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"abstract": "Recently, combination regimens based on programmed cell death-1 (PD-1) blockade have become increasingly common in clinical practice for the treatment of cancer. Such combinations significantly improve efficacy, but treatment-related adverse events have also become more complex and severe. Here, we report an acute toxic epidermal necrolysis (TEN)-like reaction in a patient with gallbladder cancer who received camrelizumab (an anti-PD-1 antibody) in combination with apatinib. Interestingly, distinct clinical and pathological characteristics were observed that differed from those of the reported cases of severe cutaneous reactions induced by anti-PD-1 antibodies alone; thus, we speculate that it was induced by the combination of camrelizumab and apatinib. It is worth noting that the TEN-like reaction showed resistance to methylprednisolone initially, which was gradually resolved after the addition of intravenous immunoglobulin (IVIg). Immunohistochemical staining revealed that the skin lesion was infiltrated by moderate numbers of CD4+ T cells and large numbers of CD8+ T cells during the progression of the TEN-like reaction, and mass cytometry by time-of-flight showed a significant reduction in the CD4+ and CD8+ T cell proportions in the peripheral blood after the rash improved. All these findings highlight the essential role of CD4+ T cells and CD8+ T cells in the TEN-like reaction induced by camrelizumab plus apatinib treatment, and we speculate that T cells, especially CD8+ T cells, attack keratinocytes. In conclusion, the TEN-like reaction induced by camrelizumab and apatinib deserves clinical attention, and further work is needed to elucidate the exact pathophysiologic mechanism as well as the optimal management strategy.",
"affiliations": "Department of Immunotherapy, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China.;Department of Molecular Pathology, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States.;Department of Oncology, First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Lung Cancer Institute, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Jinan, China.;Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China.;Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.;Department of Immunotherapy, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China.;Department of Immunotherapy, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China.;Department of Immunotherapy, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China.;Department of Immunotherapy, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China.;Department of Immunotherapy, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China.",
"authors": "Yang|Yonghao|Y|;Li|Jun|J|;Till|Brian G|BG|;Wang|Jun|J|;Zhang|Bicheng|B|;Wang|Hanping|H|;Huang|Hao|H|;Li|Tiepeng|T|;Gao|Quanli|Q|;Li|Hongle|H|;Wang|Zibing|Z|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fonc.2021.728253",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X\nFrontiers Media S.A.\n\n10.3389/fonc.2021.728253\nOncology\nCase Report\nToxic Epidermal Necrolysis-Like Reaction Following Combination Therapy With Camrelizumab and Apatinib for Advanced Gallbladder Carcinoma\nYang Yonghao 1 †\n\nLi Jun 2 †\n\nTill Brian G. 3\nWang Jun 4\n\nZhang Bicheng 5\n\nWang Hanping 6\nHuang Hao 1\nLi Tiepeng 1\nGao Quanli 1\nLi Hongle 1 *\nWang Zibing 1 *\n1 Department of Immunotherapy, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China\n2 Department of Molecular Pathology, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China\n3 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States\n4 Department of Oncology, First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Lung Cancer Institute, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Jinan, China\n5 Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China\n6 Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China\nEdited by: Xiangsong Wu, Shanghai Jiao Tong University School of Medicine, China\n\nReviewed by: Tibor Bakacs, Alfred Renyi Institute of Mathematics, Hungary; Wen-Hung Chung, Chang Gung Memorial Hospital, Taiwan\n\n*Correspondence: Zibing Wang, zlyywzb2118@zzu.edu.cn; Hongle Li, llhl73@163.com\n†These authors have contributed equally to this work\n\nThis article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Oncology\n\n29 10 2021\n2021\n11 72825321 6 2021\n06 10 2021\nCopyright © 2021 Yang, Li, Till, Wang, Zhang, Wang, Huang, Li, Gao, Li and Wang\n2021\nYang, Li, Till, Wang, Zhang, Wang, Huang, Li, Gao, Li and Wang\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.\nRecently, combination regimens based on programmed cell death-1 (PD-1) blockade have become increasingly common in clinical practice for the treatment of cancer. Such combinations significantly improve efficacy, but treatment-related adverse events have also become more complex and severe. Here, we report an acute toxic epidermal necrolysis (TEN)-like reaction in a patient with gallbladder cancer who received camrelizumab (an anti-PD-1 antibody) in combination with apatinib. Interestingly, distinct clinical and pathological characteristics were observed that differed from those of the reported cases of severe cutaneous reactions induced by anti-PD-1 antibodies alone; thus, we speculate that it was induced by the combination of camrelizumab and apatinib. It is worth noting that the TEN-like reaction showed resistance to methylprednisolone initially, which was gradually resolved after the addition of intravenous immunoglobulin (IVIg). Immunohistochemical staining revealed that the skin lesion was infiltrated by moderate numbers of CD4+ T cells and large numbers of CD8+ T cells during the progression of the TEN-like reaction, and mass cytometry by time-of-flight showed a significant reduction in the CD4+ and CD8+ T cell proportions in the peripheral blood after the rash improved. All these findings highlight the essential role of CD4+ T cells and CD8+ T cells in the TEN-like reaction induced by camrelizumab plus apatinib treatment, and we speculate that T cells, especially CD8+ T cells, attack keratinocytes. In conclusion, the TEN-like reaction induced by camrelizumab and apatinib deserves clinical attention, and further work is needed to elucidate the exact pathophysiologic mechanism as well as the optimal management strategy.\n\ncombination immunotherapy\nadverse event\nPD-1\nTEN\ncamrelizumab\napatinib\n==== Body\npmcIntroduction\n\nIn recent years, immunotherapy, mostly in the form of immune checkpoint inhibitors, has progressed substantially as a treatment for different types of cancer. In particular, monoclonal antibodies targeting PD-1 provide significant clinical benefits by inducing durable regression for many types of advanced and metastatic carcinomas. However, the response rate of single-agent PD-1 blockade is only approximately 20% or lower for most advanced malignancies (1). To improve response rates, combination regimens based on PD-1 blockade are being explored, and some, such as cytotoxic T lymphocyte associated protein 4 (CTLA-4) and PD-1 dual blockades (2), chemotherapy plus PD-1 blockade (3), and anti-angiogenic tyrosine kinase inhibitors plus PD-1 blockade (4), have achieved initial success. Unfortunately, more complex and severe adverse events (AEs) often follow such combination therapies. For example, one early phase trial (5) reported that the combination of nivolumab plus pazopanib and nivolumab plus sunitinib resulted in grade 3/4 treatment-related AEs in 70% and 82% of patients, respectively, limiting future investigation of either combination regimen.\n\nApatinib, a selective vascular endothelial growth factor receptor-2 (VEGFR2) tyrosine kinase inhibitor (TKI), has been approved for the treatment of advanced gastric cancer in China and has also been explored in combination with an anti-PD-1 antibody, camrelizumab, with promising preliminary results against some types of solid carcinomas (6–8). Here, we reported a toxic epidermal necrolysis (TEN)-like reaction that occurred following combination treatment with camrelizumab and apatinib of a patient with metastatic gallbladder carcinoma.\n\nCase Description\n\nA 47-year-old man with metastatic gallbladder carcinoma developed generalized pruritic maculopapular rash three days after receiving camrelizumab (200 mg, once every 3 weeks) and apatinib (250 mg, once daily) as third-line therapy. Careful review indicated no concomitant medication had been administered in the previous four weeks and that the patient had no prior history of rash. The patient discontinued apatinib treatment after consulting his doctor. Thereafter, the pruritic rash progressed rapidly, and he was admitted to our hospital five days after the combination treatment began. The clinical diagnosis of a dermatologic immune-related adverse event (irAE) was established, and he was initially treated with 80 mg methylprednisolone (1.14 mg/kg) daily for three days; however, the rash became more extensive and severe, with most of the rash becoming blisters ( Figures 1A–C ). Nikolsky’s sign was positive, and the detachable superficial epidermis comprised over 30% of the body surface area. Very interestingly, the rash was particularly severe on his hands and feet with associated swelling, which caused intolerable pain ( Figure 1D ). The rash was much more severe in areas of compression (e.g., hip, back, and posterior aspect of the arms) ( Figures 1B, C ). Simultaneously, he also felt moderate fatigue and loss of appetite. All signs indicated that the rash was rapidly worsening. After discussion with a dermatology consultant, a clinical diagnosis of TEN was established, and the severity-of-illness score for toxic epidermal necrolysis (SCORTEN) was 4, with a predicted mortality rate of 58.3%, as previously reported (9). After a skin biopsy was performed, intravenous immunoglobulin (IVIg; 30 g daily) was added to his treatment regimen, and methylprednisolone was continuously administered at the previous dose.\n\nFigure 1 Dermatologic findings. (A–C) Initial inspection revealed generalized rash with blistering which was more severe in load-bearing areas (yellow asterisk), such as the hip, back, and posterior aspect of the arms. (D) Peripheral examination showed severe rash in the hands and feet with associated swelling. (E) Treatment with intravenous immunoglobulin gradually improved his rash.\n\nPathologic examination ( Figure 2A ) showed epidermal hyperkeratosis with intraepidermal edema and blister formation, basal and suprabasal apoptotic keratinocytes with focal confluent apoptosis, and moderate infiltration of lymphocytes around vessels in the superficial dermis. These pathological characteristics also supported the clinical diagnosis of TEN. The day when IVIg was first administered was defined as Day 1, and since then, the rash improved daily ( Figure 1E ). IVIg was administered for five days at a cumulative dose of 150 g (> 2 g/kg), and the methylprednisolone was tapered over approximately 1 month.\n\nFigure 2 Histopathologic and immunohistochemical findings. (A) Histopathologic analysis demonstrated (1) epidermal hyperkeratosis with intraepidermal edema and blister formation (2), basal and suprabasal apoptotic keratinocytes with focal confluent apoptosis, and (3) moderate perivascular lymphocytic infiltration in the superficial dermis. Immunostaining shows (B) PD-1-positive lymphocytes (anti-PD-1, ×200) and (C) no PD-L1-positive cells (anti-PD-L1, ×200). Immunostaining revealed (D) CD4+ (anti-CD4, ×200) and (E) CD8+ T cell infiltration (anti-CD8, ×200). Immunohistochemistry confirmed the absence of (F) B cells (anti-CD20, ×200) and (G) NK cells (anti-CD56, ×200).\n\nMore than a month after the diagnosis of TEN, the follow-up revealed complete resolution of the rash with associated exfoliation of the necrotic epidermis. However, a positron emission tomography-computed tomography (PET-CT) scan showed cancer progression compared to the pretreatment scan. After consultation, he received fourth-line therapy with albumin-bound paclitaxel. However, because of disease progression and severe lower limb neurotoxicity, this was discontinued after two cycles. Thereafter, the patient was discharged from the hospital based on his personal decision.\n\nDiscussion\n\nTo the best of our knowledge, this is the first report of an acute severe TEN-like reaction following combination treatment with camrelizumab and apatinib. While we cannot identify the culprit drugs with certainty, we suspect that it was the drug combination. It was unlikely that the AE was caused only by apatinib, considering that no similar toxicities have been reported about apatinib, which has been widely used to treat advanced gastric cancer in China since 2014. Compared to the previously reported severe cutaneous reactions induced by anti-PD-1 antibodies (10, 11), our case has unique clinical characteristics: 1. the patient’s skin reaction occurred much earlier and progressed rapidly; 2. the patient presented with a very severe syndrome of rash, swelling, and pain in the hands and feet; 3. the rash was more severe in the load-bearing areas (e.g., hips, back, and posterior aspect of the arms) than in other areas. Potentially consistent with these findings, hand-foot syndrome is a very common adverse reaction to apatinib commonly aggravated by wearing shoes with hard soles, which could increase the pressure on the soles of the feet. Furthermore, through immunohistochemistry (IHC) analysis of the skin biopsy sample, we identified a small number of lymphocytes that were positive for PD-1 expression, and PD-L1 expression was not detected ( Figures 2B, C ). This result is not consistent with previously reported data of cutaneous adverse reactions caused by anti-PD-1 therapy alone (12), in which both PD-1 and PD-L1 expression were clearly detectable. It is well known that the interaction of PD-1 and programmed death-ligand 1 (PD-L1) is very important for immunity homeostasis (13), especially in the skin, which is the most commonly targeted organ for irAE occurrence during anti-PD-1/PD-L1 therapy (14). Therefore, we strongly suspect that the skin reaction triggered by apatinib was significantly amplified by anti-PD-1 therapy. This is also evidenced by another interesting case of severe localized well-demarcated bullous eruption which was reported in a patient with renal cell carcinoma following anti-PD-1 therapy with radiotherapy (15). The adverse reaction would not have been as severe if only radiotherapy was administered. We believe that anti-PD-1 inhibitor therapy aggravated the adverse dermatologic reaction to radiotherapy, similar to that observed in our case.