currently unknown.\n\nMyoclonusprostate cancerparaneoplasticmovement disorders\n==== Body\nIntroduction\nNeurologic complications of prostate cancer may be related directly to the cancer, to metastatic disease, or to the side effects of treatment. Paraneoplastic syndromes associated with prostate cancer are quite rare, and include endocrinologic, hematologic, dermatologic, inflammatory, hepatobiliary, and neurologic syndromes.1 Neurologic paraneoplastic movement disorders (PMDs) associated with prostate cancer are even rarer, and these include ataxia secondary to paraneoplastic cerebellar degeneration, ataxia associated with limbic encephalitis, and myoclonus in limbic encephalitis and brainstem syndromes.\n\nHere we describe two very unusual patients with prostate cancer, with remarkably similar alcohol-responsive unilateral leg action myoclonus. Alternative explanations for this unusual movement disorder (metastatic disease, known paraneoplastic syndrome) were excluded. We propose the possibility that these patients represent a novel paraneoplastic syndrome associated with prostate cancer.\n\nCase reports\nPatient 1\nA 74-year-old man was diagnosed with prostate cancer in 2010 and underwent an uncomplicated laparoscopic prostatectomy. Histopathologic examination revealed adenocarcinoma, and abiraterone acetate in combination with prednisone was started for treatment. Three weeks after surgery, he became aware of jerking movements of the left foot and ankle triggered by movement or weight bearing. Two months after surgery he developed similar jerking of the right proximal leg, which then became much more prominent. Movements were triggered by moving the right leg against resistance and by walking, requiring use of a walker. On examination, muscle tone, strength, sensation, and reflexes were normal, and there was no myoclonus at rest or with stimulus. On attempting to use the right leg to resist the examiner or to stand, he developed significant action myoclonus (Video 1, Segment 1), and he could walk only with assistance. We did not observe myoclonus of the left leg. An extensive evaluation including magnetic resonance imaging (MRI) of the brain and total spine, serum erythrocyte sedimentation rate (ESR), white blood cell and protein in cerebrospinal fluid (CSF; personal communication with his outside neuro-oncologist and neurologist), CSF studies for malignancy, and commercially available paraneoplastic antibody testing was unremarkable. An overnight ambulatory electroencephalography (EEG) was also normal. Intravenous steroids (methylprednisolone 1 g/day for a total of 5 days) produced a transient benefit in myoclonus, but intravenous immunoglobulin (IVIG; 2 g/kg/course) did not help at all. A combination of levetiracetam (2,000 mg/day) and clonazepam (0.5 mg/day; he developed sedation at higher doses) provided only modest benefit.\n\nHe discovered on his own that the movements were attenuated when drinking alcohol, and in fact reported that he was able to walk without using his walker when he ingested two stiff drinks of Scotch. This fact prompted us to start sodium oxybate as a symptomatic therapy (titrated up to 3 g/day), with moderate improvement noted in a dose-dependent fashion (Video 1, Segment 2). Four years after his original diagnosis he eventually succumbed to metastatic prostate cancer.\n\nVideo 1 Patient 1 before and 1 Month after Initiation of Sodium Oxybate. Segment 1. Pre-sodium Oxybate. The examination in Segment 1 was performed 2 years after the onset of myoclonus. In this segment, myoclonus of the right leg, not present at rest, emerged when the patient stretched his leg out in a seated position. The myoclonus was prominent and mainly generated from the proximal leg. It was also present when standing and walking, and limited his ability to perform these activities. Bearing weight on the right foot (such as when standing on the right foot only) also triggered the myoclonus. After this visit, sodium oxybate was initiated and titrated up to 1.5 g twice a day. He had moderate benefit in dose-dependent fashion (not shown in the video at the lower dose). Segment 2. After Initiation of Sodium Oxybate. Segment 2 demonstrates Patient 1 after taking sodium oxybate for 1 month. The examination was performed 2 hours after the last dose. Myoclonic jerks of the right leg were moderately improved, and his ability to perform daily activities improved as well. He was able to walk independently, but still required his wife by his side due to fear of falling.\nPatient 2\nA 76-year-old male presented for evaluation of involuntary movements of the left leg. He had been diagnosed with metastatic adenocarcinoma of the prostate with diffuse bony metastases 2 years previously and had been treated with leuprolide. He did not undergo any surgical intervention or local radiation. One year after the cancer diagnosis, he developed involuntary jerking movements of the left leg, especially around the hip joint. Movements were triggered by moving the leg when seated, and especially by attempting to stand. Because of the severity of the movements he was confined to a wheelchair for 6 months. Imaging of the spine and CSF examination revealed no evidence of metastatic disease. Serum ESR and CSF white blood cell count and protein were within normal limits (personal communication with his outside neuro-oncologist and neurologist). Serum and CSF commercial testing for known paraneoplastic antibodies was negative. He had been treated with IVIG 2 g/kg/course) without apparent benefit. On examination, there was no myoclonus at rest or with stimuli. Violent action myoclonus of the left leg was generated when he attempted to move the leg while in the chair, and was especially noticeable when he tried to stand (Video 2, Segment 1). His neurologic examination was otherwise notable only for 3+ reflexes in both knees and ankles with crossed adductor signs.\n\nVideo 2 Patient 2. Segment 1. The Examination Performed 1 Year after the Onset of Myoclonus (2 Years after the Diagnosis of Prostate Cancer). There was no myoclonus at rest. When he pushed the left thigh or extended the left knee against the examiner’s hand, prominent myoclonic jerks of the left leg emerged, especially from the proximal region around the hip joint. In one part of the video, he attempted to counter the jerks with his right leg. Upon arising from the chair and standing, myoclonic jerks of the left proximal leg became prominent leading to difficulty performing these activities and walking. Segment 2. Home Video Demonstrating Walking Immediately after Ingesting Two Glasses of Wine. Although walking with his walker, mild intermittent myoclonus of the left leg, mainly generated from the proximal region, was present; however, he was able to ambulate.\nGiven our prior therapeutic experience in Patient 1, we suggested that he try a small amount of alcohol to evaluate his level of response. His myoclonus was markedly improved with alcohol (Video 2, Segment 2). Unfortunately, we were unable to obtain insurance approval for sodium oxybate, and a therapeutic trial could not be attempted.\n\nDiscussion\nWe present two unusual patients with almost identical phenomenologies in the setting of prostate cancer. Common clinical features included unilateral action myoclonus of one leg triggered by movements such as standing or walking. Both patients experienced significant improvement with alcohol, and sodium oxybate was used in one patient (up to 3 g/day) with good initial benefit. Patient 1 also tried a combination of levetiracetam 2,000 mg/day and clonazepam 1.25 mg/day with only modest benefit, intravenous methylprednisolone 1 g/day for a total of 5 days with only transient benefit, and IVIG 2 g/kg/course without benefit. Extensive work up for neoplastic or known paraneoplastic syndromes was negative. No clear evidence of inflammation in serum or CSF was found in our patients.\n\nWe postulate that the myoclonus in our patients was likely spinal in origin. Although electrophysiologic testing was not available, their clinical features support this possibility. Myoclonus that is localized to only one limb, affects the leg, is proximal rather than distal, and is stimulus-insensitive supports a spinal rather than a cortical origin. In addition, there were no associated cortical findings on examination. The distribution of myoclonus did not follow a nerve root or peripheral nerve pattern, and the relatively widespread distribution of muscles involved argues against a peripheral generator in a root or plexus trunk.\n\nAn interesting clinical feature in our patients was their robust response to alcohol. While immunotherapies were disappointing, myoclonus in both patients markedly improved immediately after drinking alcohol. This may be attributed to alcohol’s enhancement of the effect of γ-aminobutyric acid, a major inhibitory neurotransmitter.2 Of note, alcohol responsivity is a feature of other forms of subcortical myoclonus, including myoclonus–dystonia syndrome (DYT11) and subcortical posthypoxic myoclonus, as well as essential tremor and spasmodic dysphonia, among others.3–5 Administration of sodium oxybate, a derivative of γ-hydroxybutyric acid, as a symptomatic therapy in alcohol-responsive movement disorders has been studied.3–5 Patient 1 had moderate improvement noted in a dose-dependent fashion.\n\nWhile we cannot prove a paraneoplastic etiology, we believe that it is unlikely that the identical phenotypes and histories of prostate cancer in our patients are coincidental. The myoclonus in Patient 1 is not well explained as a surgical-related complication for several reasons: 1) the laparoscopic surgery was uncomplicated and the site of surgery was relatively distant from the lumbar plexus, nerve roots, or spinal cord; 2) the onset of myoclonus was subacute (3 weeks after the surgical procedure), rather than acute in the immediate postoperative period; 3) Patient 2 with identical phenotypes had not undergone any previous prostate surgery. Although focal neuropathies or neurapraxia involving the ulnar, median, obturator, and femoral nerves, as well as the lumbosacral plexus have been reported after laparoscopic prostatectomy,6–8 the subacute presentation and distribution of myoclonus in Patient 1 argues against these causes.\n\nOf note, a focal neurologic presentation does not exclude the possibility of paraneoplastic etiology as demonstrated in several reports, for example, in cases of paraneoplastic spinal segmental myoclonus or paraneoplastic stiff limb syndrome.9,10 To our knowledge, myoclonus has never been reported to be a side effect of abiraterone acetate or leuprolide. In addition, there was no clear temporal relationship between the initiation of these medications and the onset of myoclonus in our patients. The other medications in Patient 1 including levetiracetam and clonazepam are in fact anti-myoclonic agents, and unlikely to cause myoclonus.\n\nLack of evidence of inflammation in the CSF also does not exclude the possibility of paraneoplastic neurologic syndrome. Psimaras et al.11 found no inflammatory CSF in 7% of 295 patients in their series. Malter et al.12 described 123 of 304 and 89 of 298 patients with selected autoimmune neurologic syndromes in their series. Although serum ESR is frequently checked in clinical practice in patients with suspected paraneoplastic syndromes, it may not be a sensitive marker for central nervous system (CNS) inflammation as the process may confine to the CNS. N-methyl-d-aspartate (NMDA) encephalitis is one example where evidence of the peripheral inflammatory process may be absent on clinical investigations.13\n\nUnfortunately, there is currently no true gold standard in the diagnosis of paraneoplastic neurologic syndrome. Clinicians typically confirm the diagnosis by the presence of previously described antibodies, classic neurologic syndromes, and cancers.14 This method, while it can be feasibly applied to clinical practice, may limit the diagnosis of novel paraneoplastic syndromes. Immunopathological identification of antigenic targets in a human brain or spinal cord may be performed on a research basis, but not in routine clinical practice. With no proven gold standard or more immunological techniques to confirm the paraneoplastic etiology in our cases, we would not prematurely exclude the possibility of paraneoplastic neurologic syndrome based on the lack of inflammatory evidence in the CSF since this will limit the opportunity of further discovery of novel antibodies related to this potential paraneoplastic syndrome.