\n\nHere, we reviewed previous reports of rash associated with apatinib and/or camrelizumab in PubMed with a sample size of > 40 patients ( Table 1 ). In four clinical trials about apatinib or camrelizumab monotherapy (No. 1-4) (16–19), rash was either not reported or the incidence was <10%. However, the incidence of rash observed with the combination of camrelizumab and apatinib was much higher, at over 20% or even 30%. The most convincing comparison was that of trial No. 4 (19) versus trials No. 6 (6) and No. 8 (21), which were all clinical trials of patients with advanced hepatocellular carcinoma in China. In these studies, the incidence of grade 1 or 2 rash observed with the combination of camrelizumab and apatinib (trials No. 6 and No. 8) was much higher than that with camrelizumab monotherapy (trial No. 4), with incidence of 28.4% and 27% versus <10%. Moreover, from all the studies listed in Table 1 , the combination therapy also appeared to lead to an increased incidence of grade 3 or 4 rashes than that with apatinib or camrelizumab monotherapy. These observations suggest that combination therapy with camrelizumab and apatinib increases the frequency and severity of dermatologic AEs, consistent with the findings of our case. With the increasing use of combination therapies based on PD-1 blockade, the possibility of potentially fatal grade 3/4 dermatologic AEs will also increase, which deserves further investigation.\n\nTable 1 Previous reports of rash following apatinib and/or camrelizumab therapy with sample sizes > 40 patients.\n\nRegimen\tNo.\tAuthor/year\tNature\tType of cancer\tSize\tDose of apatinib\tGrade 1 or 2\tGrade 3 or 4\t\nApatinib monotherapy\t1\tHu et al., 2014 (16)\tProspective\tTNBC\t84\t750 mg or 500 mg, daily\tNo\tNo\t\n2\tLi et al., 2016 (17)\tProspective\tGC\t176\t850 mg, daily\tNo\tNo\t\nCamrelizumab monotherapy\t3\tHuang et al., 2020 (18)\tProspective\tOSCC\t228\tNo\t<10%*\t<1%*\t\n4\tQin et al., 2020 (19)\tProspective\tHCC\t217\tNo\t<10%*\t<1%*\t\nCamrelizumab plus apatinib\t5\tLiu et al., 2020 (20)\tProspective\tTNBC\t40\t250 mg, daily or 7 days on/7 days off\t25%\t0\t\n6\tXu et al., 2020 (6)\tProspective\tHCC\t190\t250 mg, daily\t28.4%\t0.5%\t\n7\tZhou et al., 2020 (7)\tProspective\tNonsquamous NSCLC\t105\t250 mg or 375 mg or 500 mg, daily\t33.3%\t1.0%\t\n8\tYuan et al., 2020 (21)\tRetrospective\tHCC\t63\t250 mg, daily\t27.0%\t3.2%\t\n9\tLan et al., 2020 (8)\tProspective\tCC\t45\t250 mg, daily\t26.7%\t2.2%\t\n10\tXie et al., 2020 (22)\tProspective\tOsteosarcoma\t43\t500 mg or 250 mg or 125 mg, daily\t28.0%\t4.7%\t\n*Due to the low incidence, specific numerical values were not provided in the original article.\n\nTNBC, triple-negative breast cancer; GC, gastric cancer; OSCC, esophageal squamous cell carcinoma; HCC, hepatocellular carcinoma; NSCLC, non-small-cell lung cancer; CC, cervical cancer.\n\nFurther IHC analysis of the specimen indicated that the skin lesion was infiltrated by moderate numbers of CD4+ T cells ( Figure 2D ) and large numbers of CD8+ T cells ( Figure 2E ) but was not infiltrated by B cells ( Figure 2F ) or NK cells ( Figure 2G ). In addition, mass cytometry by time-of-flight (CyTOF) was used to compare the distribution of immune cell subgroups among peripheral blood mononuclear cells from Day 2 to Day 10. The t-distributed stochastic neighbor embedding (t-SNE) plots ( Figure 3A ) and relative log2-fold changes of the percentage for each subgroup ( Figure 3B ) revealed a marked reduction in the proportions of CD4+ and CD8+ T cells and stable numbers of B cells and NK cells after the rash improved on Day 10, consistent with the IHC findings. All these findings highlight the essential role of CD4+ T cells and CD8+ T cells in the progression of the TEN-like reaction induced by camrelizumab plus apatinib treatment, and we speculate that T cells, especially CD8+ T cells, attack keratinocytes, and B cells and NK cells might not have a role in this acute skin reaction. It is interesting to note that the proportion of Th1 cells within the CD4+ T cell subgroup also decreased dramatically after the rash improved ( Figures 3A, B ), suggesting the potential role of Th1 cells. This was consistent with a previous preclinical study demonstrating that PD-1 inhibition induces Th1/Th17 responses while producing fewer Th2 responses in patients with cancer (23). We also observed that the proportions of γδ T cells, conventional dendritic cells, and basophils in the peripheral blood decreased on Day 10, which also suggest a potential contribution of these immune cells to the pathogenesis of cutaneous adverse reactions. However, the exact pathophysiology of this condition remains unclear.\n\nFigure 3 (A) t-distributed stochastic neighbor embedding images of immune cell subgroups in the peripheral blood of the patient on Day 2 and Day 10. (B) The relative log2-fold changes of the percentages for each immune cell subgroup reveals a significant reduction of CD4+ and CD8+ T cells with stable levels of B cells and NK cells on Day 10. (C) Cytometric bead array demonstrated a significant reduction of IL-2, IL-4, IL-6, IL-10, IL-17A, and TNF-α levels and slight elevation of IFN-γ levels on Day 10.\n\nThe diagnosis of this case was challenging. It was crucial to exclude bullous lichenoid dermatitis because it can also present with bullous lesions. Moreover, it has been reported that lichenoid dermatitis induced by immune checkpoint inhibitors (ICI) has diverse clinical manifestations, with some cases showing bullous lesions (24) However, in terms of clinical manifestations, the patient did not present with lichenoid morphology throughout the course of the illness. In terms of pathology, TEN is mainly characterized by significant epidermal necrosis, while bullous lichenoid dermatitis (including those induced by anti-PD-1 therapy) is mainly characterized by typical lichenoid/interface dermatitis (25). Although apoptotic keratinocytes can also be present in the pathology of lichenoid dermatitis, significant full-thickness epidermal necrosis does not occur. Additionally, both classic and ICI-induced lichenoid dermatitis tend to have a later onset and a longer disease course (24, 26) Therefore, lichenoid dermatitis was unlikely in the patient. Nevertheless, different from classic TEN, our case, which was likely induced by camrelizumab plus apatinib, did not present with mucosal involvement and prodromal fever, and the distribution of his rash was unique, so the patient was diagnosed with a TEN-like reaction.\n\nThe treatment of this case is also worth discussing. In classic TEN, many cytotoxic T lymphocytes (CTL) associated cytokines, chemokines, or cytotoxic proteins are involved in epidermal necrolysis, especially granulysin (27) and TNF-α (28), and the interaction between Fas and Fas ligand (FasL) also participates in the process but is not the main pathomechanism. To this patient with a TEN-like reaction and glucocorticoid resistance, IVIg was administered; subsequently, surprisingly good results were achieved. Based on the previous studies on classic TEN (29), one possible mechanism is that IVIg contains anti-Fas antibodies, which could block the FasL-mediated apoptosis of keratinocytes. Therefore, we hypothesized that the severe skin reaction induced by apatinib and camrelizumab has a pathological mechanism that is not completely consistent with the classic TEN, and perhaps the interaction between Fas-FasL plays a key role. In a line with this, we speculated the T cells, especially CD8+ T cells (CTL), attack keratinocytes, and as is known, Fas-FasL is an major pathway for both CD4+ T cell- (30) and CD8+ T cell- mediated (31) cytotoxicity.\n\nThe contribution of methylprednisolone to the improvement of the rash should not be overlooked either. In our case, cytometric bead array (CBA) was used to compare the concentrations of seven cytokines (IL-2, IL-4, IL-6, IL-10, IL-17A, TNF-α, and IFN-γ) in the peripheral blood between Day 2 and Day 10. On Day 10, the levels of all cytokines except IFN-γ significantly decreased ( Figure 3C ), concomitant with the improvement of rash. These findings might be attributed to the use of methylprednisolone, as a previous study demonstrated that methylprednisolone could decrease the peripheral cytokine levels (i.e., IL-4, IL-6, IL-10, IL-17, IFN-γ, and TNF-α) in patients with rheumatoid arthritis (32). Moreover, it might be possible that IFN-γ levels on Day 2 had decreased significantly because during that time, methylprednisolone had already been used for four days.\n\nAnother topic worth discussing is the discontinuation of the anti-PD-1 therapy. Undoubtedly, continuing anti-PD-1 therapy may re-induce severe skin reactions, but on the other hand, emerging data suggest that the development of cutaneous toxicity may correlate with effective response to ICI therapy in patients with metastatic melanoma (33, 34). In fact, cutaneous irAEs could be a surrogate for clinical benefit. Therefore, it would be important that the ICI therapy is continued despite cutaneous toxicities, particularly because they can be managed without the discontinuation of therapy. The PET-CT scan showed disease progression; however, the continuation of ICI therapy might have resulted in the stabilization of the disease, and even reduction of the tumor burden. In fact, delayed clinical responses, such as an increase in total tumor burden (pseudoprogression) followed by tumor regression have often been observed in studies of immunotherapeutic agents since these agents may require additional time to achieve measurable or sustained clinical effects compared to traditional cytotoxic chemotherapy (35).\n\nCurrently, a variety of PD-1-based combination regimens have emerged, most of which demonstrated better clinical efficacy, but were always accompanied with increased toxicities. Consistent with this, a meta-analysis of nivolumab plus ipilimumab combination therapy raised the issue that the deleterious effects of severe irAEs might outweigh the benefit from the addition of ipilimumab (36). Recently, however, Kleef et al. demonstrated that the use of off-label low doses of nivolumab and ipilimumab in a combined treatment resulted in irAEs that were significantly safer than those observed upon following the established protocols without compromising efficacy (37). This may also give us a clue: it is important to design a rational combination regimen to reduce adverse events without compromising efficacy, or with even improving the anti-tumor effect.\n\nIn conclusion, we reported the first acute TEN-like reaction likely induced by the combination of camrelizumab and apatinib, which showed resistance to methylprednisolone but was gradually resolved after the addition of IVIg. According to the pathological analysis and examination of the changes of the immune cell subgroups in the peripheral blood, we speculate that T cells, especially CD8+ T cells, attack keratinocytes. Further work is needed to elucidate the exact pathophysiologic mechanism as well as the optimal management strategy.\n\nPatient Perspective\n\nWritten informed consent for the publication was obtained from the patient. From patient perspective, he was not satisfied with the combination therapy of apatinib and camrelizumab, not only because the tumor was not under control, but also because of the fear of the rash. However, the patient was very satisfied with the treatment of the rash. Although the rash developed rapidly during the initial phase of methylprednisolone therapy and caused great anxiety and fear, it gradually improved after the addition of IVIg, without significant treatment-related adverse reactions.\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\nThe studies involving human participants were reviewed and approved by Henan Cancer Hospital Medical Ethics Committee. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nYY and JL collected data and wrote the manuscript. ZW conceived and corrected the manuscript. BT reviewed and edited the manuscript. HH and TL performed the immunostaining and cytokine detection work, respectively. All authors commented on and corrected the manuscript. All authors contributed to the article and approved the submitted version.\n\nFunding\n\nThis work was supported by the Henan Medical Science and Technology Research Plan (Grant No. LHGJ20190646), the National Natural Science Foundation of China (Grant No. 81972690, 81000914, and 81272526), the Medical Science and Technology Research Project of Health Commission of Henan Province (2018010033) and the Henan Provincial Scientific and Technological Project (212102310750). The funding bodies played no role in the design of the study; the collection, analysis, and interpretation of data; or manuscript preparation.\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\nPublisher’s Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n\nAcknowledgments\n\nWe would like to thank the patient and her family for their cooperation.\n\nAbbreviations\n\nAEs, Adverse events; CBA, Cytometric bead array; CTL, Cytotoxic T lymphocytes; CTLA-4, Cytotoxic T lymphocyte associated protein 4; CyTOF, Mass cytometry by time-of-flight; ICI, Immune checkpoint inhibitors; irAE, Immune-related adverse event; IHC, Immunohistochemistry; PBMC, Peripheral blood mononuclear cells; PET-CT, Positron emission tomography-computed tomography; PD-1, Programmed cell death-1; SCORTEN, Severity-of-illness score for toxic epidermal necrolysis; t-SNE, t-distributed stochastic neighbor embedding; TEN, Toxic epidermal necrolysis; TKI, Tyrosine kinase inhibitor; VEGFR2, Vascular endothelial growth factor receptor-2.\n==== Refs\nReferences\n\n1 Wu X Gu Z Chen Y Chen B Chen W Weng L . 