\n\nPMDs associated with prostate cancer are reviewed in Table 1. The most common neurologic complications of prostate cancer, 19% in one large series,15 are due to metastasis to the vertebrae and their neighboring structures through venous drainage of the lower paravertebral plexus (Batson’s plexus) leading to spinal cord or nerve root compression.16 Brain metastases are rare in prostate cancer.16 Paraneoplastic syndromes related to prostate cancer can involve neurologic, endocrinologic, hematologic, inflammatory, and hepatobiliary systems. Among the paraneoplastic neurologic syndromes reported are limbic encephalitis, neuropathy (anti-Hu reported in one case), brainstem syndromes, cerebellar degeneration, and Lambert–Eaton myasthenic syndrome (LEMS) with or without cerebellar degeneration (anti-voltage-gated calcium channel [anti-VGCC] reported in LEMS with cerebellar degeneration).1 Antibodies to exact targets were discovered in only some cases.\n\n\nTable 1 Paraneoplastic Movement Disorders (PMD) in Prostate Cancer\nReference\tPhenomenology\tNeurologic Syndrome\tAge (yrs)\tT Dx→Syn (yrs)\tTumor Stage\tTumor Histopath\tAntibody (Site of Sample)\tTreatment1 (Response)\tOutcome\t\nOur case (Patient 1), 2015\tMyoclonus—action, rt leg\tAlcohol-responsive action myoclonus of the leg\t74\t0.1 (3 wks)\tMetastatic disease\tAdeno\tUnknown (serum and CSF)\tIVMP (only transient benefit), IVIG (no); combination of Aza, LEV, CLZ (modest); sod oxybate (mod but less over time)\tInitially stable but died 6 years after tumor diagnosis due to metastatic prostate cancer\t\nOur case (Patient 2), 2015\tMyoclonus—action, lt leg\tAlcohol-responsive action myoclonus of the leg\t76\t1\tDiffuse bony metastasis\tAdeno\tUnknown(serum and CSF)\tIVIG (no)\tStable neurologic sx\t\nBaloh et al.17\tMyoclonus—face, masseter, pharyngeal and abdominal muscles\tBrainstem syndrome—progressive loss of voluntary horizontal eye mvmts, dysphagia\t71\t1\tRetroperitoneal pelvic mass contiguous with the prostate but no evidence of the tumor at other sites\tAdeno\tUnknown\tRx of the cancer by bil orchiectomy; CLZ and VPA (mod); PLEx (no)\tDied of aspiration 3 years after tumor diagnosis\t\nBaloh et al.17\tContinuous “muscle spasms”—rt face → both sides of face → pharyngeal and laryngeal muscles; mild gait ataxia\tBrainstem syndrome—progressive loss of voluntary horizontal eye mvmts with relatively preserved vertical eye mvmts\t66\t5\tMultiple pelvic lymphadenopathies but negative bone scan\tAdeno\tUnknown\tDZP, VPA, baclofen LZP (modest with all); BoNT (“some relief”)\tVentilator-dependent; committed suicide 2 yrs after the onset\t\nModrego et al.18\tMyoclonus—generalized, developed later\tLimbic encephalitis—disorientation, incoherent, non-fluent speech, unstable gait\t74\t−0.1 (1 mo)\tTumor invaded the prostatic capsule and spread to the rectal wall\tAdeno\tUnknown\tRx of the 1° tumor only\tDied within 2–3 mo after the onset of limbic encephalitis, thought to be due to pneumonia\t\nMcLoughlin et al.19\tAtaxia—trunk\tCerebellar syndrome—rapidly progressive; pseudobulbar palsy, diplopia, transient migratory paresis of rt inferior rectus, rotatory nystagmus\t67\t0.25 (3 mo)\tT3NxM02\t“Poorly differentiated”\tUnknown\tRx of the 1° tumor only\tStable cerebellar syndrome; progression of eye mvmts, thought to be “opsoclonus myoclonus”\t\nClouston et al. 20\tAtaxia—trunk and gait\tCerebellar syndrome—subacute, cerebellar atrophy on neuroimaging LEMS\t68\t5\tBony metastasis of the pelvis 2 years after the original tumor diagnosis, and later to L2 and L3 vertebral bodies\tOriginally adeno; small-cell ca on repeat biopsy 5 yrs later\tAnti-VGCC (serum)\tRecurrent cancer was treated with bil orchiectomy; corticosteroids, PLEx and guanidine HCl (all no)\tStable neurologic sx → rapid deterioration after hepatic metastasis 6 mo after the recurrence\t\nMatschke et al.21\tAtaxia—limbs and gait\tCerebellar syndrome—unsteadiness, scanning dysarthria, nystagmus, saccadic dysmetria\t79\t−0.5 (6 mo)\tT4N1M1\tAdeno with focal neuroendocrine differentiation\tAnti-Yo (or anti-PCA1; serum and CSF)\tNone\tDeteriorated rapidly and died of heart failure within one week after admission\t\nIorio et al.22\tAtaxia—gait\tCerebellar syndrome—cerebellar speech, nystagmus\t65\t1.5\tT3aN0Mx\tAdeno\tAnti-mGluR1 (serum and CSF)\tA course of IVIG (good) followed by oral prednisone (1 mg/kg/day) and monthly IVIG\tContinued to improve on 9-mo follow up\t\nAliprandi et al.23\tAtaxia—limbs and gait\tCerebellar syndrome—progressive dysarthria\t80\t−0.8 (10 mo)\tNo evidence of extracapsular dissemination\tAdeno\tAnti-CV2/CRMP5 (serum)\tIVIG (2 courses; on Dx [modest] and 3 mo later [no]); Rx of the 1° tumor with bicalutamide and tamoxifen\tRemained markedly impaired despite the 2nd course of IVIG and no progression of underlying malignancy\t\nStern and Hulette24\tAtaxia—trunk\tLimbic encephalitisCerebellar syndrome\t76\t−0.1 (1 mo)\tN/A\tSmall cell ca with a minor component of adeno\tUnknown (negative anti-Hu, anti-Ri and anti-Yo)\tNone\tDied 12 days after admission\t\nJakobsen et al.25\tAtaxia\tLimbic encephalitis—marked short-term memory impairment, personality changes, seizures, diplopia\t64\t−0.1 (1 mo)\tT3bN0M0\tAdeno\tAnti-Hu (ANNA-1; CSF)\tIVMP (500 mg/day) for unknown duration, IVIG and PLEx; Rx of the 1° tumor incl palliative external beam XRT\tDied 6 mo after the onset of limbic encephalitis\t\nBerger et al.26\tAtaxia—gait\tRecurrent brainstem syndrome—ophthalmoplegia, dysarthria, dysphagia, facial pruritus, facial numbness; leg stiffness\t59\t−0.7 (8 mo)\tN/A but no evidence of metastasis\tN/A\tIntraneuronal Abs (serum and CSF) but unknown exact Ag\tIVIG and IVMP (good initially, but no after the last recurrence; rituximab, IV CTX (no), PLEx (no)\tRituximab led to respiratory arrest; leukopenia from CTX\t\nAbbreviations: 1°, Primary; Abs, Antibodies; Adeno, Adenocarcinoma; Ag, Antigen; ANNA1, Anti-neuronal Nuclear Antibody Type 1; Aza, Azathioprine; bil, Bilateral; BoNT, Botulinum Toxin Injections; ca, Carcinoma; CLZ, Clonazepam; CSF, Cerebrospinal Fluid; CTX, xxx; CV2/CRMP5, Collapsing Response Mediator Protein 5; DZP, Diazepam; HCl, Hydrochloride; incl, Including; IVIG, Intravenous Immunoglobulin; IVMP, Intravenous Methylprednisolone; LEMS, Lambert–Eaton Myasthenic Syndrome; LEV, Levetiracetam; lt, Left; LZP, Lorazepam; mGluR1, Metabotropic Glutamate Receptor 1; mo, Month(s); mod, Moderate; mvmt(s), Movement(s); N/A, Not Applicable or Information Not Available; PCA1, Purkinje Cell Cytoplasmic Antibody Type 1; PLEx, Plasma Exchange; rt, Right; Rx, Treatment; sod, Sodium; sx, Symptoms; T Dx→Syn, Time from Tumor Diagnosis to the Onset of the Neurologic Syndromes; VGCC, Voltage-gated Calcium Channel; VPA, Valproic Acid; wks, Weeks; XRT, Radiation; yr(s), Year(s).\n\nTable 1. This table demonstrates previously reported cases of PMDs in prostate cancer in the literature, with the addition of our cases (in dark pink). PMDs in prostate cancer are classified based on the phenomenology and neurologic syndromes. Among these cases, two phenomenologies have been reported including myoclonus (in shades of pink) and ataxia (in shades of green). Neurologic syndromes associated with myoclonus include isolated alcohol-responsive unilateral leg action myoclonus (in dark pink), brainstem syndromes (in light pink) and limbic encephalitis (in medium pink), whereas ataxia has been reported in cerebellar syndromes (in light green in the middle of the table), limbic encephalitis (dark green), and recurrent brainstem syndrome (in light green at the bottom).\n\nIn each case, age, time from tumor diagnosis to the onset of the neurologic syndromes (T Dx→Syn, in years), tumor stages, tumor histopathology (histopath), antibodies (with sites from which the samples were obtained), treatments (with responses in parentheses), and outcomes are listed. Note that a negative number of T Dx→Syn indicates that the neurologic syndromes were diagnosed before tumor diagnosis.\n\n1 Treatments to the primary tumor were also given in every patient unless indicated “none” (in one case).\n\n2 This case was staged according to Union for International Cancer Control classification in 1978.\n\n\n\n\nTwo phenomenologies reported in the literature included ataxia (with a greater number of reports) and myoclonus.17–26 Ataxia has been reported in cerebellar syndromes, limbic encephalitis, and brainstem syndromes.19–26 Myoclonus has been reported in one case with a brainstem syndrome (another case in the same report with “continuous muscle spasms”) and one with limbic encephalitis.17,18 Of note, myoclonus is very rare in paraneoplastic syndromes with the exception of opsoclonus–myoclonus syndrome and NMDA encephalitis.27\n\nPMDs may be harbingers of prostate cancer. The neurologic syndrome associated with the PMDs occurred up to 10 months before the diagnosis of prostate cancer, and the most common tumor histopathology was adenocarcinoma. Small cell carcinoma was reported in one PMD case with paraneoplastic cerebellar degeneration. While it has been stated that paraneoplastic syndromes are more common in small cell-type carcinoma,28 our review showed that most PMDs were associated with adenocarcinoma. A VGCC antibody was found in a case with LEMS and cerebellar degeneration.20 Yo or Purkinje cell cytoplasmic antibody type 1 and metabotropic glutamate receptor 1 (mGluR1) and collapsing response mediator protein 5 (CV2/CRMP5) antibodies were found in three other patients with a pure cerebellar syndrome.21–23 One patient with ataxia in the setting of limbic encephalitis had positive anti-Hu antibody (or anti-neuronal nuclear antibody 1, ANNA 1).25 An intraneuronal antibody was identified in one patient with gait ataxia and a recurrent brainstem syndrome; however, the exact antigen is unclear.26 Other patients did not have antibodies that were identified. The failure to identify the exact antigen in our cases does not exclude the possibility of a paraneoplastic syndrome.\n\nWhile treatment of the primary tumor is crucial, immunomodulatory therapies including IVIG, intravenous steroids, and plasma exchange have also been used with variable success: poor responses in cases with anti-Hu and anti-Yo (and our cases);21,25 initially good but non-sustained responses in cases with anti-CV2/CRMP5 and unidentified intraneuronal antibodies;23,26 and sustained responses in cases with anti-mGluR1.22 These findings may indicate a poor response for cell-mediated processes to intraneuronal/onconeuronal antigens (such as Hu, Yo, and CV2/CRMP5), and a better response to antibody-mediated processes to cell surface receptor antigens (such as mGluR1).\n\nFor symptomatic treatment of myoclonus, diazepam and valproic acid were employed in one brainstem syndrome case with moderate benefit.17 Our patient (Patient 1) had modest benefit from a combination of azathioprine, levetiracetam, and clonazepam. To our knowledge, alcohol responsivity has never been reported in PMD associated with prostate cancer. It is our hope that this paper will engender future reports of similar phenomena.\n\nFunding: None.\n\nFinancial Disclosures: None.\n\nConflict of Interest: The authors report no conflict of interest.\n\nEthics Statement: This study was performed in accordance with the ethical standards detailed in the Declaration of Helsinki. Written informed consent was obtained from the patients 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==== Refs\nReferences\n1 Hong MK Kong J Namdarian B Paraneoplastic syndromes in prostate cancer Nat Rev Urol 2010 7 681 692 doi: http://dx.doi.org/10.1038/nrurol.2010.186 21139643 \n2 Davies M The role of GABAA receptors in mediating the effects of alcohol in the central nervous system J Psychiatry Neurosci 2003 28 263 274 12921221 \n3 Kirke DN Frucht SJ Simonyan K Alcohol responsiveness in laryngeal dystonia: A survey study J Neurol 2015 262 1548 1556 doi:http://dx.doi.org/10.1007/s00415-015-7751-2 25929664 \n4 Frucht SJ Houghton WC Bordelon Y Greene PE Louis ED A single-blind, open-label trial of sodium oxybate for myoclonus and essential tremor Neurology 2005 65 1967 1969 doi: http://dx.doi.org/10.1212/01.wnl.0000188670.38576.bd 16382538 \n5 Frucht SJ Bordelon Y Houghton WH Reardan D A pilot tolerability and efficacy trial of sodium oxybate in ethanol-responsive movement disorders Mov Disord 2005 20 1330 1337 doi: http://dx.doi.org/10.1002/mds.20605 15986420 \n6 Saidha S Spillane J Mullins G McNamara B Spectrum of peripheral neuropathies associated with surgical interventions; A neurophysiological assessment J Brachial Plex Peripher Nerve Inj 2010 5 9 doi: http://dx.doi.org/10.1186/1749-7221-5-9 20398427 \n7 Hu JC Nelson RA Wilson TG Perioperative complications of laparoscopic and robotic assisted laparoscopic radical prostatectomy J Urol 2006 175 541 546 discussion 546, doi: http://dx.doi.org/10.1016/S0022-5347(05)00156-4 16406991 \n8 Guillonneau B Rozet F Cathelineau X Perioperative complications of laparoscopic radical prostatectomy: The Montsouris 3-year experience J Urol 2002 167 51 56 doi: http://dx.doi.org/10.1016/S0022-5347(05)65381-5 11743274 \n9 Roobol TH Kazzaz BA Vecht CJ Segmental rigidity and spinal myoclonus as a paraneoplastic syndrome J Neurol Neurosurg Psychiatry 1987 50 628 631 doi: http://dx.doi.org/10.1136/jnnp.50.5.628 3035105 \n10 Silverman IE Paraneoplastic stiff limb syndrome J Neurol Neurosurg Psychiatry 1999 67 126 127 doi: http://dx.doi.org/10.1136/jnnp.67.1.126 10454877 \n11 Psimaras D Carpentier AF Rossi C Euronetwork PNS Cerebrospinal fluid study in paraneoplastic syndromes J Neurol Neurosurg Psychiatry 2010 81 42 45 doi: http://dx.doi.org/10.1136/jnnp.2008.159483 19324868 \n12 Malter MP Elger CE Surges R Diagnostic value of CSF findings in antibody-associated limbic and anti-NMDAR-encephalitis Seizure 2013 22 136 140 doi: http://dx.doi.org/10.1016/j.seizure.2012.12.013 23318046 \n13 Dalmau J Lancaster E Martinez-Hernandez E Rosenfeld MR Balice-Gordon R Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis Lancet Neurol 2011 10 63 74 doi: http://dx.doi.org/10.1016/S1474-4422(10)70253-2 21163445 \n14 Dalmau J Rosenfeld MR Paraneoplastic syndromes of the CNS Lancet Neurol 2008 7 327 340 doi: http://dx.doi.org/10.1016/S1474-4422(08)70060-7 18339348 \n15 Bach F Larsen BH Rohde K Metastatic spinal cord compression. Occurrence, symptoms, clinical presentations and prognosis in 398 patients with spinal cord compression Acta Neurochir (Wien) 1990 107 37 43 2096606 \n16 Benjamin R Neurologic complications of prostate cancer Am Fam Physician 2002 65 1834 1840 12018806 \n17 Baloh RW DeRossett SE Cloughesy TF Novel brainstem syndrome associated with prostate carcinoma Neurology 1993 43 2591 2596 doi: http://dx.doi.org/10.1212/WNL.43.12.2591 8255462 \n18 Modrego PJ Cay A Pina MA Monge A Paraneoplastic subacute encephalitis caused by adenocarcinoma of prostate: A clinico-pathological case report Acta Neurol Scand 2002 105 351 353 doi: http://dx.doi.org/10.1034/j.1600-0404.2002.1l227.x 11939955 \n19 McLoughlin J Gingell JC Harper G Hinchliffe A Cerebellar manifestations of prostatic carcinoma Postgrad Med J 1992 68 584 586 doi: http://dx.doi.org/10.1136/pgmj.68.801.584 1437959 \n20 Clouston PD Saper CB Arbizu T Paraneoplastic cerebellar degeneration. III. Cerebellar degeneration, cancer, and the Lambert-Eaton myasthenic syndrome Neurology 1992 42 1944 1950 1407577 \n21 Matschke J Kromminga A Erbersdobler A Lamszus K Anders S Kofuncu E Paraneoplastic cerebellar degeneration and anti-Yo antibodies in a man with prostatic adenocarcinoma J Neurol Neurosurg Psychiatry 2007 78 775 777 doi: http://dx.doi.org/10.1136/jnnp.2006.112961 17189300 \n22 Iorio R Damato V Mirabella M Cerebellar degeneration associated with mGluR1 autoantibodies as a paraneoplastic manifestation of prostate adenocarcinoma J Neuroimmunol 2013 263 155 158 doi: http://dx.doi.org/10.1016/j.jneuroim.2013.07.015 23958353 \n23 Aliprandi A Terruzzi A Rigamonti A Paraneoplastic cerebellar degeneration with anti-CV2/CRMP5 antibodies and prostate adenocarcinoma Neurol Sci 2015 36 1501 1503 doi: http://dx.doi.org/10.1007/s10072-015-2113-5 25686614 \n24 Stern RC Hulette CM Paraneoplastic limbic encephalitis associated with small cell carcinoma of the prostate Mod Pathol 1999 12 814 818 10463484 \n25 Jakobsen JK Zakharia ER Boysen AK Andersen H Schlesinger FE Lund L Prostate cancer may trigger paraneoplastic limbic encephalitis: A case report and a review of the literature Int J Urol 2013 20 734 737 doi: http://dx.doi.org/10.1111/iju.12030 23186204 \n26 Berger JR Bensalem M Dalmau J A brainstem paraneoplastic syndrome associated with prostate cancer J Neurol Neurosurg Psychiatry 2009 80 934 935 doi: http://dx.doi.org/10.1136/jnnp.2008.153015 19608787 \n27 Dalmau J Rosenfeld MR Paraneoplastic syndromes causing movement disorders Handb Clin Neurol 2011 100 315 321 doi: http://dx.doi.org/10.1016/B978-0-444-52014-2.00024-0 21496591 \n28 Palmgren JS Karavadia SS Wakefield MR Unusual and under-appreciated: Small cell carcinoma of the prostate Semin Oncol 2007 34 22 29 doi: http://dx.doi.org/10.1053/j.seminoncol.2006.10.026 17270662\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2160-8288",
"issue": "5()",
"journal": "Tremor and other hyperkinetic movements (New York, N.Y.)",
"keywords": "Myoclonus; movement disorders; paraneoplastic; prostate cancer",
"medline_ta": "Tremor Other Hyperkinet Mov (N Y)",
"mesh_terms": null,
"nlm_unique_id": "101569493",
"other_id": null,
"pages": "357",
"pmc": null,
"pmid": "26759739",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": "20398427;12921221;8255462;11939955;16406991;12018806;2096606;16382538;17270662;23318046;15986420;19608787;25686614;18339348;21163445;3035105;21496591;23186204;23958353;25929664;10454877;1437959;21139643;19324868;1407577;17189300;10463484;11743274",
"title": "Alcohol-responsive Action Myoclonus of the Leg in Prostate Cancer: A Novel Paraneoplastic Syndrome?",
"title_normalized": "alcohol responsive action myoclonus of the leg in prostate cancer a novel paraneoplastic syndrome"
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"abstract": "BACKGROUND\n: INNO-406, a dual v-abl Abelson murine leukemia viral oncogene homolog (Abl)/v-yes-1 Yamaguchi sarcoma viral-related oncogene homolog (Lyn) tyrosine kinase inhibitor (TKI), has demonstrated specific Lyn kinase inhibitory activity with no or limited activity against other sarcoma (Src) family member kinases. Several breakpoint cluster region (Bcr)-Abl kinase domain mutations are sensitive to INNO-406 in vitro, including mutations that involve a phenylalanine-to-leucine or phenylalanine-to-valine substitution at codon 317 (F317L and F317V, respectively). In the current study, the authors evaluated the use of INNO-406 in patients with Philadelphia (Ph) chromosome-positive chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) after imatinib resistance or intolerance.\n\n\nMETHODS\n: A dose-escalation study was conducted at a starting dose of oral INNO-406 30 mg once daily. Cohorts of at least 3 patients were treated at each dose level until the maximum tolerated dose (MTD) was reached. Twice-daily dosing also was evaluated. Therapy was allowed to continue for a maximum of 24 months.\n\n\nRESULTS\n: INNO-406 was administered to 56 patients with imatinib resistance (n = 40) or intolerance (n = 16). Other previous treatments included nilotinib (n = 20 patients), dasatinib (n = 26 patients), and dasatinib/nilotinib (n = 9 patients). Common mutations at the time of study entry included a tyrosine-to-histidine substitution at codon 253 (Y253H) (n = 6 patients), a glycine-to-glutamic acid substitution at codon 250 (G250E) (n = 4 patients), a threonine-to-isoleucine substitution at codon 315 (T315I) (n = 4 patients), and F317L (n = 3 patients). Of 31 patients with CML in chronic phase who received INNO-406, the major cytogenetic response rate was 19%. No responses were observed in patients who had CML in accelerated phase, CML in blastic phase, or Ph-positive ALL. The dose-limiting toxicities (DLTs) at an INNO-406 dose of 480 mg twice daily were liver function abnormalities and thrombocytopenia.\n\n\nCONCLUSIONS\n: INNO-406 had anti-CML efficacy in a heavily pretreated study population. On the basis of the classic determinations of both DLT and MTD, the recommended phase 2 dose of oral INNO-406 was 240 mg twice daily. Lower doses of INNO-406 may be equally effective and should be explored.",
"affiliations": "Leukemia Department, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.",
"authors": "Kantarjian|Hagop|H|;le Coutre|Phillipp|P|;Cortes|Jorge|J|;Pinilla-Ibarz|Javier|J|;Nagler|Arnon|A|;Hochhaus|Andreas|A|;Kimura|Shinya|S|;Ottmann|Oliver|O|",
"chemical_list": "D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C506918:bafetinib",
"country": "United States",
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"doi": "10.1002/cncr.25079",
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"issn_linking": "0008-543X",
"issue": "116(11)",
"journal": "Cancer",
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"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D001549:Benzamides; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D008875:Middle Aged; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines",
"nlm_unique_id": "0374236",
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"pages": "2665-72",
"pmc": null,
"pmid": "20310049",
"pubdate": "2010-06-01",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural",
"references": "11423618;14534339;10403855;19662183;17138817;18759691;18287387;15215876;18603549;16775235;16105974;18191450;17179059;18223278;16954504;17151364;4957125;18024653;15169981;16642048;17431887;16316612;17715389;16775234",
"title": "Phase 1 study of INNO-406, a dual Abl/Lyn kinase inhibitor, in Philadelphia chromosome-positive leukemias after imatinib resistance or intolerance.",
"title_normalized": "phase 1 study of inno 406 a dual abl lyn kinase inhibitor in philadelphia chromosome positive leukemias after imatinib resistance or intolerance"
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"abstract": "Head and neck cancer is a diverse group of rare diseases such as neuroendocrine tumors which can be thought of as extrapulmonary small-cell cancer. Surgery, chemotherapy, and radiation can frequently cure this disease, possibly due to early detection.",
"affiliations": "Department of Medicine UT Southwestern Medical Center Dallas Texas.;Division of Hematology and Oncology/Harold C. Simmons Comprehensive Cancer Center UT Southwestern Medical Center Dallas Texas.;Department of Pathology UT Southwestern Medical Center Dallas Texas.;Department of Clinical Sciences UT Southwestern Medical Center Dallas Texas.;Department of Otolaryngology UT Southwestern Medical Center Dallas Texas.;Department of Otolaryngology UT Southwestern Medical Center Dallas Texas.;Department of Otolaryngology UT Southwestern Medical Center Dallas Texas.;Department of Radiation Oncology UT Southwestern Medical Center Dallas Texas.;Department of Radiation Oncology UT Southwestern Medical Center Dallas Texas.;Division of Hematology and Oncology/Harold C. Simmons Comprehensive Cancer Center UT Southwestern Medical Center Dallas Texas.;Division of Hematology and Oncology/Harold C. Simmons Comprehensive Cancer Center UT Southwestern Medical Center Dallas Texas.",
"authors": "Bacalao|Maria|M|;Beg|Muhammad S|MS|;Cavuoti|Dominick|D|;Zhu|Hong|H|;Sumer|Baran|B|;Myers|Larry|L|;Truelson|John|J|;Nedzi|Lucien|L|;Sher|David|D|;Hughes|Randall|R|;Khan|Saad A|SA|https://orcid.org/0000-0002-3440-9774",