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CTLA-4 and PD-1 Pathways: Similarities, Differences, and Implications of Their Inhibition. Am J Clin Oncol (2016) 39 :98–106. doi: 10.1097/COC.0000000000000239 26558876\n14 Geisler AN Phillips GS Barrios DM Wu J Leung D Moy AP . Immune Checkpoint Inhibitor-Related Dermatologic Adverse Events. J Am Acad Dermatol (2020) 83 :1255–68. doi: 10.1016/j.jaad.2020.03.132\n15 Saw S Lee HY Ng QS . Pembrolizumab-Induced Stevens-Johnson Syndrome in Non-Melanoma Patients. Eur J Cancer (2017) 81 :237–9. doi: 10.1016/j.ejca.2017.03.026\n16 Hu X Zhang J Xu B Jiang Z Ragaz J Tong Z . Multicenter Phase II Study of Apatinib, a Novel VEGFR Inhibitor in Heavily Pretreated Patients With Metastatic Triple-Negative Breast Cancer. Int J Cancer (2014) 135 :1961–9. doi: 10.1002/ijc.28829\n17 Li J Qin S Xu J Xiong J Wu C Bai Y . Randomized, Double-Blind, Placebo-Controlled Phase III Trial of Apatinib in Patients With Chemotherapy-Refractory Advanced or Metastatic Adenocarcinoma of the Stomach or Gastroesophageal Junction. J Clin Oncol (2016) 34 :1448–54. doi: 10.1200/JCO.2015.63.5995\n18 Huang J Xu J Chen Y Zhuang W Zhang Y Chen Z . Camrelizumab Versus Investigator's Choice of Chemotherapy as Second-Line Therapy for Advanced or Metastatic Oesophageal Squamous Cell Carcinoma (ESCORT): A Multicentre, Randomised, Open-Label, Phase 3 Study. Lancet Oncol (2020) 21 :832–42. doi: 10.1016/S1470-2045(20)30110-8\n19 Qin S Ren Z Meng Z Chen Z Chai X Xiong J . Camrelizumab in Patients With Previously Treated Advanced Hepatocellular Carcinoma: A Multicentre, Open-Label, Parallel-Group, Randomised, Phase 2 Trial. Lancet Oncol (2020) 21 :571–80. doi: 10.1016/S1470-2045(20)30011-5\n20 Liu J Liu Q Li Y Li Q Su F Yao H . Efficacy and Safety of Camrelizumab Combined With Apatinib in Advanced Triple-Negative Breast Cancer: An Open-Label Phase II Trial. J Immunother Cancer (2020) 8 (1 ):e000696. doi: 10.1136/jitc-2020-000696 32448804\n21 Yuan G Cheng X Li Q Zang M Huang W Fan W . Safety and Efficacy of Camrelizumab Combined With Apatinib for Advanced Hepatocellular Carcinoma With Portal Vein Tumor Thrombus: A Multicenter Retrospective Study. Onco Targets Ther (2020) 13 :12683–93. doi: 10.2147/OTT.S286169\n22 Xie L Xu J Sun X Guo W Gu J Liu K . Apatinib Plus Camrelizumab (Anti-PD1 Therapy, SHR-1210) for Advanced Osteosarcoma (APFAO) Progressing After Chemotherapy: A Single-Arm, Open-Label, Phase 2 Trial. J Immunother Cancer (2020) 8 (1 ):e000798. doi: 10.1136/jitc-2020-000798 32376724\n23 Dulos J Carven GJ van Boxtel SJ Evers S Driessen-Engels LJ Hobo W . PD-1 Blockade Augments Th1 and Th17 and Suppresses Th2 Responses in Peripheral Blood From Patients With Prostate and Advanced Melanoma Cancer. J Immunother (2012) 35 :169–78. doi: 10.1097/CJI.0b013e318247a4e7\n24 Jacoby TV Chang MS Thompson LL Foreman RK Reynolds KL Chen ST . Histopathologically-Confirmed Lichenoid Eruptions From Immune Checkpoint Inhibitor Therapy: A Retrospective Cohort Analysis. Br J Dermatol (2021). doi: 10.1111/bjd.20698\n25 Siegel J Totonchy M Damsky W Berk-Krauss J Castiglione FJ Sznol M . Bullous Disorders Associated With Anti-PD-1 and Anti-PD-L1 Therapy: A Retrospective Analysis Evaluating the Clinical and Histopathologic Features, Frequency, and Impact on Cancer Therapy. J Am Acad Dermatol (2018) 79 :1081–8. doi: 10.1016/j.jaad.2018.07.008\n26 Asarch A Gottlieb AB Lee J Masterpol KS Scheinman PL Stadecker MJ . Lichen Planus-Like Eruptions: An Emerging Side Effect of Tumor Necrosis Factor-Alpha Antagonists. J Am Acad Dermatol (2009) 61 :104–11. doi: 10.1016/j.jaad.2008.09.032\n27 Chung WH Hung SI Yang JY Su SC Huang SP Wei CY . Granulysin Is a Key Mediator for Disseminated Keratinocyte Death in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. Nat Med (2008) 14 :1343–50. doi: 10.1038/nm.1884\n28 Wang CW Yang LY Chen CB Ho HC Hung SI Yang CH . Randomized, Controlled Trial of TNF-Alpha Antagonist in CTL-Mediated Severe Cutaneous Adverse Reactions. J Clin Invest (2018) 128 :985–96. doi: 10.1172/JCI93349\n29 Viard I Wehrli P Bullani R Schneider P Holler N Salomon D . Inhibition of Toxic Epidermal Necrolysis by Blockade of CD95 With Human Intravenous Immunoglobulin. Science (1998) 282 :490–3. doi: 10.1126/science.282.5388.490\n30 Stalder T Hahn S Erb P . Fas Antigen Is the Major Target Molecule for CD4+ T Cell-Mediated Cytotoxicity. J Immunol (1994) 152 :1127–33.\n31 Kojima H Shinohara N Hanaoka S Someya-Shirota Y Takagaki Y Ohno H . Two Distinct Pathways of Specific Killing Revealed by Perforin Mutant Cytotoxic T Lymphocytes. Immunity (1994) 1 :357–64. doi: 10.1016/1074-7613(94)90066-3\n32 Xu W Chen S Wang X Wu H Tahara K Tanaka S . Effects of Sinomenine on the Proliferation, Cytokine Production, and Regulatory T-Cell Frequency in Peripheral Blood Mononuclear Cells of Rheumatoid Arthritis Patients. Drug Dev Res (2021) 82 :251–8. doi: 10.1002/ddr.21748\n33 Quach HT Dewan AK Davis EJ Ancell KK Fan R Ye F . Association of Anti-Programmed Cell Death 1 Cutaneous Toxic Effects With Outcomes in Patients With Advanced Melanoma. JAMA Oncol (2019) 5 :906–8. doi: 10.1001/jamaoncol.2019.0046\n34 Sanlorenzo M Vujic I Daud A Algazi A Gubens M Luna SA . Pembrolizumab Cutaneous Adverse Events and Their Association With Disease Progression. JAMA Dermatol (2015) 151 :1206–12. doi: 10.1001/jamadermatol.2015.1916\n35 Chiou VL Burotto M . Pseudoprogression and Immune-Related Response in Solid Tumors. J Clin Oncol (2015) 33 :3541–3. doi: 10.1200/JCO.2015.61.6870\n36 Xing P Zhang F Wang G Xu Y Li C Wang S . Incidence Rates of Immune-Related Adverse Events and Their Correlation With Response in Advanced Solid Tumours Treated With NIVO or NIVO+IPI: A Systematic Review and Meta-Analysis. J Immunother Cancer (2019) 7 :341. doi: 10.1186/s40425-019-0779-6 31801636\n37 Kleef R Nagy R Baierl A Bacher V Bojar H McKee DL . Low-Dose Ipilimumab Plus Nivolumab Combined With IL-2 and Hyperthermia in Cancer Patients With Advanced Disease: Exploratory Findings of a Case Series of 131 Stage IV Cancers - A Retrospective Study of a Single Institution. Cancer Immunol Immunother (2021) 70 :1393–403. doi: 10.1007/s00262-020-02751-0\n\n",
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"journal": "Frontiers in oncology",
"keywords": "PD-1; TEN; adverse event; apatinib; camrelizumab; combination immunotherapy",
"medline_ta": "Front Oncol",
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"pages": "728253",
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"pmid": "34778042",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
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"title": "Toxic Epidermal Necrolysis-Like Reaction Following Combination Therapy With Camrelizumab and Apatinib for Advanced Gallbladder Carcinoma.",
"title_normalized": "toxic epidermal necrolysis like reaction following combination therapy with camrelizumab and apatinib for advanced gallbladder carcinoma"
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"abstract": "BACKGROUND\nGram-positive infections caused by susceptible and resistant strains of Staphylococcus aureus, coagulase-negative staphylococci and enterococci are increasing problems in neonates. Linezolid, a new oxazolidinone, is active against these pathogens and has recently been approved by the Food and Drug Administration for treating Gram-positive infections in pediatric patients.\n\n\nOBJECTIVE\nTo compare the clinical efficacy and safety of intravenous and oral linezolid with vancomycin (10 to 15 mg/kg every 6 to 24 h) in neonates (age 0 to 90 days).\n\n\nMETHODS\nHospitalized infants with known or suspected hospital-acquired pneumonia, complicated skin or skin structure infections, bacteremia or other infections (e.g. pyelonephritis, abdominal abscess) were eligible. Test-of-cure clinical response was evaluated at follow-up.\n\n\nRESULTS\nSixty-three neonates, randomized 2:1 to linezolid (n = 43) or vancomycin (n = 20) were included in the intent-to-treat group. Clinical cure rates at follow-up in the intent-to-treat group were higher, but not significantly different, for linezolid vs. vancomycin (78% vs. 61%; P = 0.196). Corresponding cure rates in clinically evaluable patients were 84% vs. 77% (P = 0.553) for linezolid and vancomycin, respectively. Pathogen eradication rates were as follows in the linezolid and vancomycin groups, respectively: S. aureus (67% vs. 60%; P = 0.850); coagulase-negative staphylococci (88% vs. 100%; P = 0.379); and enterococci (71% vs. 0%; P = 0.168). Results for hematology and chemistry assays were similar between treatment groups. Fewer linezolid-treated neonates had drug-related adverse events than vancomycin-treated neonates (12% vs. 32%; P = 0.058).\n\n\nCONCLUSIONS\nLinezolid is well-tolerated and as effective as vancomycin in the treatment of resistant Gram-positive infections in neonates.",
"affiliations": "UCLA School of Medicine, Los Angeles, CA, USA.",
"authors": "Deville|Jaime G|JG|;Adler|Stuart|S|;Azimi|Parvin H|PH|;Jantausch|Barbara A|BA|;Morfin|Maria Rayo|MR|;Beltran|Sandra|S|;Edge-Padbury|Barbara|B|;Naberhuis-Stehouwer|Sharon|S|;Bruss|Jon B|JB|",
"chemical_list": "D000081:Acetamides; D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D023303:Oxazolidinones; D014640:Vancomycin; D000069349:Linezolid",
"country": "United States",
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"doi": "10.1097/01.inf.0000086955.93702.c7",
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"issue": "22(9 Suppl)",
"journal": "The Pediatric infectious disease journal",
"keywords": null,
"medline_ta": "Pediatr Infect Dis J",
"mesh_terms": "D000081:Acetamides; D000284:Administration, Oral; D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D005260:Female; D016908:Gram-Positive Bacterial Infections; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases; D007262:Infusions, Intravenous; D000069349:Linezolid; D008297:Male; D023303:Oxazolidinones; D016896:Treatment Outcome; D014640:Vancomycin",
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"pubdate": "2003-09",
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"references": null,
"title": "Linezolid versus vancomycin in the treatment of known or suspected resistant gram-positive infections in neonates.",
"title_normalized": "linezolid versus vancomycin in the treatment of known or suspected resistant gram positive infections in neonates"
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"companynumb": "US-STRIDES ARCOLAB LIMITED-2017SP005828",
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"abstract": "Disseminated Varicella zoster virus infection (DVI) is a severe infection associated with severe abdominal pain of unknown cause. We report a case in which periarterial (the celiac artery and superior mesenteric artery) fat stranding (PFS) on computed tomography (CT) was the presumed cause of abdominal pain in a patient taking pomalidomide.\nA 62-year-old woman was admitted to our hospital with abdominal pain. Her medical history was multiple myeloma treated with pomalidomide. Computed tomography showed no remarkable findings on admission, but 1 day later, a contrast-enhanced CT showed PFS. A skin eruption appeared on day 4 and we started acyclovir. On day 10, Varicella zoster virus antigen and antibody tests were positive, confirming the diagnosis of DVI. The abdominal pain subsequently improved, together with the PFS, and she was discharged.\nWhen patients present with severe abdominal pain and PFS, DVI and acyclovir must be considered.",
"affiliations": "Department of Critical Care Medicine and Trauma National Hospital Organization Disaster Medical Center Tokyo Japan.;Department of Critical Care Medicine and Trauma National Hospital Organization Disaster Medical Center Tokyo Japan.;Department of Critical Care Medicine and Trauma National Hospital Organization Disaster Medical Center Tokyo Japan.;Department of Critical Care Medicine and Trauma National Hospital Organization Disaster Medical Center Tokyo Japan.;Department of Critical Care Medicine and Trauma National Hospital Organization Disaster Medical Center Tokyo Japan.;Department of Critical Care Medicine and Trauma National Hospital Organization Disaster Medical Center Tokyo Japan.;Department of Critical Care Medicine and Trauma National Hospital Organization Disaster Medical Center Tokyo Japan.;Department of Critical Care Medicine and Trauma National Hospital Organization Disaster Medical Center Tokyo Japan.",
"authors": "Takada|Hiroaki|H|https://orcid.org/0000-0001-9110-6772;Kohara|Saeko|S|;Ito|Takashi|T|;Yoshioka|Hayato|H|;Okada|Ichiro|I|;Kiriu|Nobuaki|N|;Koido|Yuichi|Y|;Hasegawa|Eijyu|E|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/ams2.494",