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"doi": "10.1002/ccr3.2545",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.2545CCR32545Case ReportCase ReportsHead and neck neuroendocrine tumors at a single institution over 15 years BACALAO et al.Bacalao Maria \n1\nBeg Muhammad S. \n2\nCavuoti Dominick \n3\nZhu Hong \n4\nSumer Baran \n5\nMyers Larry \n5\nTruelson John \n5\nNedzi Lucien \n6\nSher David \n6\nHughes Randall \n2\nKhan Saad A. https://orcid.org/0000-0002-3440-9774\n2\nSaad.Khan@UTSouthwestern.edu \n1 \nDepartment of Medicine\nUT Southwestern Medical Center\nDallas\nTexas\n\n2 \nDivision of Hematology and Oncology/Harold C. Simmons Comprehensive Cancer Center\nUT Southwestern Medical Center\nDallas\nTexas\n\n3 \nDepartment of Pathology\nUT Southwestern Medical Center\nDallas\nTexas\n\n4 \nDepartment of Clinical Sciences\nUT Southwestern Medical Center\nDallas\nTexas\n\n5 \nDepartment of Otolaryngology\nUT Southwestern Medical Center\nDallas\nTexas\n\n6 \nDepartment of Radiation Oncology\nUT Southwestern Medical Center\nDallas\nTexas\n* Correspondence\n\nSaad A. Khan, Division of Hematology and Oncology/Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390‐8852.\n\nEmail: Saad.Khan@UTSouthwestern.edu\n17 11 2019 12 2019 7 12 10.1002/ccr3.v7.122508 2512 22 8 2019 14 10 2019 15 10 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.Abstract\nHead and neck cancer is a diverse group of rare diseases such as neuroendocrine tumors which can be thought of as extrapulmonary small‐cell cancer. Surgery, chemotherapy, and radiation can frequently cure this disease, possibly due to early detection.\n\nHead and neck cancer is a diverse group of rare diseases such as neuroendocrine tumors which can be thought of as extrapulmonary small‐cell cancer. Surgery, chemotherapy, and radiation can frequently cure this disease, possibly due to early detection.\n\n\nhead and neck cancerlarynx cancerneuroendocrine cancer source-schema-version-number2.0cover-dateDecember 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.7.3 mode:remove_FC converted:29.12.2019\n\n\nBacalao \nM \n, \nBeg \nMS \n, \nCavuoti \nD \n, et al. Head and neck neuroendocrine tumors at a single institution over 15 years . Clin Case Rep . 2019 ;7 :2508 –2512 . 10.1002/ccr3.2545\n==== Body\n1 BACKGROUND\nNeuroendocrine head and neck tumors are rare with limited data guiding management. Our institutional series of 11 patients showed age ranges from 21 to 81 years old. Median survival was 21.3 months. Head and neck neuroendocrine tumors can be seen at the extremes of age, and multimodality management can yield good outcomes.\n\nNeuroendocrine tumors of the head and neck are very rare with unclear optimal management strategies. Out of the 1000 cases of extrapulmonary small‐cell carcinoma diagnosed annually in the United States, approximately 60‐120 are in the head and neck region, but the true incidence is unclear.1 Risk factors are similar to small‐cell lung carcinoma (SCLC), although recent data suggest that there is less of a correlation with cigarette smoking and extrapulmonary small‐cell carcinoma than there is for SCLC.1 In a large case series of extrapulmonary small‐cell tumors, 51% of patients have a history of tobacco use, in comparison with SCLC in which more than 80% of patients have a smoking history.2\n\n\n2 PATHOLOGY\nGrossly, the tumors often arise in a submucosal location.3 Histologically, the cells usually appear small and hyperchromatic with scant cytoplasm, especially in the oat cell type. An intermediate type has been characterized as well, with a similar growth pattern but with more abundant cytoplasm. Areas of necrosis and high mitotic activity are common.3\n\n\nIn young adults, nonhematologic tumors of the head and neck region are rare. We review all cases of head and neck neuroendocrine cancer in the cancer registries of UT Southwestern Medical Center and Parkland Hospital. We report the case of a patient with a neuroendocrine tumor of the larynx and their outcome. To our knowledge, this is the youngest reported case of head and neck neuroendocrine tumor in the literature.\n\n3 CASE\nThe patient is a 21‐year‐old woman who presented with a 6‐month history of progressive hoarseness and dysphagia for solids worse than liquids and a 15 lb weight loss. She had a 3 pack‐year smoking history and did not use alcohol. On physical examination, there was palpable, tender left cervical adenopathy in levels III and IV, largest measuring 2 cm.\n\nComputed Tomography (CT) of the neck showed a locally advanced supraglottic mass extending from the vallecula along the AE folds to the true vocal cords. It eroded the thyroid cartilage and extended into the strap muscles. Biopsy of an enlarged left cervical lymph node showed chromogranin and synaptophysin positivity with a high Ki67; CK 5/6 was negative. The tumor was described as poorly differentiated though no formal grade assigned. The initial diagnosis was unclear and a repeat biopsy of the supraglottic mass showed positivity for CKAE1/AE3 and synaptophysin. It was focally positive for CD99 and negative for chromogranin, CK5/6, SALL4, desmin, and TTF‐1. Stains for CD31 and D2‐40 localized to the lymphovascular spaces. There was no evidence of EWSR1 (22q12) rearrangement. Figures 1 and 2 show biopsies from the liver metastasis and larynx.\n\nFigure 1 H&E stain of liver metastasis at 20× magnification\n\nFigure 2 H&E stain of primary laryngeal tumor at low magnification\n\nCT of the chest did not reveal any suspicious nodularity or evidence of metastases. MRI scan showed multiple liver lesions which on biopsy were consistent with metastatic neuroendocrine carcinoma. She was diagnosed as having a T4N2M1 neuroendocrine tumor of the supraglottis. A tracheostomy tube was placed for airway protection.\n\nShe was started on etoposide and cisplatin, but developed neutropenic fever with negative cultures shortly afterward, later developing intractable nausea and vomiting requiring hospitalization. After 2 cycles, she was switched to carboplatin and etoposide. In spite of these changes, she still could not tolerate chemotherapy. She subsequently developed neutropenic fever, requiring a lowering of the dose and the addition of pegfilgrastim. Repeat CT of the neck conducted shortly before the second carboplatin/etoposide cycle showed that the supraglottic tumor size was unchanged, but that the associated lymphadenopathy at the level 3 lymph nodes had improved. She did not tolerate chemotherapy and discontinued all therapy, expiring shortly thereafter.\n\n4 METHODS\nIRB approval was obtained from the institution for this work. We searched the cancer registries of UT Southwestern and Parkland Memorial Hospital for patients with small‐cell carcinoma or neuroendocrine carcinoma in the head and neck from 1997 to 2014. The overall survival was estimated by the Kaplan‐Meier analysis, and we compared the overall survival between the UT Southwestern University Hospital and Parkland Hospital by the log‐rank test. A P‐value of <.05 indicates the statistical significance. We used Stata software for analysis.\n\n5 RESULTS\nA total of 11 cases of head and neck neuroendocrine tumors were identified: 7 from Parkland Memorial Hospital and 4 from UT Southwestern. Of the Parkland patients, 5 were male and 2 were female, consistent with the male predominance noted in the other case studies and meta‐analyses.2, 4 Although the Parkland system treats many Hispanic patients, only one patient in the series was of Hispanic origin. Most of the patients presented with locoregionally advanced disease, and 3 had metastases present at diagnosis. For treatment, two patients received surgery alone and two received chemotherapy alone. Three patients received combination therapy: one received chemoradiation, another received chemotherapy and surgery, and a third received radiation and surgery. Overall, this represents a higher percentage of patients receiving monotherapy than expected based on these other series, considering the advanced stage of the disease.\n\nAn additional 4 cases were seen from the registry at UT Southwestern. These patients were significantly older (68‐81 years, mean 75) and had less advanced disease. Only 2/4 patients received chemotherapy, and all received surgery, either for an excisional biopsy or definitively. In this dataset, histologic grade of the tumor was not available. At the time of analysis, only the eldest patient had deceased, and others were listed in our registry as living.\n\nOur institutional experience shows that these tumors also occur in other sites such as the parotid and nasopharynx. There was one surviving patient in his early twenties, and the key factor in achieving long‐term survival appeared to be early intervention. Table 1 details the patients that were analyzed.\n\nTable 1 Patients presenting to Parkland and UT Southwestern with small‐cell/neuroendocrine tumor of the head and neck region\n\nAge at diagnosis\tRace\tSex\tPrimary site\tListed AJCC stage\tModality\t1st course Rx summary\tDate of diagnosis to last contact\tVital status\t\nParkland hospital cases\t\n63\tBlack\tM\tGlottis\t4A (T4a N0 M0)\tSmall‐cell carcinoma, NOS\tSurgery, Radiation\t1/6/2013‐05/15/2013\tDeceased (cancer)\t\n68\tBlack\tM\tSupraglottis\t4C (T2 N2c M1)\tSmall‐cell neuroendocrine carcinoma\tChemotherapy\t2/29/12‐11/28/2013\tDeceased (cancer)\t\n56\tWhite\tM\tTonsillar fossa\tNot available\tCombined small‐cell carcinoma\tSurgery, radiation, chemotherapy\t10/26/2001‐07/11/2003\tDeceased (cancer)\t\n47\tWhite\tM\tParotid gland\t4 (T1 N2 M0)\tNeuroendocrine carcinoma, NOS\tSurgery\t6/16/1997‐02/01/2014\tAlive\t\n23\tWhite, Hispanic\tM\tNasal cavity\tNot available\tNeuroendocrine carcinoma, NOS\tRadiation and chemotherapy\t11/12/1999‐07/07/2003\tAlive\t\n21\tWhite\tF\tSupraglottis\t4C (T4a N2 M1)\tNeuroendocrine carcinoma, NOS\tchemotherapy\t5/20/2014‐02/05/2015\tDeceased (cancer)\t\n44\tWhite\tF\tNasal cavity\t4C (T3 N2c M1)\tNeuroendocrine carcinoma, NOS\tSurgery\t4/20/2011‐07/14/2011\tDeceased (cancer)\t\nUT Southwestern cases\t\n81\tWhite\tM\tParotid gland\t4A (T4a N2 M0)\tSmall‐cell carcinoma, NOS\tSurgery\t09/16/2003‐12/18/2003\tDeceased (cancer)\t\n68\tWhite\tF\tNasopharynx\t2 (T1 NX M0)\tAdenocarcinoma with neuroendocrine differentiation\tSurgery, radiation\t02/13/2006‐01/24/2014\tAlive\t\n78\tWhite\tM\tParotid gland\tNot available\tPrimitive neuroectodermal tumor, NOS\tSurgery, radiation, chemotherapy\t12/14/2011‐06/18/2014\tAlive\t\n71\tWhite\tF\tTongue anterior 2/3\t1 (T1 N1 M0)\tNeuroendocrine carcinoma, NOS\tSurgery, radiation, chemotherapy\t01/31/2012‐02/11/2014\tAlive\t\nJohn Wiley & Sons, LtdIn our cohort, the most common site was the parotid gland with 3/11 (27.3%). For all the patients, median overall survival was 21.3 months. Survival did not significantly differ between patients treated at the university compared to Parkland Hospital (log‐rank P = .240). In our limited sample, no statistically significant survival variation was noted by race, primary site, or age.\n\n6 DISCUSSION\nThe biology of neuroendocrine tumors of the head and neck is being better understood, and factors which predict for survival are being recognized. Neuroendocrine tumors show higher levels of hypoxia‐inducible factor 1‐α (HIF‐1α), the cellular glucose uptake transporter (GLUT‐1), and the phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (AKT), which may regulate GLUT‐1 and HIF‐1α6 than precancerous lesions. The prognostic significance of this remains unclear. Known poor prognostic factors include distant metastases6, 7 and ectopic hormone production.6, 8 There does not appear to be a correlation between tumor size or number of mitoses and survival.6, 7\n\n\n7 TREATMENT RECOMMENDATIONS\nThe treatment of extrapulmonary neuroendocrine tumors depends on whether the tumor is resectable, locoregionally advanced but unresectable, or metastatic. Treatment options include surgical resection follow by chemotherapy and/or radiation; but if the tumor is unresectable then chemotherapy and radiation is used. Patients with small‐cell tumors are more likely to receive chemoradiation as the primary treatment modality, while those with other neuroendocrine tumor types are more likely to undergo surgical resection.4 For small‐cell head and neck tumors, chemotherapy with a small‐cell lung cancer regimen such as cisplatin or carboplatin with etoposide is used regardless of whether the tumor is resected as recommended in the NCCN guidelines. A small case series of 14 patients with head and neck small‐cell cancer showed 1 patient receiving surgery alone as treatment,2 while a larger meta‐analysis consisting of patients with laryngeal small‐cell carcinoma showed 14% of such patients receiving surgery alone.4 Radiation therapy plays an important role as well, as a case series of 12 patients from the University of Miami showed a 73% 1‐year survival rate in those receiving radiation or chemoradiation vs 67% in those undergoing other treatment modalities.5 Overall, the most common treatment modality for small‐cell head and neck tumors remains chemoradiation, received by 34.5% of the patients studied by van der Laan.\n\n8 CONCLUSIONS\nHead and neck neuroendocrine tumors remain a rare condition, and therefore, it is unlikely that prospective randomized control trials will ever provide clear guidance as to optimal treatment. However, the reported cases provide retrospective data regarding the epidemiology, treatment, and outcomes of small‐cell carcinoma in the head and neck.\n\nThese tumors respond to the same chemotherapy and radiation regimens used for small‐cell lung cancer. Unlike small‐cell lung cancer, small‐cell head and neck tumors are sometimes managed surgically, though rarely as the sole treatment modality.