"fulltext": "\n==== Front\nAcute Med Surg\nAcute Med Surg\n10.1002/(ISSN)2052-8817\nAMS2\nAcute Medicine & Surgery\n2052-8817 John Wiley and Sons Inc. Hoboken \n\n10.1002/ams2.494\nAMS2494\nCase Report\nCase Reports\nDisseminated Varicella zoster infection with abdominal pain and periarterial fat stranding in a patient taking pomalidomide\nDisseminated Varicella zoster infectionH. Takada et al.Takada Hiroaki https://orcid.org/0000-0001-9110-6772\n1\nhiroaki_takada@msn.com Kohara Saeko \n1\n Ito Takashi \n1\n Yoshioka Hayato \n1\n Okada Ichiro \n1\n Kiriu Nobuaki \n1\n Koido Yuichi \n1\n Hasegawa Eijyu \n1\n \n1 \nDepartment of Critical Care Medicine and Trauma\nNational Hospital Organization Disaster Medical Center\nTokyo\nJapan\n\n* \nCorresponding: Hiroaki Takada, MD, Department of Critical Care Medicine and Trauma, National Hospital Organization Disaster Medical Center, 3256 Midoricho, Tachikawa, Tokyo, Japan. E‐mail: hiroaki_takada@msn.com.\n\n06 3 2020 \nJan-Dec 2020 \n7 1 10.1002/ams2.v7.1e49420 12 2019 21 1 2020 04 2 2020 © 2020 The Authors. Acute Medicine & Surgery published by John Wiley & Sons Australia, Ltd on behalf of Japanese Association for Acute Medicine.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/3.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Background\nDisseminated Varicella zoster virus infection (DVI) is a severe infection associated with severe abdominal pain of unknown cause. We report a case in which periarterial (the celiac artery and superior mesenteric artery) fat stranding (PFS) on computed tomography (CT) was the presumed cause of abdominal pain in a patient taking pomalidomide.\n\nCase Presentation\nA 62‐year‐old woman was admitted to our hospital with abdominal pain. Her medical history was multiple myeloma treated with pomalidomide. Computed tomography showed no remarkable findings on admission, but 1 day later, a contrast‐enhanced CT showed PFS. A skin eruption appeared on day 4 and we started acyclovir. On day 10, Varicella zoster virus antigen and antibody tests were positive, confirming the diagnosis of DVI. The abdominal pain subsequently improved, together with the PFS, and she was discharged.\n\nConclusion\nWhen patients present with severe abdominal pain and PFS, DVI and acyclovir must be considered.\n\nWe report a case of in which periarterial (the celiac artery and superior mesenteric artery) fat stranding on computed tomography was the presumed cause of abdominal pain in a patient taking pomalidomide.\n\n\nAbdominal fatgastroenterology and hepatologypomalidomidesepsis/multiple organ failureVaricella zoster virus infection source-schema-version-number2.0cover-dateJanuary/December 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.6 mode:remove_FC converted:31.12.2020\nFunding Information\n\n\nNo Funding information provided.\n==== Body\nIntroduction\nDisseminated Varicella zoster virus (VZV) infection (DVI) is a severe form of the disease that can take a complicated course, including progression to multiple organ failure.1 However, the diagnosis is difficult because the characteristic rash of VZV is typically absent in the initial stages. In 82–100% of cases, DVI develops with acute severe abdominal pain, leading to the potential for misdiagnosis as an acute abdomen.2 Misdiagnosis can be critical given that the prognosis is worse when antiviral therapy is delayed.1 Although several causes have been proposed, the reason for the severity of this pain is poorly understood. Although DVI mainly develops in patients receiving immunosuppressive or immunomodulatory therapy,3 we could not find any reports of DVI occurring during treatment with pomalidomide.\n\nIn this case report, we detail the first case of DVI in a patient taking pomalidomide. We considered that the cause of severe abdominal pain in DVI might be periarterial fat stranding (PFS) around the celiac artery (CA) and superior mesenteric artery (SMA) on computed tomography scan (CT).\n\nCase report\nA 62‐year‐old woman was admitted to our hospital with a 3‐day history of abdominal pain. Her medical history included multiple myeloma that was in complete remission, but for which she received pomalidomide and trimethoprim‐sulfamethoxazole.\n\nOn presentation, her vital signs were as follows: Glasgow Coma Scale, 15 (E4 V5 M6); body temperature, 36.4°C; blood pressure, 175/90 mmHg; heart rate, 63 b.p.m.; and respiratory rate, 22 breaths/min. Abdominal examination revealed tenderness of the epigastrium and left abdomen, but without swelling or guarding. Skin and other examinations were unremarkable.\n\nAbdominal non‐contrast CT was unremarkable at admission. Laboratory testing revealed the following: white blood cell count, 2,100/μL; platelet count, 127,000/μL; aspartate transaminase, 24 IU/L; alanine transaminase, 23 IU/L; amylase, 77/L; and C‐reactive protein, 0.12 mg/dL. No coagulopathy was observed.\n\nThe initial examination and investigation therefore failed to uncover a clear cause for her symptoms. She was admitted to hospital for observation because the pain was severe and did not improve despite receiving acetaminophen and buprenorphine.\n\nThe day after hospitalization, several hours after the first CT, a contrast‐enhanced CT was undertaken because the pain deteriorated. This showed PFS of the CA and SMA (Fig. 1). On day 3, thrombocytopenia (platelet count 17,000 μg/dL) were observed. On day 4, an eruption appeared around the abdomen, but without blistering. On day 5, elevated aspartate transaminase (3,248 IU/L) and alanine transaminase (1,732 IU/L) were observed, and fever developed with neutropenia (neutrophil count, 324/μL). Therefore, we started therapy with meropenem, linezolid, and caspofungin. Following this, the skin eruption spread over the face, body trunk, and limbs, and some blisters also erupted. Although these were not characteristic of a typical Varicella rash, we suspected DVI and started acyclovir. On day 7, the patient’s body temperature normalized and she reported that the abdominal pain had improved. On day 10, VZV antigen and antibody tests were positive, confirming the diagnosis of DVI. The skin eruptions began crusting on the same day. On day 14, acyclovir therapy was stopped and blood tests showed that the patient’s liver enzymes had normalized. On day 21, although the abdominal pain had disappeared, the patient reported feeling “strangeness” in the area where the pain had been, so we carried out a non‐contrast CT. Although PFS remained, it had improved (Fig. 2). All the patient’s laboratory data were normal on day 35, and she was discharged. On day 41, upper gastrointestinal endoscopy revealed no abnormal findings. Follow‐up CT at the same time also showed that PFS had almost disappeared (Fig. 3).\n\nFigure 1 Fat stranding around the celiac and superior mesenteric arteries on the day after hospitalization of a 62‐year‐old woman with disseminated Varicella zoster infection. Periarterial fat stranding appeared around the superior mesenteric artery (arrow) on the day after hospitalization.\n\nFigure 2 Fat stranding around the celiac and superior mesenteric arteries on day 21 of hospitalization of a 62‐year‐old woman with disseminated Varicella zoster infection. Periarterial fat stranding remained around the superior mesenteric artery (arrow) on day 21 of hospitalization.\n\nFigure 3 Fat stranding around the celiac and superior mesenteric arteries on day 41 of hospitalization of a 62‐year‐old woman with disseminated Varicella zoster infection. Periarterial fat stranding around the superior mesenteric artery (arrow) had almost disappeared by day 41 of hospitalization.\n\nDiscussion\nWe are not aware of any previous case reports of DVI presenting with severe abdominal pain in a patient taking pomalidomide. In addition, the suggestion that PFS of the CA and SMA might have been the cause of the abdominal pain is a novel consideration.\n\nFirst, we found no reports that DVI has occurred in patients receiving pomalidomide, which is a derivative of thalidomide. Pomalidomide is anti‐angiogenic and also acts as an immunomodulator. Pomalidomide is used as a treatment for relapsed and refractory multiple myeloma. There are, however, studies of DVI occurring in patients receiving thalidomide.4\n\n\nSecond, we propose that PFS of the CA and SMA was the cause of the severe abdominal pain. There have been several reports of other potential causes, including infection and inflammation of the celiac ganglia, hemorrhagic spots on the liver and upper gastrointestinal tract, and infection of the esophagus and gastric mucosa.5, 6, 7 However, none of these abnormal findings were observed on CT or upper gastrointestinal endoscopy. There has been one case report in Japanese publications of PFS of the CA and SMA in immunocompromised patients with DVI and severe abdominal pain,8 but this earlier report also showed expansion of the small and large intestines. These abnormal findings were not present at admission, only appearing on day 5, and they resolved as the abdominal pain settled. Moreover, intestinal dilation was a plausible alternative cause of the abdominal pain. By contrast, intestinal dilation was never observed in our case, with infection and inflammation around the CA and SMA being the only demonstrable cause. Thus, the present case represents the first report in the English literature of PFS as a potential cause of severe abdominal pain in DVI.\n\nDisseminated Varicella zoster virus infection is clinically and serologically diagnosed as typical varicella, however, diagnosis is complicated by the lack of a characteristic rash at onset.2 In recent years, diagnosis has become available by polymerase chain reaction, allowing diagnosis before the rash appears.8 This is important because the prognosis is poor when antiviral drug therapy is delayed.2 In our case, acyclovir was started on day 5, and the patient might not have survived if there had been further delay in receiving appropriate therapy. Thus, it is important to suspect DVI and to give empiric acyclovir therapy when immunocompromised patients present with severe abdominal pain of unknown etiology, even in the absence of a characteristic rash.\n\nIn conclusion, this case prompts us to make two important clinical suggestions. First, clinicians should consider that patients receiving pomalidomide could be at increased risk of developing DVI. Second, the presence of PFS of the CA and SMA might reflect the pathology underlying the severe abdominal pain in at least some cases of DVI. When patients present with severe abdominal pain and the CT findings reported in this case, DVI and the need for empiric acyclovir therapy must be considered. Further reports are needed to determine whether the CT findings of PFS of the CA and SMA are a consistent cause of severe pain and whether DVI is common in patients taking pomalidomide.\n\nDisclosure\nApproval of the research protocol: N/A.\n\nInformed consent: Informed consent was obtained from the patient for publication of this case report.\n\nRegistry and registration no. of the study/trial: N/A.\n\nAnimal studies: N/A.\n\nConflict of interest: None.\n==== Refs\nReferences\n1 \n\nJong \nMD \n, \nWeel \nJFL \n, \nOers \nMHJ \n, \nBoom \nR \n, \nDillen \nPMEW \n. Molecular diagnosis of visceral herpes zoster\n. Lancet \n2001 ; 357 : 2101 –2\n.11445106 \n2 \n\nYagi \nT \n, \nKarasuno \nT \n, \nHasegawa \nT \n\net al\nAcute abdomen without cutaneous signs of varicella zoster virus infection as a late complication of allogeneic bone marrow transplantation: importance of empiric therapy with acyclovir\n. Bone Marrow Transplant. \n2000 ; 25 : 1003 –5\n.10800071 \n3 \n\nFujisato \nS \n, \nUrushibara \nT \n, \nKasai \nH \n\net al\nA fatal case of atypical disseminated herpes zoster in a patient with meningoencephalitis and seizures associated with steroid immunosuppression\n. Am. J. Case Rep. \n2018 ; 19 : 1162 –7\n.30270342 \n4 \n\nCurley \nMJ \n, \nHussein \nSA \n, \nHassoun \nPM \n. Disseminated herpes simplex virus and varicella zoster virus coinfection in a patient taking thalidomide for relapsed multiple myeloma\n. J. Clin. Microbiol. \n2002 ; 40 : 2302 –4\n.12037117 \n5 \n\nNomdedéu \nJF \n, \nNomdedëu \nJ \n, \nMartino \nR \n\net al\nOgilvie’s syndrome from disseminated varicella‐zoster infection and infarcted celiac ganglia\n. J. Clin. Gastroenterol. \n1995 ; 20 : 157 –9\n.7769201 \n6 \n\nTakatoku \nM \n, \nMuroi \nK \n, \nKawano‐Yamamoto \nC \n, \nNagai \nT \n, \nKomatsu \nN \n, \nOzawa \nK \n. Involvement of the esophagus and stomach as a first manifestation of varicella zoster virus infection after allogeneic bone marrow transplantation\n. Intern. Med. \n2004 ; 43 : 861 –4\n.15497526 \n7 \n\nShiroshita \nA \n, \nNakashima \nK \n, \nAoshima \nM \n. Disseminated varicella‐zoster virus infection with abdominal pain possibly caused by pirfenidone: a case report\n. Respir. Med. Case Rep. \n2018 ; 25 : 330 –2\n.30406013 \n8 \n\nYamada \nS \n, \nIwasaki \nT \n, \nSatoh \nA \n\net al\nCase of visceral varicella‐zoster virus infection after autologous peripheral blood stem cell transplantation in which severe abdominal pain preceded the skin rash\n. Nihon Shokakibyo Gakkai Zasshi \n2010 ; 107 : 1947 –55\n.21139364\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2052-8817",
"issue": "7(1)",
"journal": "Acute medicine & surgery",
"keywords": "Abdominal fat; Varicella zoster virus infection; gastroenterology and hepatology; pomalidomide; sepsis/multiple organ failure",
"medline_ta": "Acute Med Surg",
"mesh_terms": null,
"nlm_unique_id": "101635464",
"other_id": null,
"pages": "e494",
"pmc": null,
"pmid": "33391765",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "15497526;10800071;11445106;21139364;30270342;12037117;7769201;30406013",
"title": "Disseminated Varicella zoster infection with abdominal pain and periarterial fat stranding in a patient taking pomalidomide.",
"title_normalized": "disseminated varicella zoster infection with abdominal pain and periarterial fat stranding in a patient taking pomalidomide"
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"abstract": "Intrahepatic cholangiocarcinoma (ICC) is a rare hepatobiliary cancer characterized by a poor prognosis and a limited response to conventional therapies. Currently chemotherapy is the only therapeutic option for patients with Stage IV ICC. Due to the poor response rate, there is an urgent need to identify novel molecular targets to develop novel effective therapies. Precision oncology tests utilizing targeted next-generation sequencing (NGS) platforms have rapidly entered into clinical practice. Profiling the genome and transcriptome of cancer to identify potentially targetable oncogenic pathways may guide the clinical care of the patient.\nWe present a 56-year-old male patient affected with metastatic ICC, whose cancer underwent several precision oncology tests by different NGS platforms. A novel BAP1 mutation (splice site c.581-17_585del22) and a RAD21 amplification were identified by a commercial available platform on a metastatic lesion. No germline BAP1 mutations were identified. Several lines of evidences indicate that PARP inhibitor administration might be an effective treatment in presence of BAP1 and/or RAD21 alterations since both BAP1 and RAD21 are involved in the DNA repair pathway, BAP1 interacts with BRCA1 and BRCA1-mediated DNA repair pathway alterations enhance the sensitivity to PARP inhibitor administration. In this case, after failing conventional therapies, patient was treated with PARP inhibitor olaparib. The patient had a partial response according to RECIST criteria with an overall survival of 37.2 months from the time of diagnosis of his ICC. Following 11.0 months on olaparib treatment, sustained stable disease control is ongoing. The patient is still being treated with olaparib and no significant toxicity has been reported.\nThese findings have clinical relevance since we have shown PARP inhibitor as a potential treatment for ICC patients harboring BAP1 deletion and RAD21 amplification. We have also highlighted the utility of NGS platforms to identify targetable mutations within a cancer.",