\n\nFive out of 11 patients were alive at the time of analysis. This better‐than‐expected survival may reflect a more aggressive treatment approach at our institution or a better prognosis compared to other extrapulmonary small cells, perhaps due to earlier opportunities for detection. Even in cases where chemotherapy was not administered, a young patient was still living more than 15 years from diagnosis. Our series provides additional data about this rare disease and how it can affect very young adults as well. The anatomic distribution varied; the parotid was the most commonly involved site. Nearly all patients listed as alive had surgery, though long‐term survival was noted in one case with combined radiation and chemotherapy. This series should also lead to future evaluation of racial predisposition toward neuroendocrine cancer. Though treating doctors at both institutions are the same, 85% of the patient population at Parkland Hospital self‐identifies as an ethnic minority. Out of our 7 patients at Parkland Hospital, 5 were white; while all of the patients in the University Hospital were white. An analysis of head and neck small cases from the SEER‐Medicare database9 found that 86% occurred in white patients.\n\nLimitations of this analysis include those inherent to retrospective studies, such as inability to collect histologic differentiation data in all but the most recent patient. Poorly differentiated neuroendocrine tumors are expected to have worse outcomes, but that information was not available in this analysis.10 The small sample size makes it difficult to develop meaningful conclusions.\n\nThis series represents one of the larger institutional reports on small‐cell neuroendocrine cancer and suggests that with an aggressive multimodality approach, long‐term survival is a possibility.\n\nCONFLICT OF INTEREST\nNone declared.\n\nAUTHOR CONTRIBUTIONS\nAll authors were involved in the following aspects of this work: substantial contribution to the study concept and design or acquisition, analysis, or interpretation of the data, and drafted or critically revised the manuscript's intellectual content. All authors approved the final version for publication and agreed to be accountable for all aspects of the work, as well as ensuring all questions related to accuracy and integrity of this work are appropriately answered.\n==== Refs\nREFERENCES\n1 \n\nWalenkamp \nAME \n, \nSonke \nGS \n, \nSleijfer \nDT \n. Clinical and therapeutic aspects of extrapulmonary small cell carcinoma . Cancer Treat Rev . 2009 ;35 (3 ):228 ‐236 .19068273 \n2 \n\nBrennan \nSM \n, \nGregory \nDL \n, \nStillie \nA \n, \nHerschtal \nA \n, \nMac Manus \nM \n, \nBall \nDL \n. Should extrapulmonary small cell cancer be managed like small cell lung cancer? \nCancer . 2010 ;116 (4 ):888 ‐895 .20052730 \n3 \n\nFerlito \nA \n, \nSilver \nCE \n, \nBradford \nCR \n, \nRinaldo \nA \n. Neuroendocrine neoplasms of the larynx: An overview . Head Neck . 2009 ;31 (12 ):1634 ‐1646 .19536850 \n4 \n\nvan der Laan \nTP \n, \nPlaat \nBEC \n, \nvan der Laan \nBFAM \n, \nHalmos \nGB \n. Clinical recommendations on the treatment of neuroendocrine carcinoma of the larynx: A meta‐analysis of 436 reported cases . Head Neck . 2015 ;37 (5 ):707 ‐715 .24596175 \n5 \n\nHatoum \nGF \n, \nPatton \nB \n, \nTakita \nC \n, \nAbdel-Wahab \nM \n, \nLaFave \nK \n, \nWeed \nD \n, \nReis \nIM \n. Small cell carcinoma of the head and neck: the University of Miami experience . International Journal of Radiation Oncology Biology Physics . 2009 ;74 (2 ):477 ‐481 .\n6 \n\nChai \nL \n, \nYing \nH‐F \n, \nWu \nT‐T \n, et al. Clinical features and hypoxic marker expression of primary sinonasal and laryngeal small‐cell neuroendocrine carcinoma: a small case series . World J Surg Oncol . 2014 ;12 (1 ):199 .24980293 \n7 \n\nGnepp \nDR \n. Small cell neuroendocrine carcinoma of the larynx . ORL J Otorhinolaryngol Relat Spec . 1991 ;53 (4 ):210 ‐219 .1653928 \n8 \n\nFerlito \nA \n, \nRinaldo \nA \n. Paraneoplastic syndromes in patients with cancer of the larynx and hypopharynx . Ann Otol Rhinol Laryngol . 2007 ;12 :502 ‐513 .\n9 \n\nPointer \nKB \n, \nKo \nHC \n, \nBrower \nJV \n, et al. Small cell carcinoma of the head and neck: an analysis of the national cancer database . Oral Oncol . 2017 ;69 :92 ‐98 .28559027 \n10 \n\nMeacham \nR \n, \nMatrka \nL \n, \nOzer \nE \n, \nOzer \nHG \n, \nWakely \nP \n, \nShah \nM \n. Neuroendocrine carcinoma of the head and neck: a 20‐year case series . Ear Nose Throat J . 2012 ;91 (3 ):E20 ‐E24 .\n\n",
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"issn_linking": "2050-0904",
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"medline_ta": "Clin Case Rep",
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"pages": "2508-2512",
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"pubdate": "2019-12",
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"title": "Head and neck neuroendocrine tumors at a single institution over 15 years.",
"title_normalized": "head and neck neuroendocrine tumors at a single institution over 15 years"
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"abstract": "Cytomegalovirus (CMV) reactivation during chemotherapy or after organ or hematopoietic stem cell transplantation is a major cause of morbidity and mortality, and the risk of reactivation increases with patients' age. Bendamustine, an alkylating agent currently used for treatment of indolent and aggressive non-Hodgkin lymphomas, can augment the risk of secondary infections including CMV reactivation. In this real-world study, we described an increased incidence of CMV reactivation in older adults (age >60 years old) with newly diagnosed and relapsed/refractory indolent and aggressive diseases treated with bendamustine-containing regimens. In particular, patients who received bendamustine plus rituximab and dexamethasone were at higher risk of CMV reactivation, especially when administered as first-line therapy and after the third course of bendamustine. In addition, patients with CMV reactivation showed a significant depression of circulating CD4+ T cell count and anti-CMV IgG levels during active infection, suggesting an impairment of immune system functions which are not able to properly face viral reactivation. Therefore, a close and early monitoring of clinical and laboratory findings might improve clinical management and outcome of non-Hodgkin lymphoma patients by preventing the development of CMV disease in a subgroup of subjects treated with bendamustine more susceptible to viral reactivation.",
"affiliations": "Hematology and Transplant Center, University Hospital \"San Giovanni di Dio e Ruggi d'Aragona\", Salerno, 84131, Italy.;Hematology and Transplant Center, University Hospital \"San Giovanni di Dio e Ruggi d'Aragona\", Salerno, 84131, Italy.;Hematology and Transplant Center, University Hospital \"San Giovanni di Dio e Ruggi d'Aragona\", Salerno, 84131, Italy.;Hematology and Transplant Center, University Hospital \"San Giovanni di Dio e Ruggi d'Aragona\", Salerno, 84131, Italy.;Hematology and Transplant Center, University Hospital \"San Giovanni di Dio e Ruggi d'Aragona\", Salerno, 84131, Italy.;Hematology and Transplant Center, University Hospital \"San Giovanni di Dio e Ruggi d'Aragona\", Salerno, 84131, Italy.;Hematology and Transplant Center, University Hospital \"San Giovanni di Dio e Ruggi d'Aragona\", Salerno, 84131, Italy.;Hematology and Transplant Center, University Hospital \"San Giovanni di Dio e Ruggi d'Aragona\", Salerno, 84131, Italy.;Hematology and Transplant Center, University Hospital \"San Giovanni di Dio e Ruggi d'Aragona\", Salerno, 84131, Italy.;Hematology and Transplant Center, University Hospital \"San Giovanni di Dio e Ruggi d'Aragona\", Salerno, 84131, Italy.;Transfusion Medicine, Molecular Biology Section, University Hospital \"San Giovanni di Dio e Ruggi d'Aragona\", Salerno, 84131, Italy.;Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\", University of Salerno, Baronissi, 84081, Salerno, Italy.;Department of Translational Medical Sciences, \"Federico II\" University, 80138, Naples, Italy.;Clinical Pharmacology, University Hospital \"San Giovanni di Dio e Ruggi d'Aragona\", Salerno, 84131, Italy.;Hematology and Transplant Center, University Hospital \"San Giovanni di Dio e Ruggi d'Aragona\", Salerno, 84131, Italy.",
"authors": "Pezzullo|Luca|L|;Giudice|Valentina|V|;Serio|Bianca|B|;Fontana|Raffaele|R|;Guariglia|Roberto|R|;Martorelli|Maria Carmen|MC|;Ferrara|Idalucia|I|;Mettivier|Laura|L|;Bruno|Alessandro|A|;Bianco|Rosario|R|;Vaccaro|Emilia|E|;Pagliano|Pasquale|P|;Montuori|Nunzia|N|;Filippelli|Amelia|A|;Selleri|Carmine|C|",
"chemical_list": null,
"country": "Poland",
"delete": false,
"doi": "10.1515/med-2021-0274",
"fulltext": "\n==== Front\nOpen Med (Wars)\nOpen Med (Wars)\nmed\nOpen Medicine\n2391-5463\nDe Gruyter\n\nmed-2021-0274\n10.1515/med-2021-0274\nResearch Article\nReal-world evidence of cytomegalovirus reactivation in non-Hodgkin lymphomas treated with bendamustine-containing regimens\nPezzullo Luca 1\nGiudice Valentina 1\nSerio Bianca\nFontana Raffaele\nGuariglia Roberto\nMartorelli Maria Carmen\nFerrara Idalucia\nMettivier Laura\nBruno Alessandro\nBianco Rosario\nVaccaro Emilia\nPagliano Pasquale\nMontuori Nunzia\nFilippelli Amelia\nSelleri Carmine\nHematology and Transplant Center, University Hospital “San Giovanni di Dio e Ruggi d’Aragona”, Salerno, 84131, Italy\nClinical Pharmacology, University Hospital “San Giovanni di Dio e Ruggi d’Aragona”, Salerno, 84131, Italy\nDepartment of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Baronissi, 84081, Salerno, Italy\nTransfusion Medicine, Molecular Biology Section, University Hospital “San Giovanni di Dio e Ruggi d’Aragona”, Salerno, 84131, Italy\nInfectious Disease Unit, University Hospital “San Giovanni di Dio e Ruggi d’Aragona”, Salerno, 84131, Italy\nDepartment of Translational Medical Sciences, “Federico II” University, 80138, Naples, Italy\n1 Equal contribution.\n\ntel: +39-089-673150, fax: +39-089-673153\n21 4 2021\n2021\n16 1 672682\n27 12 2020\n28 2 2021\n19 3 2021\n© 2021 Luca Pezzullo et al., published by De Gruyter\n2021\nLuca Pezzullo et al., published by De Gruyter\nhttps://creativecommons.org/licenses/by/4.0/ This work is licensed under the Creative Commons Attribution 4.0 International License.\n\nAbstract\n\nCytomegalovirus (CMV) reactivation during chemotherapy or after organ or hematopoietic stem cell transplantation is a major cause of morbidity and mortality, and the risk of reactivation increases with patients’ age. Bendamustine, an alkylating agent currently used for treatment of indolent and aggressive non-Hodgkin lymphomas, can augment the risk of secondary infections including CMV reactivation. In this real-world study, we described an increased incidence of CMV reactivation in older adults (age >60 years old) with newly diagnosed and relapsed/refractory indolent and aggressive diseases treated with bendamustine-containing regimens. In particular, patients who received bendamustine plus rituximab and dexamethasone were at higher risk of CMV reactivation, especially when administered as first-line therapy and after the third course of bendamustine. In addition, patients with CMV reactivation showed a significant depression of circulating CD4+ T cell count and anti-CMV IgG levels during active infection, suggesting an impairment of immune system functions which are not able to properly face viral reactivation. Therefore, a close and early monitoring of clinical and laboratory findings might improve clinical management and outcome of non-Hodgkin lymphoma patients by preventing the development of CMV disease in a subgroup of subjects treated with bendamustine more susceptible to viral reactivation.\n\nKeywords\n\ncytomegalovirus\nnon-Hodgkin lymphoma\nchemotherapy\nimmunity\n==== Body\n1 Introduction\n\nNon-Hodgkin lymphomas (NHL) are a heterogeneous group of hematologic diseases with various biological and clinical features classified in B, NK, or T cell lymphomas with different morphology, immunophenotype, genetic, and clinical features [1,2,3]. Diffuse large B-cell lymphoma (DLBCL) and Chronic Lymphocytic Leukemia (CLL) are the most common B-cell NHL, while mantle cell lymphoma (MCL) is less frequent (3% of cases) [1,4]. Prognosis varies for each entity also based on clinical and molecular signatures. For example, in DLBCL, a mature B cell NHL frequently affecting older people, five-year overall survival (OS) ranges from 36 to 67% depending on nodal or extranodal involvement and combination of standard chemotherapy with rituximab [4,5,6]. In CLL, five-year OS can vary from 23.3 to 93.2% based on disease stage and serum markers [7,8,9]. Similarly, in follicular lymphoma (FL), the second most diagnosed lymphoma in Western Countries and frequently occurring in older patients, prognosis is influenced by clinical features, such as disease stage or number of involved nodal areas and two-year OS varies from 87% in high-risk to 98% in low-risk patients [10].\n\nBendamustine, an alkylating chemotherapeutic agent consisting of a purine analog-like benzimidazole ring, an alkylating agent group, and an alkane carboxylic chain, causes more durable intra- and inter-strand DNA cross-links than other alkylators and induces DNA damage and mitotic catastrophe [11,12,13]. Bendamustine is currently approved as first-line treatment of CLL Binet stage B or C, indolent NHL (iNHL) as monotherapy in patients relapsed or refractory to rituximab-based chemotherapy, and as first-line treatment in multiple myeloma patients not eligible for autologous stem cell transplantation [11]. This chemotherapeutic agent has also been used in newly diagnosed or relapsed/refractory DLBCL and T-cell NHL [14,15,16,17]. Bendamustine-containing regimens are well-tolerated. The most frequent toxicities are thrombocytopenia, lymphopenia, an increased risk of infections by opportunistic pathogens, such as Pneumocystis jirovecii, and higher risk of reactivation of chronic viral infections, including cytomegalovirus (CMV), Epstein-Barr, and Varicella-Zoster virus (VZV) [18,19,20]. CMV, a human herpesvirus, has an estimated seroprevalence worldwide of 45–100% in general population, and primary infection always occurs asymptomatically in immunocompetent subjects; however, immunocompromised patients experience a more aggressive disease with fever, hepatitis, severe pneumonia, encephalopathy and polyradiculopathy, myelosuppression, and graft rejection [21,22].\n\nBendamustine alone and in association with other immunosuppressive agents, such as steroids and rituximab, might increase the risk of CMV reactivation; however, literature lacks prospective longitudinal studies in large cohorts. In this real-world study, we investigated incidence of CMV reactivation in 167 consecutive patients with indolent and aggressive lymphoproliferative disorders treated with bendamustine-containing regimens, and candidate biomarkers of viral reactivation were also explored.\n\n2 Subjects and methods\n\n2.1 Patients and therapeutic regimens\n\nPatients received diagnosis and chemotherapy as per international guidelines after informed consent obtained in accordance with the Declaration of Helsinki at the Hematology and Transplant Center, University Hospital “San Giovanni di Dio e Ruggi d’Aragona” of Salerno, Italy, from June 2010 to April 2020. For assessment of CMV reactivation, a total of 167 patients with diagnosis of NHL were included in this retrospective study. Inclusion criteria were: age >18 years old; diagnosis of NHL; and treatment with bendamustine alone or in combination as first or above line of therapy. Median age was 70 years old (range, 41–88) and males were 59% (N = 99) (Table 1). NHL was diagnosed following the 2008 or 2016 revision of the World Health Organization classification of lymphoid neoplasms [1,23]; in particular, 95% (N = 158) B-cell NHL: DLBCL (N = 38; 23%); FL (N = 39; 23%); CLL/small lymphocytic lymphoma (SLL; N = 32; 19%); mantle cell lymphoma (MCL; N = 17; 10%); marginal zone lymphoma (MZL; N = 18; 11%); lymphoplasmacytic lymphoma (PLP; N = 4); plasmablastic lymphoma (PbL; N = 1); B-cell NHL not otherwise specified (NOS; N = 4); mucosa-associated lymphoid tissue (MALT) lymphoma (N = 4); and acute lymphoblastic leukemia (ALL; N = 1). Two subjects were diagnosed with Hodgkin’s lymphoma, one with multiple myeloma, one with Waldenstrom disease, and 3% (N = 5) of patients with T-cell NHL.\n\nTable 1 Baseline patients’ characteristics\n\nCharacteristics\tN = 167\t\nAge, years\t70 (41–88)\t\nSex, M/F\t99/68\t\nDiagnosis\t\nDLBCL\t38\t\nFL\t39\t\nCLL/SLL\t32\t\nMCL\t17\t\nMZL\t18\t\nOther B-cell NHL\t14\t\nT-cell NHL\t5\t\nOthers\t4\t\nStage\t\nI\t4\t\nII\t21\t\nIII\t23\t\nIV\t82\t\nFirst-line therapy\t\nBendamustine-based\t138\t\nStandard chemotherapy\t20\t\nStem cell transplantation\t2\t\nNo treatment\t7\t\nSecond-line therapy\t\nBendamustine-based\t18\t\nStandard chemotherapy\t3\t\n>2 lines of chemotherapy\t12\t\nMedian cycles of bendamustine\t6 (1–10)\t\nMedian follow-up, months\t15.3 (0.6–99.5)\t\nCMV serology\t\nIgG−\t4\t\nIgG+\t80\t\nAbbreviations: DLBCL, diffuse large B cell lymphoma; FL, follicular lymphoma; CLL, chronic lymphocyte leukemia; SLL, small lymphocytic lymphoma; MCL, mantle cell lymphoma; MZL, marginal zone lymphoma; NHL, non-Hodgkin lymphoma; CMV, cytomegalovirus; IgG, immunoglobulin G.\n\nPatients received bendamustine in combination with rituximab (RB regimen), rituximab and/or dexamethasone (DB, dexamethasone plus bendamustine; RDB, rituximab, dexamethasone, and bendamustine), and/or lenalidomide (LB, lenalidomide plus bendamustine; RLB, rituximab, lenalidomide, and bendamustine), or gemcitabine (GB). Bendamustine was given at doses of 70–90 mg/m2 for two consecutive days every 21 days for a maximum of four (RDB) or six (RB) cycles; while rituximab was administered at 375 mg/m2 every 21 days for a maximum of eight cycles, and dexamethasone was started at 20 mg/daily on days 1–4 and then tapered. Lenalidomide was administered at 25 mg/every other day. Patients with iNHL who achieved a complete remission received a maintenance therapy with rituximab at 375 mg/m2 every two months for two years. Therapeutic strategies non-containing bendamustine are summarized in Table 1. All patients received acyclovir and trimethoprim plus sulfamethoxazole as prophylaxis for VZV reactivation and for Pneumocystis jirovecii pneumonia, respectively.\n\n2.2 Flow cytometry\n\nImmunophenotyping was performed on fresh heparinized whole peripheral blood by flow cytometry (Figure 1). Neoplastic clones were identified using appropriate combinations of monoclonal antibodies as per manufacturer’s instructions (Beckman Coulter). CD4+ T cells were studied using the following antibodies: CD45; CD3; CD4; and CD8; and cell count assessed using beads as per manufacturer’s instructions (Beckman Coulter). Sample acquisition was carried out on a five-color FC500 cell analyzer cytometer (Beckman Coulter, Brea, CA, USA) or on a ten-color three-laser Beckman Coulter Navios Flow Cytometer (Beckman Coulter). At least 1 million events per sample were recorded. Post-acquisition analysis was performed using CPX or Navios tetra software (Beckman Coulter).\n\nFigure 1 Flow cytometry gating strategy. After post-acquisition compensation using FlowJo, cell populations were first identified using linear parameters (forward scatter area [FSC-A] vs side scatter area [SSC-A], and double cells were excluded (FSC-A vs FSC-W)). On single cells, CD3+ cells were identified (CD3 vs SSC-A), and CD4 and CD8 expression was further studied. Flow cytometry analysis of a representative patient who experienced CMV reactivation is reported before starting treatment, after the first cycle of RDB and the third, and then after one year. Percent of CD3+ and CD4+ cells is shown for each timepoint.\n\n2.3 CMV-DNA quantification\n\nPlasma CMV-DNA was quantified by real-time TaqMan CMV-DNA polymerase chain reaction (PCR) according to manufacturers’ instructions (Roche). During chemotherapy, CMV-DNA levels were measured every three weeks before starting each cycle, while CMV-DNA was monitored every week during CMV reactivation. After the end of treatment, CMV-DNA levels were measured every three months for two years. The instrument cut-off for positive results was CMV-DNA >137 copies/µL.\n\n2.4 Statistical analysis\n\nData were collected in spreadsheet and analyzed using Prism (v.8.3.0; GraphPad software, San Diego, CA). Categorical variables were compared by Fisher exact test, while continuous variable using Mann-Whitney nonparametric test. Two-group comparison was carried out by unpaired t-test. Differences in cumulative incidence of CMV reactivation between groups were assessed by Log-rank (Mantel-Cox) test and Hazard Ratio (HR) by log-rank. Multivariate analysis was performed by logistic regression model using SPSS Statistics software (IBM, Armonk, NY). A P value of <0.05 was considered statistically significant.\n\n3 Results\n\n3.1 Patients characteristics at baseline\n\nA total of 167 NHL patients were included in the study for assessment of CMV reactivation during bendamustine-based chemotherapy. At diagnosis, disease stage was evaluable in 130 out of 167 subjects: 3% of cases (N = 4) showed a stage I disease; 16% (N = 21) stage II; 18% (N = 23) stage III; and 63% (N = 82) stage IV disease. In addition, 44 patients (26%) showed involvement of extra lymphatic organ or site, especially gastrointestinal tract (N = 14). A total of 160 patients received a first-line chemotherapy and 138 of them (86%) were treated with a bendamustine-based regimen: two subjects (1% of total treated patients) with bendamustine as single agent; one (1%) with DB; four (3%) with GB; 107 patients (67%) received RB and 22 (14%) RDB; while 2 subjects (1%) with LB or RLB. The remaining 22 subjects did not receive bendamustine containing regimens as first-line therapy, and 19 out of these 22 patients did not achieve a partial or complete remission requiring RB (N = 16) or other regimens as second-line therapy. Two subjects nonresponsive to RB as first-line therapy received GB or RB with bendamustine at 90 mg/m2. Eleven subjects had a third-line therapy (three bendamustine alone; six RB; and two RLB) and one a fourth-line treatment (R-CHOP to R-GemOx to R-CHOP to RB). Median complete cycles with bendamustine were six (range, 1–10). The presence of specific IgG against CMV at baseline was assessed in 90 subjects, and 89% of them (N = 80) were positive for CMV-IgG. Median follow-up was 15.3 months (range, 19 days to 99.5 months).\n\n3.2 Clinical characteristics of patients with CMV reactivation\n\nForty-one patients (25%) experienced CMV reactivation with a median time to reactivation after starting bendamustine of 54 days (range, 11–309 days). Median age of this group of patients was 69 years old (range, 54–86), and 66% were males. Patients with CMV reactivation had a diagnosis of B-cell NHL in 95% of cases (N = 39) and T-cell NHL in 5% of subjects (N = 2; two Sézary syndrome). Among B-cell NHL, 6 subjects had DLBCL (15%), 9 (22%) FL, 8 (20%) CLL/SLL, 6 (15%) MCL, 5 (12%) MZL, and the remaining 5 cases (12%) were diagnosed as following: three cases with MALT and two with PLP. At diagnosis, disease stage was evaluable in 35 out of 41 subjects: 10% of cases (N = 4) showed a stage II disease; 7% (N = 3) stage III; and 68% (N = 28) stage IV disease. One CLL subject received bendamustine plus rituximab as second-line therapy after failure of fludarabine plus alemtuzumab; an FL patient was treated with rituximab plus higher dose of bendamustine after partial response to rituximab plus bendamustine at 70 mg/m2; the two subjects with Sézary syndrome received bendamustine alone as third-line therapy after failure of interferon-based regimens, while one MZL subject received RB after nonresponsiveness to chlorambucil first and R-FluCy later. The remaining 36 patients were treated with RD in 78% of cases (N = 28) or RDB in 22% of cases (N = 8) as first-line therapy with a median bendamustine cycle of 7 (range, 2–8). At baseline, median anti-CMV IgG levels were 108 UI/mL (range, 42–180 UI/mL), median lymphocyte count was 1,340 cells/µL (range, 530–14,895), and median CD4+ T cell count was 617 cells/µL (range, 180–1,278). Clinical manifestations of CMV reactivation were present in 15 patients (37%) and were: fever (20%; N = 8); diarrhea (5%; N = 2); anemia (5%; N = 2); chorioretinitis (2%; N = 1); and mucositis (2%; N = 1). The nadir lymphocyte count was 365 cells/µL (range, 0–1,590 cells/µL), while nadir anti-CMV IgG levels were 532 UI/mL (range, 129–1,320), nadir anti-CMV IgM levels were 42.5 UI/mL (range, 19–190), and nadir anti-CMV IgA were 82 UI/mL (range, 24–410). Median CMV-DNA levels were 2,120 copies/µL (range, 151–2,230,000). The maximum peak of 2,230,000 copies/µL was described after 69 days of treatment with RB with bendamustine at 90 mg/m2 in a patient with FL. Valganciclovir (VGCV) was administered at 900 or 1,800 mg/daily or twice per week based on clinical symptoms. One patient received first intravenous (IV) immunoglobulins (Ig) and then VGCV at 900 mg/daily. A total of four CMV-related deaths occurred in our cohort of patients. A 54 years old male patient with a diagnosis of MZL, stage IVb, died because of severe CMV disease. Reactivation occurred within 11 days after initiation of RB, and VGCV first at 900 mg/daily and then IVIg were administered; however, he died because of nonresponsiveness to antiviral therapy and severe CMV disease. OS was 31.7 months in patients with CMV reactivation, while subjects who did not experience CMV reactivation had an OS of 81.3 months; however, there were no statistically significant differences between groups (P = 0.2929).