"affiliations": "Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\", University of Salerno, Salerno, Italy.;Department of Clinical Medicine and Surgery, University of Naples \"Federico II\", Naples, Italy.;Public Health, University of Naples \"Federico II\", Naples, Italy.;Familial Cancer Clinic and Oncoendocrinology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.;Department of Clinical Medicine and Surgery, University of Naples \"Federico II\", Naples, Italy.;Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\", University of Salerno, Salerno, Italy.;Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\", University of Salerno, Salerno, Italy.;Oncologia Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica Del Sacro Cuore, Roma, Italy.;Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.;Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\", University of Salerno, Salerno, Italy.",
"authors": "Sabbatino|Francesco|F|;Liguori|Luigi|L|;Malapelle|Umberto|U|;Schiavi|Francesca|F|;Tortora|Vincenzo|V|;Conti|Valeria|V|;Filippelli|Amelia|A|;Tortora|Giampaolo|G|;Ferrone|Cristina R|CR|;Pepe|Stefano|S|",
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"doi": "10.3389/fonc.2020.567289",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X Frontiers Media S.A. \n\n10.3389/fonc.2020.567289\nOncology\nCase Report\nCase Report: BAP1 Mutation and RAD21 Amplification as Predictive Biomarkers to PARP Inhibitor in Metastatic Intrahepatic Cholangiocarcinoma\nSabbatino Francesco \n1\n\n2\n\n*\n Liguori Luigi \n3\n Malapelle Umberto \n4\n Schiavi Francesca \n5\n Tortora Vincenzo \n3\n Conti Valeria \n1\n\n6\n Filippelli Amelia \n1\n\n6\n Tortora Giampaolo \n7\n Ferrone Cristina R. \n8\n Pepe Stefano \n1\n\n2\n \n1\nDepartment of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Salerno, Italy\n\n\n2\nOncology Unit, University Hospital San Giovanni di Dio e Ruggi D’Aragona, Salerno, Italy\n\n\n3\nDepartment of Clinical Medicine and Surgery, University of Naples “Federico II”, Naples, Italy\n\n\n4\nPublic Health, University of Naples “Federico II”, Naples, Italy\n\n\n5\nFamilial Cancer Clinic and Oncoendocrinology, Veneto Institute of Oncology IOV–IRCCS, Padua, Italy\n\n\n6\nClinical Pharmacology and Pharmacogenetics Unit, University Hospital “San Giovanni di Dio e Ruggi D’Aragona”, Salerno, Italy\n\n\n7\nOncologia Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica Del Sacro Cuore, Roma, Italy\n\n\n8\nDepartment of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States\n\nEdited by: Rosa Maria Bermudez-Cruz, National Polytechnic Institute of Mexico (CINVESTAV), Mexico\n\nReviewed by: Mohamed H. Abdel-Rahman, The Ohio State University, United States; Giovanni Gaudino, Retired, Bellinzona, Switzerland; David Y. Lee, University of New Mexico, United States\n\n*Correspondence: Francesco Sabbatino, fsabbatino@unisa.it\nThis article was submitted to Molecular and Cellular Oncology, a section of the journal Frontiers in Oncology\n\n\n27 11 2020 \n2020 \n10 56728929 5 2020 30 10 2020 Copyright © 2020 Sabbatino, Liguori, Malapelle, Schiavi, Tortora, Conti, Filippelli, Tortora, Ferrone and Pepe2020Sabbatino, Liguori, Malapelle, Schiavi, Tortora, Conti, Filippelli, Tortora, Ferrone and PepeThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Introduction\nIntrahepatic cholangiocarcinoma (ICC) is a rare hepatobiliary cancer characterized by a poor prognosis and a limited response to conventional therapies. Currently chemotherapy is the only therapeutic option for patients with Stage IV ICC. Due to the poor response rate, there is an urgent need to identify novel molecular targets to develop novel effective therapies. Precision oncology tests utilizing targeted next-generation sequencing (NGS) platforms have rapidly entered into clinical practice. Profiling the genome and transcriptome of cancer to identify potentially targetable oncogenic pathways may guide the clinical care of the patient.\n\nCase presentation\nWe present a 56-year-old male patient affected with metastatic ICC, whose cancer underwent several precision oncology tests by different NGS platforms. A novel BAP1 mutation (splice site c.581-17_585del22) and a RAD21 amplification were identified by a commercial available platform on a metastatic lesion. No germline BAP1 mutations were identified. Several lines of evidences indicate that PARP inhibitor administration might be an effective treatment in presence of BAP1 and/or RAD21 alterations since both BAP1 and RAD21 are involved in the DNA repair pathway, BAP1 interacts with BRCA1 and BRCA1-mediated DNA repair pathway alterations enhance the sensitivity to PARP inhibitor administration. In this case, after failing conventional therapies, patient was treated with PARP inhibitor olaparib. The patient had a partial response according to RECIST criteria with an overall survival of 37.2 months from the time of diagnosis of his ICC. Following 11.0 months on olaparib treatment, sustained stable disease control is ongoing. The patient is still being treated with olaparib and no significant toxicity has been reported.\n\nConclusion\nThese findings have clinical relevance since we have shown PARP inhibitor as a potential treatment for ICC patients harboring BAP1 deletion and RAD21 amplification. We have also highlighted the utility of NGS platforms to identify targetable mutations within a cancer.\n\nBAP1precision oncologycholangio carcinomaPoly ADP ribose polymerase (PARP) inhibitorRAD21olaparibMinistero dell’Istruzione, dell’Università e della Ricerca10.13039/5011000034072017PHRC8X_003\n==== Body\nIntroduction\nCholangiocarcinoma (CCA) is historically classified by location into intrahepatic, perihilar (or Klatskintumor) and distal cancers. Intrahepatic cholangiocarcinoma (ICC) is the second most common primary intrahepatic tumor, with an estimated incidence of 1.6 per 100,000/year in the United States (1). Unfortunately, ICC carries an extremely poor prognosis with an overall 5-year survival of 5–15% (1). For patients with early stage ICC, surgical resection of the cancer and removal of local lymph nodes remains the only curative option (2). However, even with a complete resection, most patients succumb to both loco-regional and distant metastases (3). Unfortunately, most patients present with advanced disease. Palliative chemotherapy is of limited efficacy (4), highlighting the urgent need for novel effective therapies.\n\nDifferent cancers express different oncogenic alterations which drive tumor progression. Several lines of evidences demonstrate that some of these alterations can be effectively targeted by tailored targeted agents, improving the overall survival of treated patients (5). These results have increased the use of precision oncology tests by targeted next-generation sequencing (NGS) platforms into clinical practice, to inform clinicians in making appropriate therapeutic decisions (6). Unselected ICC patients have been often included in “basket” trials (7), most of which have unfortunately failed to demonstrate a clinical benefit (7). As a result, there is a high interest to identifying oncogenic alterations in ICC to design potentially effective strategies in biomarker-enriched populations.\n\nNGS of ICC has already allowed identification of molecular alterations which are involved in ICC carcinogenesis such as those in KRAS, BRAF, IDH1, IDH2, EGFR, FGFR2, ROS1, ARID1A, PBRM1, BRCA1, and BAP1 (8–16). FGFR kinase inhibitors have demonstrated anti-tumor activity in ICC patients harboring activating FGFR2 gene fusions (17–19). However, no effective therapeutic strategies have currently changed the standard of care of ICC patients harboring different types of alterations.\n\nHere, we describe the case of a chemorefractory patient with ICC harboring BAP1 mutation and RAD21 amplification. The patient was successfully treated with the PARP inhibitor olaparib.\n\nCase Presentation\nIn March 2017, a 56-year-old Caucasian male was admitted to San Giovanni di Dio and Ruggi D’Aragona University Hospital for mild abdominal pain and nausea. The patient’s past medical history included i) Hodgkin’s lymphoma of the spleen in 1987, treated with splenectomy and radiotherapy; ii) myocardial infarction in 2006, treated with coronary angioplasty; and iii) myocardial infarction in 2012, treated with multiple coronary artery bypass grafting. He was also a former-smoker. Patient did not present with any ICC risk factors including biliary lithiasis, alcoholic liver disease, chronic hepatitis B or C infections, or primary sclerosing cholangitis. His family history was negative for any inherited-familial cancers. Abdominal ultrasound and computed tomography (CT) scan revealed a 10 cm intrahepatic lesion in the left lobe of the liver, as well as stable right basal lung thickening (\nFigure 1A\n). The latter was already described in a previous chest CT scan. Ultrasound guided biopsy of the liver mass demonstrated ICC (CK7+, CK19+, HepPar1-, AFP-). In April 2017, the patient underwent a left hepatectomy and sub-total gastrectomy and cholecystectomy. Histological examination demonstrated a Stage II ICC with vascular invasion [TNM staging, American Joint Committee on Cancer (AJCC) 8th edition]. Post operatively he was seen by the multidisciplinary team. Genomic analysis of NRAS, KRAS and BRAF V600 by polymerase chain reaction (PCR) sequencing, as well as immunohistochemical (IHC) staining for detection of HER2 amplification were performed on ICC tumor tissue. Both analyses did not show any type of alteration (\nSupplementary Table 1\n). Further genomic testing of EGFR was performed by sanger sequencing, but no alterations were found in exons 18, 19, 20, and 21 (\nSupplementary Table 1\n). In October 2017, a whole body CT scan demonstrated a 2.0 cm local recurrence in segment V of the liver (\nFigure 1B\n). Patient received a percutaneous thermal ablation (PTA) of the lesion. In February 2018, a whole body CT scan demonstrated a new 3.6 cm local recurrence in segment V of the liver, close to the previously treated lesion (\nFigure 1C\n) for which patient received a new PTA. In May 2018, a whole body CT scan demonstrated a new local recurrence in segment V of liver and multiple lesions in segment VII and VIII (\nFigure 1D\n). He then started a chemotherapeutic regimen with cisplatin (25 mg/m2) followed by gemcitabine (1,000 mg/m2), each administered on days 1 and 8 every 3 weeks. Due to his poor prognosis, patient requested additional testing of the ICC specimen. An IHC analysis of ROS1 rearrangements and NTRK fusions did not demonstrate any alterations (\nSupplementary Table 2\n). A Short Tandem Repeat (STR) analysis by PCR of BAT25, BAT26, D2S123, D5S346, D17S250, NR-21, and MONO-27 showed a Microsatellite Stable (MSS) tumor profile. Lastly an IHC analysis of MSH2, MSH6, PMS2, and MLH1 demonstrated no alterations of the mismatch repair system (\nSupplementary Table 2\n). Following six cycles of cisplatin and gemcitabine, in September 2018, a whole-body CT scan demonstrated a stable disease (according to RECIST criteria v 1.1). The patient received an additional PTA of the lesions in segments V, VII, and VIII of the liver. In February 2019, the CT scan demonstrated progression of disease (PD) (according to RECIST criteria v 1.1) due to the development of multiple small lesions localized at the hepatic dome and around the area of previous PTA, long with a large bone metastasis to the 12th vertebral body and a left upper lobe pulmonary nodule (\nFigure 2A\n). Based on the availability of additional formalin fixed tumor tissue obtained from a novel tumor biopsy, three different NGS platform studies were requested by the patient: Oncomine Comprehensive Assay (implemented at Istituto Tumori Milano, Milan, Italy) (\nTable 1\n), Oncofocus test [Oncologica® UK ltd (Cambridge, UK)] (\nTable 2\n) and Foundation One CDx [Foundation Medicine (Cambridge, MA)] (\nTable 3\n). Both the Oncomine Comprehensive Assay and the Oncofocus test did not detect any alterations of analyzed genes. In contrast the Foundation One CDx demonstrated the presence of a deletion in BAP1 (splice site c.581-17_585del22) and amplification of RAD21. Analysis of BAP1 by sanger sequencing on primary ICC tumor tissue confirmed the presence of BAP1 (splice site 581-17_585del22) alteration (\nFigure 3\n). In contrast no alterations were identified in BAP1 from nucleic acids extracted from buffy coat (\nFigure 3\n). Because of the involvement of RAD21 in the DNA repair pathway, the interaction of BAP1 with BRCA1 and the enhanced sensitivity to PARP inhibitor administration in presence of alterations in the BRCA1-mediated DNA repair pathway, it was decided first to treat the patient with FOLFIRI every 2 weeks [irinotecan 180 mg/m2, folinic acid 400 mg/m2, 5-fluorouracil (5-FU) 400 mg/m2 intravenous infusion bolus, then 5-FU 2400 mg/m2 intravenous infusion over 46 h] and then to start a PARP inhibitor. FOLFIRI is a conventional second-line chemotherapy regimen for ICC. In addition, irinotecan is a DNA-damaging agent. Following six cycles of FOLFIRI, in June 2019, a whole-body CT scan demonstrated PD (\nFigure 2B\n). A third-line therapy of off-label use with the PARP inhibitor olaparib at 800 mg/die and palliative radiotherapy (10 Gy) on the vertebral lesion was begun. In September 2019, a whole-body CT scan demonstrated a partial response (PR) (\nFigure 2C\n). The latter was confirmed on successive restaging scans in November 2019 (\nFigure 2D\n) and February 2020 (\nFigure 2E\n). Following 11 cycles of olaparib, the progression free survival has been 11.0 months. Currently, the patient has an overall survival of 37.2 months from the time of diagnosis of his ICC and has continued treatment with olaparib. He is in good health conditions and no treatment-related adverse events have been reported.