\n\n3.3 Predictors of CMV reactivation\n\nWhether to identify biomarkers of early CMV reactivation or risk factors, we compared clinical and laboratory findings between patients with CMV reactivation and subjects who did not experience viral reactivation. First, clinical and laboratory findings were compared between groups at baseline and during CMV reactivation (Table 2). No differences were described for age (P = 0.7069), number of bendamustine cycles (P = 0.6461), baseline anti-CMV IgG levels (mean ± SD, 111 ± 44.2 vs 113 ± 43.1, reactivation vs non-reactivation; P = 0.8610), and baseline CD4+ T cells (mean ± SD, 582 ± 387.8 vs 590 ± 427.5, reactivation vs non-reactivation; P = 0.9648). Significant variations were found in lymphocyte count at baseline (mean ± SD, 3,398 ± 4,366 vs 1,497 ± 1,117, reactivation vs no-reactivation; P = 0.0133), while frequencies were similar at the nadir of CMV reactivation (mean ± SD, 412 ± 282.9 vs 463 ± 259.7, reactivation vs non-reactivation; P = 0.4224) (Figure 2a and b). For CD4+ T cells, frequency similarly decreased after the first cycle of bendamustine in both CMV reactivated and non-reactivated groups; however, patients who did not experience CMV reactivation had higher CD4+ T cell count at the third bendamustine cycle compared to subjects who had CMV reactivation (mean ± SD, 80 ± 61.8 vs 159 ± 106.2, reactivation vs non-reactivation; P = 0.0133) (Figure 2c and d). In addition, anti-CMV IgG levels at the nadir of reactivation were lower in patients with CMV disease compared to patients who did not show viral reactivation (mean ± SD, 451 ± 208.7 vs 650 ± 254.6, reactivation vs non-reactivation; P = 0.0030), while anti-CMV IgA levels were similar between groups (P = 0.6259).\n\nTable 2 Patients’ characteristics at CMV reactivation\n\nCharacteristics\tCMV reactivation\tNo reactivation\tP value\t\nN = 41\tN = 126\t\nAge, years\t69 (54–86)\t71 (41–87)\t0.7069\t\nSex, M/F\t27/14\t72/54\t\t\nDead/Alive\t17/24\t46/80\t\t\nDiagnosis\t\nDLBCL\t6\t32\t\t\nFL\t9\t30\t\t\nCLL/SLL\t8\t24\t\t\nMCL\t6\t11\t\t\nMZL\t5\t13\t\t\nOther B-cell NHL\t5\t9\t\t\nT-cell NHL\t2\t3\t\t\nOthers\t—\t4\t\t\nStage\t\nI\t0\t4\t\t\nII\t4\t17\t\t\nIII\t3\t20\t\t\nIV\t28\t54\t\t\nFirst-line therapy\t\nBendamustine-based\t37\t101\t\t\nStandard chemotherapy\t3\t19\t\t\nSecond-line therapy\t\nBendamustine-based\t2\t16\t\t\nStandard chemotherapy\t1\t2\t\t\n>2 lines of chemotherapy\t3\t9\t\t\nMedian cycles of bendamustine\t7 (2–8)\t6 (1–8)\t0.6461\t\nMedian follow-up, months\t11.5 (0.7–51)\t18 (0.7–99.5)\t0.0097\t\nTime to reactivation, days\t54 (11–309)\t—\t\t\nBaseline CMV IgG, UI/mL\t108 (42–180)\t127 (25–180)\t0.861\t\nBaseline CD4+ T cells/µL\t617 (180–1,278)\t591 (118–1,761)\t0.9648\t\nBaseline lymphocytes/µL\t1,340 (530–14,895)\t1,180 (200–5,700)\t0.0133\t\nNadir lymphocytes/µL\t295 (0–1,320)\t410 (230–820)\t0.4224\t\nNadir CMV-IgG, UI/mL\t412 (129–943)\t670 (416–937)\t0.003\t\nCMV-IgM, UI/mL\t38 (20–190)\t—\t\t\nCMV-IgA, UI/mL\t83 (24–410)\t61 (49–158)\t0.6259\t\nCMV-DNA, copies/µL\t2,030 (151–2,230,000)\t—\t\t\nClinical manifestations\t\t—\t\t\nNo symptoms\t26\t\t\t\nFever\t8\t\t\t\nDiarrhea\t2\t\t\t\nAnemia\t2\t\t\t\nChorioretinitis\t1\t\t\t\nMucositis\t1\t\t\t\nDeath\t4\t\t\t\nCMV treatment\t\nValgancyclovir\t18\t\t\t\nIVIg\t4\t\t\t\nTime to negativization, days\t45.5 (17–152)\t\t\t\nAbbreviations: DLBCL, diffuse large B cell lymphoma; FL, follicular lymphoma; CLL, chronic lymphocyte leukemia; SLL, small lymphocytic lymphoma; MCL, mantle cell lymphoma; MZL, marginal zone lymphoma; NHL, non-Hodgkin lymphoma; CMV, cytomegalovirus; Ig, immunoglobulin; IVIg, intravenous immunoglobulins. P value < 0.05 was considered statistically significant and highlighted in bold italic.\n\nFigure 2 Lymphocyte and CD4+ T cell counts in CMV-reactivated and non-reactivated NHL patients. Patients were divided into two groups: subjects with CMV-reactivation (blue line or dots), and without CMV reactivation (red line or dots); and (a) lymphocyte counts are shown accordingly at baseline, before starting every cycle of bendamustine, and at regular monthly follow-up (month, mo). (b) Differences in lymphocyte counts at baseline and at the nadir of CMV reactivation were assessed by unpair t-test between patients who experienced CMV reactivation (blue dots) and those who did not have viral reactivation (blue dots). Similarly, CD4+ T cell counts were assessed from baseline through the follow-up (c), and frequencies of CD4+ cells in CMV-reactivated (blue dots) and non-reactivated (red dots) patients at the second and third cycle of bendamustine (d) are displayed. Data are shown as mean ± Standard Deviation (SD). *P < 0.05.\n\nNext, cumulative incidence of CMV reactivation was calculated in our cohort of NHL patients showing an eight-year incidence of 46% (Figure 3a). Patients were then divided based on clinical and laboratory features and incidence proportion of CMV reactivation between groups was compared. No differences in CMV reactivation incidence were described when patients were divided based on sex (M vs F, P = 0.2607), diagnosis (P = 0.3963), disease stage (I–II vs III–IV, P = 0.1542), and number of bendamustine cycles (≤3 vs >3 cycles, P = 0.1753) (Figure 3b–e). Significant differences were described when patients were divided based on age with a cut-off of 60 years old (P = 0.0293; HR, 3.392; 95% confidential interval [CI], 1.602 to 7.180) and type of bendamustine-based regimen received as first-line therapy (Figure 3f and g). In particular, patients treated with RDB had a higher incidence of CMV reactivation compared to patients who did not receive bendamustine as first-line therapy (P = 0.0278; HR, 3.764; 95% CI, 1.134–12.49), while no differences were described between patients treated with RB or standard chemotherapy (P = 0.1658). Finally, multivariable analysis was performed in patients who received bendamustine-based regimens as first-line therapy and patients who were given standard chemotherapy as first-line treatment. In this latter group, none of analyzed variables, including age, sex, disease stage, cycles of bendamustine, nadir lymphocyte count, and anti-CMV IgG levels, was significantly associated to CMV reactivation, while in patients who received bendamustine as first-line treatment, potential risk factors were age ≥60 years old (P = 0.074), more than three bendamustine cycles (P = 0.027), and nadir anti-CMV IgG levels (P = 0.018).\n\nFigure 3 Cumulative incidence of CMV reactivation in NHL patients treated with bendamustine. (a) Cumulative incidence of CMV reactivation was first assessed on the entire cohort of patients diagnosed with NHL receiving bendamustine-containing regimens as first or above line of treatment. Then, influence of various clinical categories on the incidence of CMV reactivation was assessed by dividing patients based on: (b) type of lymphoma (FL, follicular lymphoma; DLBCL, diffuse large B cell lymphoma; MZL, marginal zone lymphoma; MCL, mantle cell lymphoma; other B-NHL, other B-cell non-Hodgkin lymphomas; T-NHL, T-cell non-Hodgkin lymphomas); (c) sex (M, male; F, female); (d) disease stage (stage I–II, and stage III–IV); (e) number (No.) of bendamustine cycles (≤3 or >3); (f) age (<60 years old [yo] or ≥60 years old); and (g) therapeutic regimens administered as first-line therapy (not-containing bendamustine; RB, rituximab plus bendamustine; RDB, rituximab plus dexamethasone and bendamustine; other bendamustine-containing regimens including the drug alone).\n\n4 Discussion\n\nCMV reactivation in immunocompromised subjects can cause a life-threatening disease and NHL patients are at higher risk because immune responses are already impaired, and chemotherapy can worse this condition because of myelo- and immuno-suppression [22,24]. In this real-world study, incidence of CMV reactivation was systematically and retrospectively investigated in a large cohort of NHL patients treated with bendamustine-containing regimens, and potential risk factors were outlined, such as age ≥60 years old, number of bendamustine cycles, and nadir anti-CMV IgG levels. In addition, variations in the immune status were also described at baseline and during treatment.\n\nCMV reactivation in NHL patients has been anecdotically reported after bendamustine exposure often in older subjects with iNHL including FL, MCL, or MALT [25,26,27,28,29,30,31,32]. Most of those cases are refractory or relapsed iNHL, and they usually received bendamustine with or without rituximab as second or above line of therapy developing CMV disease after the third cycle of treatment. Two case series of 30 and 38 older relapse or refractory iNHL have reported an incidence of 20 and 6% of CMV reactivation after bendamustine exposure, respectively [26,27]. Some risk factors have also been identified, such as CD4/CD8 ratio and anti-CMV IgG levels; however, the small number of patients who experienced CMV reactivation in each cohort, the great heterogeneity in type of disease, stage, and previous treatments, and lack of data on younger adults and/or subjects diagnosed with aggressive NHL treated with bendamustine as first-line therapy could not allow the identification of univocal predictors of CMV reactivation. In this study, we presented results on a large cohort of patients with both iNHL and aggressive diseases mostly treated with bendamustine-containing regimens as first-line therapy. No differences in incidence of CMV reactivation were registered between patients with iNHL or aggressive lymphomas at any stage, suggesting that viral reactivation might be more likely related to immune impairments caused by chemotherapeutic agents than to those induced by the disease itself. Indeed, patients who received RDB as first-line therapy experienced CMV reactivation more frequently than those receiving only bendamustine or RB or than patients who received bendamustine-based regimens as second or above line of treatment [26]. These differences might be linked to a more profound immunosuppression caused by synergistic effects on both adaptive and innate immune responses of the combination of dexamethasone, rituximab, and bendamustine; while other bendamustine-containing regimens, such as RB, might not markedly impair immune system. Several studies have already described that combination of rituximab and dexamethasone has additive effects by reducing tumor cell growth, increasing apoptosis and rituximab-mediated complement-dependent cytotoxicity, and influencing or delaying immune reconstitution [33,34,35,36,37]. Bendamustine might enhance these synergistic effects and increase immunosuppression [33]. Indeed, incidence of CMV reactivation was also increased in patients on RB protocol and was similar between RB as first line of therapy and RB administered as second or above line of treatment, as already reported in several case reports of refractory or relapse iNHL receiving RB as second or above line therapy.\n\nOlder age (>65 years) has been indicated as an important risk factor of CMV reactivation in kidney (HR = 2.43) and allogeneic hematopoietic stem cell transplant (HSCT; aged >50 years old; HR 1.40; 95% CI, 1.24–1.58) recipients [38,39,40]. In HSCT patients, CMV reactivation increases with T cell depletion and long-course steroid treatment [39]. In addition, in haploidentical HSCT, T cell repletion and post-transplant cyclophosphamide also augment the risk of CMV reactivation [41]. In NHL, CMV reactivation is a frequent cause of mortality, and prophylaxis might be warranted in patients at risk, such as patients with high antigenemia burden, recurrent CMV reactivation, and antiviral-associated toxicities [24]. In older iNHL (FL, MZL, and Waldenström macroglobulinemia) treated with bendamustine-containing regimens, the risk of CMV reactivation is increased (HR, 3.98; 95% CI, 1.40–11.26) compared to patients treated without bendamustine [18]; in particular, CMV reactivation is frequent in patients treated with bendamustine as third line or above therapy and exposed to corticosteroids [25,26,27,28,29,30,31,32]. Similarly, in our cohort, incidence of CMV reactivation was higher in patients aged >60 years; however, similar rates of reactivation were documented between indolent and aggressive diseases, or between bendamustine course as first-line therapy and second-line or above treatment (26 vs 11% respectively; P = 0.1361). Thus, we showed that CMV reactivation might complicate clinical courses and outcomes of both newly diagnosed and relapse/refractory older NHL patients with aggressive or indolent diseases.