\n\nFigure 1 Chest CT-scan performed at diagnosis in March 2017 (A), in October 2017 following first relapse (B), in February 2018 at tumor progression following first percutaneous thermal ablation (C), in May 2018 at tumor progression following second percutaneous thermal ablation and before starting chemotherapy with cisplatin and gemcitabine (D). Arrows indicate tumor lesion.\n\nFigure 2 Chest CT-scan performed at diagnosis in February 2019 at tumor progression following chemotherapy with cisplatin and gemcitabine and a third percutaneous thermal ablation and before to start treatment with FOLFIRI (A), in June 2019 at tumor progression following six cycles of FOLFIRI administration and before to start treatment with olaparib (B), in September 2019 following three cycles of olaparib (C), in November 2019 following six cycles of olaparib (D), and in February 2020 following 11 cycles of olaparib (E). Arrows indicate tumor lesion.\n\nTable 1 Oncomine Comprehensive Assay.\n\nMarch 1st, 2019\t\nNGS: Hot spot Cancer Panel with PGM (Personal Genome Machine) Ion Torrent technology [Thermo Fisher Scientific Life Technologies (Waltham, MA)]\t\nABL1\tAKT1\tALK\tAPC\tATM\tBRAF\tCDH1\tCDKN2A\tCSF1R\t\nCTNNB1\tEGFR\tERBB2\tERBB4\tEZH2\tFBXW7\tFGFR1\tFGFR2\tFGFR3\t\nFLT3\tGNA11\tGNAQ\tGNAS\tHNF1A\tHRAS\tIDH1\tIDH2\tJAK2\t\nJAK3\tKDR (VEGFR2)\tKIT\tKRAS\tMET\tMLH1\tMPL\tNOTCH1\tNPM1\t\nNRAS\tPDGFRA\tPIK3CA\tPTEN\tPTPN11\tRB1\tRET\tSMAD4\tSMARCB1\t\nSMO\tSRC\tSTK11\tTP53\tVHL\t\t\t\t\t\nResults: No hot spot mutations detected.\t\nTable 2 Oncofocus test.\n\nMarch 2nd, 2019\t\nNGS: Oncofocus test (Oncologica® UK ltd (Cambridge, UK)\t\nA2M\tABCB5\tACACA\tACADM\tACBD5\tACTG2\tADAM32\tADAMTS16\tAES\tAFAP1\tAFF3\tAGAP3\tAGBL4\tAGGF1\tAGK\t\nAGTRAP\tAHCYL1\tAKAP12\tAKAP13\tAKAP9\tAKT1\tAKT2\tAKT3\tALK\tAP3B1\tAR\tARAF\tARHGEF2\tARID1A\tARMC10\t\nARMT1\tASIC2\tATAD2\tATAD5\tATF7IP\tATG7\tATIC\tATM\tATP1B1\tATR\tATRNL1\tATRX\tAXL\tB4GALT1\tBAG4\t\nBAIAP2L1\tBAP1\tBBS9\tBCAM\tBCAN\tBCL2L11\tBCR\tBEND5\tBICC1\tBICD2\tBIN2\tBIRC6\tBRAF\tBRCA1\tBRCA2\t\nBRD3\tBRD4\tBTAF1\tBTBD1\tBTF3L4\tBTK\tC11orf95\tC7orf73\tC8ORF34\tC9orf153\tCAD\tCAND1\tCAPRIN1\tCAPZA2\tCARS\t\nCASP7\tCBL\tCCAR2\tCCDC170\tCCDC6\tCCDC88A\tCCDC91\tCCND1\tCCND2\tCCND3\tCCNE1\tCCNY\tCD44\tCD74\tCDC27\t\nCDK12\tCDK2\tCDK4\tCDK5RAP2\tCDK6\tCDKN1B\tCDKN2A\tCDKN2B\tCEL\tCEP85L\tCEP89\tCHD9\tCHEK1\tCHEK2\tCHTOP\t\nCIC\tCIITA\tCIT\tCLCN6\tCLIP1\tCLIP2\tCLIP4\tCLTC\tCNTLN\tCNTRL\tCOL14A1\tCOX5A\tCPSF6\tCREB3L2\tCREB5\t\nCREBBP\tCSF1R\tCTNNB1\tCUL1\tCUX1\tDAB2\tDAB2IP\tDCTN1\tDDR2\tDIP2C\tDNAJB1\tDTD1\tDYM\tDYNC1I2\tDYNC2H1\t\nEBF1\tEGFR\tEIF3E\tELAVL3\tEML4\tEPHB2\tEPS15\tERBB2\tERBB3\tERBB4\tERC1\tERCC2\tERG\tERLIN2\tERP44\t\nERVK3_1\tESR1\tESRP1\tETV1\tETV4\tETV5\tETV6\tEZH2\tEZR\tFAM114A2\tFAM131B\tFAM76A\tFANCA\tFANCD2\tFANCI\t\nFA1\tFBXO28\tFBXW7\tFCHSD1\tFGF3\tFGFR1\tFGFR19\tFGFR1OP\tFGFR1OP2\tFGFR2\tFGFR3\tFGFR4\tFGR\tFP1L1\tFKBP15\t\nFLT3\tFN1\tFNDC3B\tFOXL2\tFOXP1\tFXR1\tFYCO1\tGABBR2\tGATA2\tGATM\tGFPT1\tGHR\tGIT2\tGLIS3\tGNA11\t\nGNAI1\tGNAQ\tGNAS\tGNS\tGOLGA4\tGOLGA5\tGOLGB1\tGOPC\tGRB7\tGRHL2\tGTF2I\tGTF2IRD1\tGTF3C2\tH3F3A\tHACL1\t\nHERPUD1\tHIP1\tHIST1H3B\tHLA_A\tHMGA2\tNHNF1A\tHOMER1\tHOOK3\tHRAS\tIDH1\tIDH2\tIGF1R\tIRF2BP2\tJAK1\tJAK2\t\nJAK3\tJAKMIP1\tKANK1\tKANK2\tKCNQ5\tKCTD1\tKCTD7\tKDELR2\tKDM7A\tKDR\tKIAA1468\tKIAA1549\tKIAA1598\tKIF5B\tKIT\t\nKLC1\tKLHL7\tKNSTRN\tKRAS\tKTN1\tLMNA\tLRIG3\tLRRFIP1\tLSM12\tLSM14A\tLYN\tMACF1\tMAD1L1\tMAGOH\tMAP2K1\t\nMAP2K2\tMAP2K4\tMAPK1\tMAX\tMBIP\tMCFD2\tMDM2\tMDM4\tMED12\tMEMO1\tMET\tMGEA5\tMIR143HG\tMKRN1\tMLH1\t\nMPRIP\tMRE11A\tMRPL24\tMRPS33\tMSH2\tMSH6\tMSN\tMTFHD1L\tMTMR12\tMTOR\tMYB\tMYBL1\tMYC\tMYCL\tMYCN\t\nMYD88\tMYH13\tMYH9\tMYO18A\tMYO5A\tMYRIP\tMZT1\tNACC2\tNAV1\tNBN\tNCOA1\tNCOA4\tNCOR2\tNDE1\tNF1\t\nNF2\tNFASC\tNFIB\tNFKB2\tNIN\tNOL4\tNOTCH1\tNOTCH2\tNOTCH3\tNOTCH4\tNPC2\tNPM1\tNRAS\tNRG1\tNSD1\t\nNTM\tNTRK1\tNTRK2\tNTRK3\tNUB1\tNUDCD3\tNUP214\tNUTM1\tOFD1\tOPHN1\tOXR1\tPALB2\tPAPD7\tPAPSS1\tPARK2\t\nPAX5\tPAX8\tPCDHGA1\tPCM1\tPCNX\tPDE10A\tPDE4DIP\tPDE7A\tPDGFRA\tPDGFRB\tPDHX\tPDP1\tPDZRN3\tPHEB\tPIK3CA\t\nPIK3CB\tPIK3R1\tPLAG1\tPLIN3\tPMS2\tPOLE\tPOLH\tPPARG\tPPFIBP1\tPPHLN1\tPPL\tPPM1G\tPPP2R1A\tPPP4R3B\tPRKACA\t\nPRKACB\tPRKAR1A\tPRKG2\tPSMD11\tPSPH\tPTCH1\tPTEN\tPTPN11\tPTPN3\tPTPRK\tPTPRZ1\tPWWP2A\tQKI\tRABEP1\tRABGAP1L\t\nRAC1\tRAD18\tRAD50\tRAD51\tRAD51B\tRAD51C\tRAD51D\tRAF1\tRANBP2\tRB1\tRBMS3\tRBPMS\tRELA\tRET\tRHOA\t\nRICTOR\tRNF11\tRNF130\tRNF213\tRNF43\tROS1\tRP2\tRSPO2\tRSPO3\tRUFY2-\tSART3\tSCAF11\tSDC4\tSDCCAG3\tSEC16A\t\nSEC31A\tSEC61G\tSETD2\tSF3B1\tSHROOM4\tSHTN1\tSLC12A7\tSLC26A4\tSLC34A2\tSLC3A2\tSLC45A3\tSLMAP\tSLX4\tSMAD4\tSMARCA4\t\nSMARCB1\tSMOP\tSND1\tSNHG7\tSNX19\tSOX6\tSPAG9\tSPECC1\tSPECC1L\tSPOP\tSPTBN1\tSQSTM1\tSRC\tSRGAP3\tSSBP2\t\nSTAT3\tSTK11\tSTK32B\tSTRN\tSTRN3\tSUGCT\tTACC1\tTACC3\tTANK\tTAX1BP1\tTBL1XR1\tTENM4\tTERF2\tTERT\tTPM1\t\nTFG\tTMEM106B\tTMEM178B\tTMPRSS2\tTNIP1\tTNKS2\tTOP1\tTP53\tTP53BP1\tTPM3\tTPM4\tTPR\tTRAF1\tTRAK1\tTRIM24\t\nTRIM27\tTRIM33\tTRIM4\tTRIO\tTRIP11\tTRMT61B\tTSC1\tTSC2\tTSEN2\tTTLL7\tTXLNA\tTYK2\tU2AF1\tUBE2L3\tUBN2\t\nUSP10\tVAMP2\tVCL\tVOPP1\tWASF2\tWDR48\tWHSC1L1\tWIPF2\tXPO1\tYAP1\tYTHDF3\tYWHAE\tZC3HAV1\tZCCHC8\tZEB2\t\nZKSCAN1\tZKSCAN5\tZMYM2\tZMYND8\tZNF226\tZNF703\tZSCAN30\t\t\t\t\t\t\t\t\t\nResults: \n- Mutations: No actionable variant detected \n- Copy Number Variations: No actionable variant detected \n- Fusion Genes: No actionable variant detected\t\nTable 3 Foundation One CDx.\n\nMarch 7nd, 2019\t\nDNA GENE LIST: ENTIRE CODING SEQUENCE FOR THE DETECTION OF BASE SUBSTITUTIONS, INSERTION/DELETIONS, AND COPY NUMBER ALTERATIONS Foundation One CDx [Foundation Medicine (Cambridge, MA)] \t\t\t\t\nABL1\tACVR1B\tAKT1\tAKT2\tAKT3\tALK\tALOX12B\tAMER1 (FAM123B)\tAPC\tAR\tARAF\tARFRP1\t\nARID1A\tASXL1\tATM\tATR\tATRX\tAURKA\tAURKB\tAXIN1\tAXL\tBAP1\tBARD1\tBCL2\t\nBCL2L1\tBCL2L2\tBCL6\tBCOR\tBCORL1\tBRAF\tBRCA1\tBRCA2\tBRD4\tBRIP1\tBTG1\tBTG2\t\nBTK\tC11orf30 (EMSY)\tC17orf39 (GID34)\tCALR\tCARD11\tCASP8\tCBFB\tCBL\tCCND1\tCCND2\tCCND3\tCCNE1\t\nCD22\tCD274 (PD-L1)\tCD70\tCD79A\tCD79B\tCDC73\tCDH1\tCDK12\tCDK4\tCDK6\tCDK8\tCDKN1A\t\nCDKN1B\tCDKN2A\tCDKN2B\tCDKN2C\tCEBPA\tCHEK1\tCHEK2\tCIC\tCREBBP\tCRKL\tCSF1R\tCSF3R\t\nCTCF\tCTNNA1\tCTNNB1\tCUL3\tCUL4A\tCXCR4\tCYP17A1\tDAXX\tDDR1\tDDR2\tDIS3\tDNMT3A\t\nDOT1L\tEED\tEGFR\tEP300\tEPHA3\tEPHB1\tEPHB4\tERBB2\tERBB3\tERBB4\tERCC4\tERG\t\nERRFI1\tESR1\tEZH2\tFAM46C\tFANCA\tFANCC\tFANCG\tFANCL\tFAS\tFBXW7\tFGF10\tFGF12\t\nFGF14\tFGF19\tFGF23\tFGF3\tFGF4\tFGF6\tFGFR1\tFGFR2\tFGFR3\tFGF4\tFH\tFLCN\t\nFLT1\tFLT3\tFOXL2\tFUBP1\tGABRA6\tGATA3\tGATA4\tGATA6\tGNA11\tGNA13\tGNAQ\tGNAS\t\nGRM3\tGSK3B\tH3F3A\tHDAC1\tHGF\tHNF1A\tHRAS\tHSD3B1\tID3\tIDH1\tIDH2\tIGF1R\t\nIKBKE\tIKZF1\tINPP4B\tIRF2\tIRF4\tIRS2\tJAK1\tJAK2\tJAK3\tJUN\tKDM5A\tKDM5C\t\nKDM6A\tKDR\tKEAP1\tKEL\tKIT\tKLHL6\tKMT2A (MLL)\tKMT2D (MLL2)\tKRAS\tLTK\tLYN\tMAF\t\nMAP2K1 (MEK1)\tMAP2K2 (MEK2)\tMAP2K4\tMAP3K1\tMAP3K13\tMAPK1\tMCL1\tMDM2\tMDM4\tMED12\tMEF2B\tMEN1\t\nMEERTK\tMET\tMITF\tMKNK1\tMLH1\tMPL\tMRE11A\tMSH2\tMSH3\tNBN\tNF1\tNF2\t\nNFE2L2\tNFKBIA\tNKX2-1\tNOTCH1\tNOTCH2\tNOTCH3\tNPM1\tNRAS\tNSD3 (WHSC1L1)\tNT5C2\tNTRK1\tNTK2\t\nNTRK3\tP2RY8\tPALB2\tPARK2\tPARP1\tPARP2\tPARP3\tPAX5\tPBRM1\tPRKAR1A\tPRKCI\tPTCH1\t\nPTEN\tPTPN11\tPTPRO\tQKI\tRAC1\tRAD21\tRAD51\tRAD51B\tRAD51C\tRAD51D\tRAD52\tRAD54L\t\nRAF1\tRARA\tRB1\tRBM10\tREL\tRET\tSF3B1\tSGK1\tSMAD2\tSMAD4\tSMARCA4\tSMARCB1\t\nSMO\tSNCAIP\tSOCS1\tSYK\tTBX3\tTEK\tTET2\tTGFBR2\tTIPARP\tTNFAIP3\tTNFRSF14\tTP53\t\nTSC1\tTSC2\tTYRO3\tU2AF1\tVEGFA\tVHL\tWHSC1\tWT1\tXPO1\t\t\t\t\n\nDNA GENE LIST: FOR THE DETECTION OF SELECT REARRANGEMENTS\n\t\t\t\t\nALK\tBCL2\tBCR\tBRAF\tBRCA1\tBRCA2\tCD74\tEGFR\tETV4\tETV5\tETV6\tEWSR1\t\nEZR\tFGFR1\tFGFR2\tFGFR3\tKIT\tKMT2A (MLL)\tMSH2\tMYB\tMYC\tNOTCH2\tNTRK1\tNTRK2\t\nNUTM1\tPGFRA\tRAF1\tRARA\tRET\tROS1\tRSPO2\tSDC4\tSLC34A2\tTERC\tTERT\tTMPRSS2\t\n\nResults:\n\n- BAP1: Splice site 581-17_585del22\n\n- RAD21: amplification\n\t\t\t\t\nFigure 3 The figure shows BAP1 molecular analysis performed on tumor tissue samples and buffy coat by using sanger sequencing platform. In details, c. 581-17_585del22 mutation was found only in tumor tissue specimen (A) while nucleic acids extracted from buffy coat did not harbor this mutation (B).\n\nDiscussion and Conclusions\nNovel effective therapies are urgently needed for metastatic ICC patients. The current clinical case has provided for the first-time evidence that ICC patients carrying a BAP1 deletion and RAD21 amplification might benefit from a PARP inhibitor treatment. BAP1 is a tumor suppressor gene which modulates several pathways including cell death, cell differentiation, DNA damage response and gluconeogenesis (20–28). In mediating DNA damage response, BAP1 interacts with BRCA1 (20, 21). BRCA1 plays a key role in the DNA repair mechanism as well as in cell cycle regulation (29). Germline heterozygous mutations in BAP1 cause an autosomal dominant condition known as BAP1-cancer syndrome which confers a high susceptibility to the development of several malignancies including mesothelioma, uveal melanoma, renal, cholangio and breast carcinomas (30–38). In the clinical case we have described, we identified a novel mutation in BAP1 (c.581-17_585del22). The variant was somatic and not detected in the germline. We have examined several databases (Cosmic, GenBank, ClinVar) and c.581-17_585del22 mutation was not identified. Some literature data reported a similar deletion of BAP1 with a pathogenic value (39, 40). Somatic mutations in BAP1 are reported to drive carcinogenesis in mesothelioma, lung adenocarcinoma and melanoma (30, 32, 34, 41). BAP1 mutations occur in 10–32% of ICC cases (10, 14, 30, 42–49). As a tumor suppressor gene, BAP1 seems to follow a classic two-hit model (Knudson model) in which probably the first hit involves loss of heterozygosity (LOH) induced by 3p21 deletion. The latter occurs in almost 50–75% of ICCs (36). A subsequent mutation occurring in the remaining allele might lead to impairment of protein function and/or homeostasis (36). Protein function impairment by c.581-17_585del22 is most likely to reflect a deletion in the 3’-splice site of BAP1. Previously a c.581(-5)_c.590delACTAGGGCCCTGGGG mutation has been reported causing a premature truncation of BAP1 (50). This type of alterations that disrupt the nuclear localizations signal (aminoacids 717-722) of BAP1 are predicted to be inactivating (14, 51).\n\nAs BAP1 interacts with BRCA1, several lines of evidence indicate that alterations in the BRCA-mediated DNA repair pathway confers sensitivity to PARP inhibitor administration (52). PARP inhibitors act through synthetic lethality, whereby genetic DNA repair defects are enhanced by drug-induced defects in a compensatory pathway (53). Carriers of heterozygous BRCA1/2 mutations are sensitive to PARP inhibitor treatment as they lose the wild-type allele during tumorigenesis and thereby become deficient of the homologous recombination (HR) pathway of double-strand break DNA repair by BRCA1/2-null status. Four PARP inhibitors, olaparib, rucaparib, niraparib, and talazoparib, have been approved by the U.S. Food and Drug Administration (FDA) and by the European Medicines Agency (EMA). In 2014, olaparib was approved as maintenance therapy for platinum-sensitive advanced ovarian cancer with germline mutations in BRCA1/2. In 2016, rucaparib was approved for advanced ovarian cancer with both germline and somatic BRCA1/2 mutations. In 2017 and 2018, olaparib, rucaparib, and niraparib were approved for the maintenance treatment of recurrent, epithelial ovarian, fallopian tube, or primary peritoneal cancer irrespective of the BRCA status. Last, in 2018, olaparib and talazoparib were approved for HER2-negative locally advanced or metastatic breast cancer with germline BRCA1/2 mutations. Besides in ovarian and breast cancer, PARP inhibitor efficacy has also been demonstrated in other types of cancer including prostate and pancreatic cancer, and small cell lung carcinoma, irrespective of the BRCA status (54–61). It has become clear that any form of HR deficiency in tumors that phenocopies BRCA1/2 mutations, often referred to as BRCAness, may sensitize cells to PARP inhibitors (62). Indeed mutations in DNA damage response genes such as ATM, PRKDC, ATR, RPA1, DSS1, NBN, RAD51, RAD54, CHEK1, CHEK2, FANC genes, ERCC1, POLB, FEN1, and CDK12 have shown synthetic lethality in combination with PARP inhibitors (63–67).\n\nBAP1 is a HR DNA repair component and its loss sensitizes cancer cells to DNA repair defects (28). Currently, further investigations are needed to establish the real efficacy of PARP inhibitor on BAP1 mutated cancer cells. Some studies on various types of BAP1 mutated cancer cell lines demonstrated the potential efficacy of PARP inhibitors (68–70). A synergistic effect of PARP inhibitor and gemcitabine is described in BAP1 deficient cholangiocarcinoma cell lines (71). As a result, PARP inhibitors are currently under investigation alone or in combination with other therapies in cancer patients harboring a BAP1 mutant tumor including ICC (ClinicalTrials.gov Identifier: NCT03207347, NCT03786796, NCT03531840, and NCT03375307).\n\nIn the current clinical case, we have shown that PARP inhibitor administration can be potentially effective in BAP1 mutated ICC. Chemotherapeutic agents, such as platinum compounds which induce double-strand DNA breaks, are usually utilized prior to PARP inhibition in order to enhance DNA damage and induce PARP inhibition-mediated cell death (72). In addition PARP inhibitors are currently administered after obtaining a disease control with platinum compounds (73, 74). In the present clinical case, the PARP inhibitor olaparib was effective in controlling tumor progression, even though the patient did not benefit from FOLFIRI administration, a combination of 5-FU and topoisomerase I inhibitor irinotecan. Irinotecan exerts its anticancer effects through induction of single- and double-strand DNA breaks. 5-FU is an antimetabolite drug that exerts its anticancer effects through inhibition of DNA synthesis by inhibition of thymidylate synthase and incorporation of its metabolites into RNA and DNA. One could speculate that efficacy to PARP inhibitor was not enhanced by FOLFIRI administration, but rather by the previous administration of cisplatin. Additional studies are needed to define the timing and schedule of DNA damaging agents for PARP inhibitor enhancement in BAP1 deficient tumors.\n\nIn addition to BAP1 mutations, many other molecular alterations have been described in ICC such as KRAS, BRAF, IDH1, IDH2, EGFR, FGFR2, ROS1, ARID1A, PBRM1, and BRCA1 (8–16). These types of alterations are frequently mutually exclusive (8–16). In the current clinical case, BAP1 mutation is not associated with KRAS, BRAF, IDH1, IDH2, EGFR, FGFR2, ROS1, ARID1A, PBRM1, and BRCA1 alterations but with a RAD21 amplification. Further studies are needed to validate this type of association. RAD21 is a gene involved in the repair of DNA double-strand breaks, as well as in chromatid cohesion during mitosis (75, 76). Amplification of RAD21 is described in approximately 1.23% of cases reported in the AACR Project Genomics Evidence Neoplasia Information Exchange (AACR Project GENIE), including invasive breast carcinoma, prostate adenocarcinoma, lung adenocarcinoma and colon adenocarcinoma having the greatest prevalence (77). However, no prior data exists regarding RAD21 amplification in ICC. Whether RAD21 amplification might enhance the activity of a PARP inhibitor in BAP1 mutant ICC should be further investigated.\n\nBoth BAP1 and RAD21 alterations were detected by utilizing NGS analysis. Patient’s tumor tissue underwent analysis by several precision oncology testing methods to identify potentially oncogenic alterations. However, most of the tests performed did not detect any alterations. By comparing the results from the two most extensive tumor genomic profiles BAP1 was analyzed in both: the Foudation One CDx and Oncofocus test. However only the Foudation One CDx test was able to detect BAP1 and RAD21 alterations. These findings are likely to reflect the different methods utilized to detect potentially oncogenic alterations, the regions of the genes included in the analysis, the potential tumor heterogeneity especially with a low allele frequency of the variants and the percentage of tumor cells in the sample tested. Since there is no targeted regions for BAP1 it is unlikely that different NGS platforms only test selected exons. In our case the novel mutation c.581-17_585del22 of BAP1 was localized on exon 8 of BAP1, at the boundary of intron 7. Most of the NGS platforms include 20-25bp in the vicinity of exons. However the Oncofocus® Test did not detect the c.581-17_585del22 alteration of BAP1 alteration most likely because this region of the gene was not included in the analysis. In contrast, the Foundation One CDx platform included in the analysis the full exonic region of BAP1 besides including also RAD21 in the analysis. Foundation One CDx report contains information only about the genomic findings without allele frequency values. As limit of detection range at non-homopolymer context (insertion up to 42 bp and deletion up to 276 bp) is 6–10%, we can assume that the BAP1 c.581-17_585del mutated allele was present with a higher variant fraction in the metastatic tumor tissue analyzed. In addition, direct sequencing has a reported limit of detection of approximately 20% mutant alleles. In our case BAP1 sanger sequencing on primary ICC tumor tissue showed the unbalanced presence of the mutated allele, even if it is not possible to have a quantitative value, as with NGS or digital PCR, we can hypothesize an allele frequency close to the limit of detection. Therefore, we can assume that BAP1 c.581-17_585del mutated allele occurred with a high allele frequency, early in ICC oncogenesis.\n\nIn conclusion, genomic characterization of ICC tumors by NGS analysis can identify potential targetable oncogenic alterations in ICC, providing the possibility to improve patient survival. Specifically, BAP1 deletion and RAD21 amplification were identified and effectively targeted by PARP inhibitor administration. These results warrant further studies to define the role of PARP inhibitor in ICC harboring BAP1 and RAD21 alterations.\n\nData Availability Statement\nThe original contributions presented in the study are included in the article/\nSupplementary Material\n. Further inquiries can be directed to the corresponding author. \n\nEthics Statement\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nAuthor Contributions\nConception and design: FSa, SP, and UM. Acquisition of data: LL, VT, and FSa. Analysis and interpretation of data: FSa, AF, VC, FSc, and UM. Writing, review, and/or revision of the manuscript: FSa, LL, and CF. Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): LL, and VT. Study supervision: SP. Other (contributed clinical and pathological material; discussed results and implications of findings): SP, GT, and CF. All authors contributed to the article and approved the submitted version.\n\nFunding\nThe work was supported by Ministero dell’Università e della Ricerca (Progetti di Rilevante Interesse Nazionale (PRIN), 2017, CODICE 2017PHRC8X_003) (to SP).\n\nConflict of Interest\nUM reports personal fees (as speaker bureau or advisor) from Boehringer Ingelheim, AstraZeneca, Roche, MSD, Amgen and Merck, unrelated to the current work.\n\nThe remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nAcknowledgements\nThe authors wish to gratefully acknowledge the patient for allowing us to publish his clinical case.\n\nSupplementary Material\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2020.567289/full#supplementary-material\n\n\nClick here for additional data file.\n\n Abbreviations\nAFP, alpha fetoprotein; AJCC, American Joint Committee on Cancer; ARID1A, AT-rich interactive domain-containing protein 1A; ATM, ataxia-telangiectasia mutated; ATR, ataxia telangiectasia and Rad3-related protein; BAP1, BRCA1 associated protein 1; BRAF, v-raf murine sarcoma viral oncogene homolog B1; BRCA1, Breast cancer type 1 susceptibility protein; CCA, Cholangiocarcinoma; CDK12, Cyclin Dependent Kinase 12; CHEK1-CHEK2, Checkpoint kinase 1-2; CK7, Cytokeratin 7; CK19, Cytokeratin 19; CT, computed tomography; EGFR, Epidermal Growth Factor Receptor; EMA, European Medicines Agency; ERCC1, excision repair cross-complementation group 1; FANC, Fanconi anaemia complementation group; FDA, Food and Drug Administration; FEN1, Flap endonuclease 1; FFPE, formalin fixed paraffin embedded; FGFR2, Fibroblast Growth Factor Receptor 2; 5-FU, 5-fluorouracil; HepPar1, Hepatocyte Paraffin 1; HER2, Human epidermal growth factor receptor 2; HR, homologous recombination; ICC, Intrahepatic cholangiocarcinoma; IDH1/IDH2, Isocitrate Dehydrogenase 1/2; IHC, immunohistochemical; KRAS, Kirsten ras oncogene homolog; LOH, loss of heterozygosity; MSS, Microsatellite Stable; NBN, Nibrin; NGS, next-generation sequencing; NRAS, neuroblastoma; RAS, viral oncogene homolog; RPA1, Replication protein A 70 kDa DNA-binding subunit; NTRK, neurotrophic receptor tyrosine kinase 1; PARP, poly ADP ribose polymerase; PCR, polymerase chain reaction; PR, partial response; PBRM1, Polybromo 1; PCR, polymerase chain reaction; PD, progression of disease; POLB, DNA Polymerase Beta; PRKDC, Protein Kinase; DNA-Activated, Catalytic Subunit; PTA, percutaneous thermal ablation; RAD51-RAD54, radiation-repair genes 51–54; RECIST, Response evaluation criteria in solid tumors; ROS1, ROS proto-oncogene 1receptor tyrosine kinase; STR, Short Tandem Repeat.\n==== Refs\nReferences\n1 \nMassarweh NN El-Serag HB \nEpidemiology of Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma\n. 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"issue": "10()",
"journal": "Frontiers in oncology",
"keywords": "BAP1; Poly ADP ribose polymerase (PARP) inhibitor; RAD21; cholangio carcinoma; olaparib; precision oncology",
"medline_ta": "Front Oncol",
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"nlm_unique_id": "101568867",
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"pages": "567289",
"pmc": null,
"pmid": "33330039",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
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"title": "Case Report: BAP1 Mutation and RAD21 Amplification as Predictive Biomarkers to PARP Inhibitor in Metastatic Intrahepatic Cholangiocarcinoma.",
"title_normalized": "case report bap1 mutation and rad21 amplification as predictive biomarkers to parp inhibitor in metastatic intrahepatic cholangiocarcinoma"
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"abstract": "Transitional cell carcinoma (TCC) arising from renal pelvis rarely gives rise to cutaneous metastasis. Due to the insufficient literature, the exact incidence is not known till date. Moreover, the diagnosis is confirmed on histopathological examination with the aid of immunohistochemistry wherever needed. We are presenting a case of a 70-year-old female with metastatic TCC from the renal pelvis to the abdominal skin, which was diagnosed on cytology alone along with the cell block preparation. We also highlight the important cytomorphological and immunohistochemical features noted, which need to be known to avoid any diagnostic delay.",
"affiliations": "Department of Pathology, VMMC & Safdarjung Hospital, New Delhi 110029, India. Electronic address: pragya986800@gmail.com.;Department of Pathology, VMMC & Safdarjung Hospital, New Delhi 110029, India.;Department of Radiotherapy, VMMC & Safdarjung Hospital, New Delhi 110029, India.",
"authors": "Singh|Pragya|P|;Kolte|Sachin|S|;Singh|Gunjesh Kumar|GK|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.jnci.2017.11.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1110-0362",
"issue": "29(4)",
"journal": "Journal of the Egyptian National Cancer Institute",
"keywords": "Cytology; Renal pelvis; Skin metastasis; Transitional cell carcinoma",
"medline_ta": "J Egypt Natl Canc Inst",
"mesh_terms": "D000368:Aged; D002295:Carcinoma, Transitional Cell; D005260:Female; D006651:Histocytochemistry; D006801:Humans; D007680:Kidney Neoplasms; D007682:Kidney Pelvis; D012878:Skin Neoplasms; D014057:Tomography, X-Ray Computed",
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"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cytological diagnosis of a rare case of cutaneous metastasis from transitional cell carcinoma, renal pelvis.",
"title_normalized": "cytological diagnosis of a rare case of cutaneous metastasis from transitional cell carcinoma renal pelvis"
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"companynumb": "IN-CIPLA (EU) LIMITED-2017IN30960",
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"abstract": "OBJECTIVE\nUsing specialized tools, we assessed patients receiving perampanel (PER) to investigate its effects on aggression and depression, as well as the impact of other concomitant antiepileptic drugs (AEDs) on those conditions.\n\n\nMETHODS\nSeventy-seven patients with epilepsy were initially enrolled, then examined at entry and 12 weeks later (endpoint). At both examinations, assessments were performed with the Buss Perry Aggression Questionnaire (BAQ) and Neurological Disorders Depression Inventory for Epilepsy (NDDI-E). Ultimately, 59 patients completed the study.\n\n\nRESULTS\nTotal BAQ (p = 0.013) and NDDI-E (p = 0.000) scores at the endpoint were significantly increased in comparison with those at entry. Analysis with 4 subscales showed increases in both verbal and physical aggression, while multivariate analysis revealed that concomitant AED administration did not have a significant impact on the increase of BAQ or NDDI-E score. A dose-dependent effect of PER was confirmed in BAQ, but not NDDI-E results. PER was discontinued due to adverse psychiatric effects in 3.9% of the patients.\n\n\nCONCLUSIONS\nThe present findings indicate that PER increases assessment scores indicative of aggression as well as depression. No additional aggression-augmenting effect was seen with concomitant AED administration.",
"affiliations": "Neuropsychiatric Department, Aichi Medical University, Japan. Electronic address: hiroko52@aichi-med-u.ac.jp.;Neuropsychiatric Department, Aichi Medical University, Japan.",
"authors": "Goji|Hiroko|H|;Kanemoto|Kousuke|K|",
"chemical_list": "D000927:Anticonvulsants; D009570:Nitriles; D011728:Pyridones; C551441:perampanel",
"country": "England",
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"issue": "67()",
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"keywords": "Aggression; BAQ; Depression; NDDI-E; Perampanel",
"medline_ta": "Seizure",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000374:Aggression; D000927:Anticonvulsants; D003863:Depression; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D011446:Prospective Studies; D011728:Pyridones; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9306979",
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"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "The effect of perampanel on aggression and depression in patients with epilepsy: A short-term prospective study.",
"title_normalized": "the effect of perampanel on aggression and depression in patients with epilepsy a short term prospective study"
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"abstract": "We report the clinical course of a diabetic patient with bilateral cataract and rubeosis in association with ocular ischemic syndrome and initially treated him with simultaneous intravitreal 2 mg aflibercept and 2 mg triamcinolone acetonide injection at the same setting prior to planned cataract surgery and further photocoagulation. However, sterile anterior segment inflammation characterized by hypopyon occurred four days apart in OU. Right eye developed the sterile inflammation at the third postinjection day and the left eye developed the sterile inflammation at the seventh postinjection day (two days after the uneventful cataract surgery with intraocular lens implantation) without any pain or significant redness. Vitreous biopsy taken during the right phacovitrectomy was negative for any microbial contamination. Both eyes were treated successfully with intensive topical prednisolone acetate with a relatively good visual outcome. It is likely that underlying ocular ischemic syndrome might have facilitated the formation of sterile inflammation as blood-aqueous barrier disruption and flare have already been present.",
"affiliations": "Department of Ophthalmology, Dokuz Eylul University, Izmir, Turkey.;Department of Ophthalmology, Dokuz Eylul University, Izmir, Turkey.;Department of Radiology, Dokuz Eylul University, Izmir, Turkey.;Department of Ophthalmology, Dokuz Eylul University, Izmir, Turkey.;Department of Ophthalmology, Dokuz Eylul University, Izmir, Turkey.",