\n\nCMV reactivation develops early in bendamustine administration usually after the third cycle of therapy, as documented in several case reports [25,26,27,28,29,30,31,32]; however, no significant differences in long-term cumulative incidence of reactivation were registered in our cohort between patients who received less than three courses of bendamustine and subjects who had more than three cycles of therapy, while in multivariate analysis the number of cycles of bendamustine increased the risk of CMV reactivation in treatment-naïve patients who received bendamustine as first-line therapy. This augmented susceptibility to viral reactivation might be caused by an impairment in T cell immunity, such as decreased circulating levels of CMV-specific CD8+ cytotoxic lymphocytes and CD4+ T cells [19,28,31,34,42,43]. In our study, patient with CMV reactivation had a significant depression of CD4+ T cell count between the second and third cycle of bendamustine compared to those subjects without CMV reactivation, in contrast with Isono et al. who documented a CD4+ cell decreased after the sixth course of bendamustine [26,43]. CD4+ T cells are important in maintaining CMV in its latent form, as a lack of CMV-specific CD4+ T cells is associated with a persistent viral shedding into urine and saliva even in healthy young subjects [44]. In addition, CMV-specific CD8+ T cells require the support of CMV-specific CD4+ T cells to prevent CMV reactivation after HSCT [45]. Therefore, CD4+ T cell depression during bendamustine treatment might affect the CMV-specific CD4+ T cell pool, thus increasing susceptibility to CMV reactivation in NHL patients. We also documented a significant decrease in circulating anti-CMV IgG at the nadir of reactivation which likely mirrors hyperactivation and/or exhaustion in both B and T cell immune responses [28].\n\nClinical manifestations and severity of CMV reactivation vary among patients treated with bendamustine, from no symptoms to severe CMV disease and death [25,26,27,28,29,30,31,32], as also described in our cohort. In symptomatic patients, various antiviral agents are employed, such as ganciclovir and VGCV at 900 or 1,800 mg/daily [46]. VGCV has also shown efficacy in prophylaxis of CMV reactivation in allogeneic HSCT at low dose (450 mg/daily for six months); however, drug-related toxicity, especially myelosuppression, might require drug discontinuation [47]. In our cohort, 18 patients who experienced CMV reactivation and high viremia with or without symptoms were treated with VGCV at low or high dose showing a median time of CMV viremia negativization of 45.5 days (range, 17–152 days) and four CMV disease-related deaths. No drug-related adverse events requiring antiviral agent discontinuation were registered.\n\nIn conclusion, CMV reactivation is a threat in hematologic patients who undergo chemotherapy for hematologic malignancies and/or conditioning regimens for HSCT [24,40]. Bendamustine, an alkylating agent, is used for treatment of iNHL; however, secondary infections are anecdotically reported, such as CMV reactivation in relapse/refractory iNHL patients [25,26,27,28,29,30,31,32]. In our study, we described an increased incidence of CMV reactivation in older adults (age >60 years old) with newly diagnosed and relapse/refractory iNHL and aggressive disease treated with bendamustine-containing regimens, especially after the third course of bendamustine accompanied by a significant depression of circulating CD4+ T cell count and anti-CMV IgG levels. Therefore, a close and early monitoring of CD4+ T cell frequency, CMV-DNA, and virus-specific IgG levels might be required in older hematologic patients who received bendamustine, especially in combination with rituximab and dexamethasone, to prevent CMV reactivation and improve clinical management and outcomes of those subjects.\n\nAcknowledgments\n\nThe authors would like to thank Bianca Cuffa and Francesca D’Alto (Hematology and Transplant Unit, University Hospital “San Giovanni di Dio e Ruggi d’Aragona”), and the Flow Cytometry Facilities of the Hematology and Transplant Center and of the Transfusion Medicine Unit, University Hospital “San Giovanni di Dio e Ruggi d’Aragona” for technical assistance. This research was supported by the Intramural Program of the Department of Medicine, Surgery and Dentistry, University of Salerno, Italy.\n\nFunding information: This research was supported by the Intramural Program of the Department of Medicine, Surgery and Dentistry, University of Salerno, Italy.\n\nAuthor contributions: L. P., V. G., A. F., and C. S. designed the study. L. P., B. S., R. F., R. G., and C. M. enrolled patients and were involved in their clinical managements. E. M. performed diagnostic tests. V. G., A. B., and R. B. collected clinical data. V. G. analyzed the data. V. G., A. F., and C. S. wrote the manuscript. All the authors reviewed the manuscript and agreed with the final version.\n\nConflict of interest: The authors declare no conflicts of interest.\n\nData availability statements: The data that support the findings of this study are available on request from the corresponding author, C. 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Transpl Immunol. 2018;49:54–8.\nvan der Heiden PLJ van Egmond HM Veld SAJ van de Meent M Eefting M de Wreede LC CMV seronegative donors: Effect on clinical severity of CMV infection and reconstitution of CMV-specific immunity Transpl Immunol 2018 49 54 8 29679650\n[46] O’Brien S, Ravandi-Kashani F, Wierda WG, Giles F, Thomas D, Huang X, et al. A randomized trial of valacyclovir versus valganciclovir to prevent CMV reactivation in patients with CLL receiving alemtuzumab. Blood. 2005;106(11):2960.\nO’Brien S Ravandi-Kashani F Wierda WG Giles F Thomas D Huang X A randomized trial of valacyclovir versus valganciclovir to prevent CMV reactivation in patients with CLL receiving alemtuzumab Blood 2005 106 11 2960\n[47] Serio B, Rosamilio R, Giudice V, Pepe S, Zeppa P, Esposito S, et al. Low-dose valgancyclovir as cytomegalovirus reactivation prophylaxis in allogeneic haematopoietic stem cell transplantation. Infez Med. 2012;20(2):26–34.\nSerio B Rosamilio R Giudice V Pepe S Zeppa P Esposito S Low-dose valgancyclovir as cytomegalovirus reactivation prophylaxis in allogeneic haematopoietic stem cell transplantation Infez Med 2012 20 2 26 34\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "16(1)",
"journal": "Open medicine (Warsaw, Poland)",
"keywords": "chemotherapy; cytomegalovirus; immunity; non-Hodgkin lymphoma",
"medline_ta": "Open Med (Wars)",
"mesh_terms": null,
"nlm_unique_id": "101672167",
"other_id": null,
"pages": "672-682",
"pmc": null,
"pmid": "33981851",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": "32509591;30811293;20564615;29314206;31191499;27185642;31640581;24752517;15322522;29313585;28447162;27448091;11215290;20616914;23072371;28782884;16640816;29201472;21811782;26495859;25643241;26211985;29800121;24828861;23042003;32375354;27363492;16147978;18172283;23109692;20497002;29679650;12176898;26980727;29670635;23650408;28030755;26699798;25760636;4629776;31758441;24951124;25107463;21300984;31004534",
"title": "Real-world evidence of cytomegalovirus reactivation in non-Hodgkin lymphomas treated with bendamustine-containing regimens.",
"title_normalized": "real world evidence of cytomegalovirus reactivation in non hodgkin lymphomas treated with bendamustine containing regimens"
} | [
{
"companynumb": "IT-CELLTRION INC.-2021IT010906",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BENDAMUSTINE"
},
"drugadditional": "3",
... |
{
"abstract": "Hepatitis C virus reactivation (HCVr) was defined previously as an increase in HCV RNA level of ≥ 1 log10 IU/mL from baseline HCV RNA level after chemotherapies or immunosuppressive therapies, but HCVr during a steroid monotherapy has rarely been reported. Here we report a 75-year-old Japanese female with chronic hepatitis C (genotype 2a) who developed HCVr after the administration of prednisolone for interstitial pneumonia. She experienced alanine aminotransferase (ALT) flare with icterus, but after the tapering of prednisolone and a liver supporting therapy, levels of HCV RNA and ALT were gradually decreased. Then, she received an anti-viral therapy with sofosbuvir/ledipasvir. Although HCV relapsed 4 weeks after the therapy, a second therapy with glecaprevir/pibrentasvir was successful. This case suggests that HCVr with hepatitis flare can occur even after a steroid monotherapy, and we should pay attention to HCVr when we administer prednisolone for patients with HCV chronic infection.",
"affiliations": "Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.;Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan. jinoue-drgn@umin.net.;Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.;Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.;Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.;Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.;Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.;Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.",
"authors": "Sato|Kosuke|K|;Inoue|Jun|J|http://orcid.org/0000-0003-1171-7835;Kakazu|Eiji|E|;Ninomiya|Masashi|M|;Iwata|Tomoaki|T|;Sano|Akitoshi|A|;Tsuruoka|Mio|M|;Masamune|Atsushi|A|",
"chemical_list": "D000998:Antiviral Agents; D000069474:Sofosbuvir",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12328-021-01432-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1865-7265",
"issue": "14(4)",
"journal": "Clinical journal of gastroenterology",
"keywords": "Direct acting antivirals; HCV reactivation; Prednisolone",
"medline_ta": "Clin J Gastroenterol",
"mesh_terms": "D000368:Aged; D000998:Antiviral Agents; D005260:Female; D005838:Genotype; D016174:Hepacivirus; D019694:Hepatitis B, Chronic; D006526:Hepatitis C; D019698:Hepatitis C, Chronic; D006801:Humans; D017563:Lung Diseases, Interstitial; D000069474:Sofosbuvir; D000067251:Symptom Flare Up",
"nlm_unique_id": "101477246",
"other_id": null,
"pages": "1221-1226",
"pmc": null,
"pmid": "33983567",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article",
"references": "20230413",
"title": "Reactivation of hepatitis C virus with severe hepatitis flare during steroid administration for interstitial pneumonia.",
"title_normalized": "reactivation of hepatitis c virus with severe hepatitis flare during steroid administration for interstitial pneumonia"
} | [
{
"companynumb": "JP-TEVA-2021-JP-1922270",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "Flecainide is a Class Ic antiarrythmic agent associated with adverse events due to its pro-arrythmic effects. We report the case of a 33-year-old female presenting in cardiac arrest after a flecainide overdose treated with intravenous fat emulsion (IFE), sodium bicarbonate (NaHCO₃), and extracorporeal membrane oxygenation (ECMO). This case reviews the pathophysiology and management of flecainide toxicity including novel strategies of IFE and ECMO.",
"affiliations": "Harvard Affiliated Emergency Medicine Residency, Brigham and Women's Hospital/Massachusetts General Hospital, Boston, MA, USA. Electronic address: ebrumfield@partners.org.;Harvard Affiliated Emergency Medicine Residency, Brigham and Women's Hospital/Massachusetts General Hospital, Boston, MA, USA. Electronic address: kbernard@partners.org.;Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: ckabrhel@partners.org.",
"authors": "Brumfield|Emily|E|;Bernard|Kenneth R L|KR|;Kabrhel|Christopher|C|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D005217:Fat Emulsions, Intravenous; D017693:Sodium Bicarbonate; D005424:Flecainide",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": "33(12)",
"journal": "The American journal of emergency medicine",
"keywords": null,
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000328:Adult; D000889:Anti-Arrhythmia Agents; D062787:Drug Overdose; D004562:Electrocardiography; D015199:Extracorporeal Membrane Oxygenation; D005217:Fat Emulsions, Intravenous; D005260:Female; D005424:Flecainide; D006323:Heart Arrest; D006801:Humans; D017693:Sodium Bicarbonate",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "1840.e3-5",
"pmc": null,
"pmid": "25921969",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Life-threatening flecainide overdose treated with intralipid and extracorporeal membrane oxygenation.",
"title_normalized": "life threatening flecainide overdose treated with intralipid and extracorporeal membrane oxygenation"
} | [
{
"companynumb": "US-TEVA-650059USA",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLECAINIDE"
},
"drugadditional": null,
"dr... |
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