"authors": "Durmaz Engin|Ceren|C|;Ayhan|Ziya|Z|;Men|Süleyman|S|;Yaman|Aylin|A|0000-0002-0391-5420;Saatci|A Osman|AO|0000-0001-6848-7239",
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"doi": "10.1155/2017/5123963",
"fulltext": "\n==== Front\nCase Rep Ophthalmol MedCase Rep Ophthalmol MedCRIOPMCase Reports in Ophthalmological Medicine2090-67222090-6730Hindawi 10.1155/2017/5123963Case ReportBilateral Severe Sterile Inflammation with Hypopyon after Simultaneous Intravitreal Triamcinolone Acetonide and Aflibercept Injection in a Patient with Bilateral Marked Rubeosis Associated with Ocular Ischemic Syndrome Durmaz Engin Ceren \n1\nAyhan Ziya \n1\nMen Süleyman \n2\nhttp://orcid.org/0000-0002-0391-5420Yaman Aylin \n1\nhttp://orcid.org/0000-0001-6848-7239Saatci A. Osman \n1\n\n*\n1Department of Ophthalmology, Dokuz Eylul University, Izmir, Turkey2Department of Radiology, Dokuz Eylul University, Izmir, Turkey*A. Osman Saatci: osman.saatci@deu.edu.trAcademic Editor: Pradeep Venkatesh\n\n2017 13 3 2017 2017 512396326 9 2016 6 3 2017 Copyright © 2017 Ceren Durmaz Engin 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.We report the clinical course of a diabetic patient with bilateral cataract and rubeosis in association with ocular ischemic syndrome and initially treated him with simultaneous intravitreal 2 mg aflibercept and 2 mg triamcinolone acetonide injection at the same setting prior to planned cataract surgery and further photocoagulation. However, sterile anterior segment inflammation characterized by hypopyon occurred four days apart in OU. Right eye developed the sterile inflammation at the third postinjection day and the left eye developed the sterile inflammation at the seventh postinjection day (two days after the uneventful cataract surgery with intraocular lens implantation) without any pain or significant redness. Vitreous biopsy taken during the right phacovitrectomy was negative for any microbial contamination. Both eyes were treated successfully with intensive topical prednisolone acetate with a relatively good visual outcome. It is likely that underlying ocular ischemic syndrome might have facilitated the formation of sterile inflammation as blood-aqueous barrier disruption and flare have already been present.\n==== Body\n1. Introduction\nOcular ischemic syndrome (OIS) is characterized with hypoperfusion related anterior and posterior segment changes in association with the occlusion or stenosis of carotid artery [1, 2]. Mild iritis, flare, and posterior synechia are the main anterior segment findings whereas flare is more marked than the cellular inflammatory reaction. Retinal vascular changes such as narrowed retinal arteries, dilated retinal veins, scattered retinal hemorrhages, and cotton wool spots are among the posterior segment findings.\n\nWe report the clinical outcome of a patient with bilateral rubeosis due to ocular ischemic syndrome who developed bilateral sterile severe inflammation with hypopyon following the bilateral simultaneous intravitreal injection of aflibercept and triamcinolone acetonide at the same setting.\n\n2. Case Report\nA 66-year-old man with a history of type 2 diabetes of 20 years' duration, high blood pressure, and previous larynx cancer surgery was referred to us for the treatment of bilateral severe rubeosis iridis and cataract. Referring physician performed two sessions of laser photocoagulation with the diagnosis of proliferative diabetic retinopathy in the left eye but no laser could be performed in the right eye due to presence of a dense cataract. He was put on a fixed combination of timolol maleate and dorzolamide twice a day in OU.\n\nOn our examination, visual acuity was hand motions in OD and counting fingers at 3 meters in OS. Slit-lamp examination revealed severe rubeosis iridis with an almost white cataract in OD and 4+ nuclear sclerosis in OS (Figures 1(a) and 1(b)). Intraocular pressure was 16 mm Hg with the Goldmann applanation tonometer in OU. While the right fundus could not be visualized, there were scattered laser scars 360° and a dry looking macula in OS with the indirect ophthalmoscopy. The right posterior segment was normal with the B-scan ultrasonography. We initially felt that bilateral rubeosis iridis was due to proliferative diabetic retinopathy and planned to complete the laser photocoagulation rapidly after the removal of cataract and intraocular lens implantation in OU. In order to obtain a relatively quiet eye prior to cataract surgery we bilaterally injected intravitreal 2 mg aflibercept (Eylea; Regeneron, Tarrytown, NY, USA) and 2 mg triamcinolone acetonide (Sinakort A, İbrahim Etem Ulagay, Turkey) simultaneously at the same setting in the operating theatre as we had a good experience with the simultaneous anti-VEGF and steroid injection in eyes with severe diabetic macular edema and proliferative diabetic retinopathy [3]. At the third postinjection day, there was one mm hypopyon with 2+ cells in the right anterior chamber (Figure 1(c)) and the left eye was quiet with markedly regressed rubeosis. Most noteworthily, the patient had no pain or any other relevant complaints in the OD. We elected to follow the right eye with hourly prednisolone acetate drops and cyclopentolate 1% three times a day and hospitalized the patient. The next day, the hypopyon was markedly diminished in the right eye and no further change was noted in the left eye. We performed an uneventful cataract surgery and intraocular lens implantation in the OS five days after the intravitreal injection. However, the left eye developed one mm hypopyon with 2+ cells again without any pain at the second postoperative day (Figure 1(d)).\n\nThe left eye was also put on hourly prednisolone acetate drops and 1% cyclopentolate tid. We immediately performed a phacovitrectomy in the OD to obtain a vitreous sample for the microbial investigation, remove the already present dense cataract, and perform the endophotocoagulation at the same time. A vitreous sample was obtained prior to start of 23 g vitrectomy and then two other 23 g sclerotomies were done. Following the completion of uneventful phacoemulsification and intraocular lens implantation, core vitrectomy was performed. The vitreous looked almost totally clear and thereby no antibiotics were injected as we were planning to do so beforehand. The severity of retinopathy was mild to moderate looking and there was no visible neovascularization. Anyhow, a 360° panretinal photocoagulation was performed. Direct microscopic evaluation of the vitreous specimen was normal and no growth was noted in the vitreous culture. Meanwhile, we suspected the presence of OIS and thereby decided to investigate the carotid artery system. Computerized tomography angiographic evaluation showed that both internal and external carotid arteries were perfused only by collaterals and there was marked stenosis in the common carotid arteries (Figure 2).\n\nThe patient was put on 100 mg acetyl salicylic acid upon the neurology consultation. We suggested that the event was bilateral sterile inflammation triggered by the intravitreal injection of aflibercept and/or triamcinolone acetonide in the presence of severe rubeosis iridis due to ocular ischemic syndrome. A week after the left cataract surgery and five days after the right phacovitrectomy both anterior segments became quieter with an hourly prednisolone acetate drops and topical steroid was tapered slowly. Two weeks later, additional laser photocoagulation was administered to complete the panretinal photocoagulation in OS. Three months later, the best-corrected visual acuity was 4/10 in OD and 1/10 in OS. Both anterior segments were quiet (Figures 3(a) and 3(b)). Intraocular pressure was normal in OU. Both posterior segments had full panretinal photocoagulation with a normal macula architecture (Figures 3(c), 3(d), 3(e), and 3(f)).\n\n3. Discussion\nSterile endophthalmitis may occur almost after intravitreal injection of any drug but when it happens, the clinician faces a great diagnostic and treatment challenge as it is difficult to differentiate the event from the infectious endophthalmitis [4].\n\nSterile inflammation following the intravitreal aflibercept injection is previously reported but its cause is still unknown [5–10]. The American Society of Retina Specialists' therapeutic surveillance subcommittee first reported 15 cases of aflibercept related sterile inflammation [6] and later expanded this series to 56 cases from the practices throughout the United States between December 2011 and February 2014 [10]. Most cases presented with an initial visual deterioration and intraocular inflammation without prominent redness, severe pain, or hypopyon and median time to presentation was two days after the injection but it could be as late as 30 days. However, there was a case presenting with a hypopyon. Thirty-seven cases (66%) were treated with topical corticosteroids and/or observation alone. The mean time to resolution was 28,6 days. No difference in visual outcome was detected in patients who received only topical corticosteroids and/or observation with the eyes treated with intravitreal antibiotics or vitrectomy. In none of the cases with a vitreous tap a microbial agent could be identified. Most cases had a history of prior aflibercept injection and even some cases were successfully rechallenged with aflibercept suggesting that the sterile inflammation might not be related to patient specific immunologic response. Goldberg et al. [7] reviewed the medical records of 20 patients who presented with noninfectious inflammation after the intravitreal aflibercept injection out of 5356 aflibercept injections. The patients presented one to 13 days after the injections (median, 3 days). While three of 20 (15%) had pain and two of 20 (10%) had conjunctival injection one patient developed also a hypopyon. Patients on average had received six prior aflibercept injections (range 0–16). Four patients were subsequently rechallenged with aflibercept and only one developed inflammation again after five additional aflibercept injections. All patients were managed with frequent topical steroids. The overall incidence of inflammation after intravitreal aflibercept injection was found to be 20 of 5356 injections (0,37%) or 19 of 844 patients (2,25%). Fine et al. [9] published a single-center retrospective study on 28 cases of intraocular inflammation noted after a total of 5905 aflibercept injections among the 1660 patients. Vitreous culture and subsequent antibiotic injection were performed in eight cases and all cultures were negative. The remaining patients received only topical corticosteroids. The authors calculated the frequency of inflammation as 0,47% per injection following the aflibercept injections.\n\nSterile endophthalmitis after the intravitreal injection of triamcinolone acetonide occurs between 0,20 and 12,3% of the injections [11–15]. Most of the time, it occurs within the first three days of injection and the patients do not complain of eye pain and hypopyon does not develop. Aetiology of the sterile inflammation is not still fully understood [4]. Several suggestions had been made. Contamination of the triamcinolone vials with endotoxins has been postulated [11]. A toxic effect of the triamcinolone itself as well as the preservatives present in the vial such as benzyl alcohol, polysorbate 80, and carboxymethylcellulose sodium has also been incriminated [16, 17]. However removal of benzyl alcohol has not eliminated the occurrence of sterile inflammation [18]. Moreover, commercial form of preservative-free triamcinolone acetonide was also reported to create a sterile inflammation [19]. Some authors suggested that triamcinolone acetonide related sterile inflammation might be induced by the migration of macrophages induced by the crystals [12, 20]. Although sterile inflammation seen after the intravitreal triamcinolone acetonide injection is generally thought to have a benign course some reported cases had a very poor visual and anatomic outcome [21].\n\nIn the present case, we concluded that the bilateral severe inflammation together with the hypopyon was sterile as there was no clue for infectious aetiology such as the presence of clear vitreous observed during the right phacovitrectomy and the negative vitreous culture. In addition, both affected eyes responded pretty well to topical frequent corticosteroid administration. Both simultaneously administered aflibercept and/or triamcinolone acetonide might be the factor in the occurrence of sterile inflammation either alone or together. It is likely that underlying ocular ischemic syndrome might facilitate the formation of sterile inflammation as ocular ischemic syndrome can be associated with a blood-aqueous barrier disruption and flare.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 Color anterior segment picture: (a) right eye, whitish cataract and rubeosis iridis at the presentation; (b) left eye, nuclear sclerosis and rubeosis iridis at the presentation; (c) right eye, hypopyon, regressed rubeotic vessels, and the whitish cataract at the third postinjection day; (d) left eye, mild corneal edema, hypopyon, and intraocular lens at the second postcataract surgery (seventh postinjection day).\n\nFigure 2 Coronal oblique reformatted computed tomography angiographic image through the neck shows occlusion of both common carotid arteries. Both internal and external carotid arteries are patent, however, filling via collateral flow. Intracranial carotid circulation and posterior circulation are patent.\n\nFigure 3 (a) Color anterior segment picture of the right eye with a quiet anterior segment and intraocular lens; (b) right composite fundus picture showing the laser scars scattered 360 degrees and a normal-looking macula; (c) right OCT scan depicting the normal macular contour; (d) color anterior segment picture of the left eye with a quiet anterior segment and intraocular lens; (e) left composite color fundus picture demonstrating the 360 degrees' scattered laser scars and a normal-looking macula; (f) left OCT scan depicting the normal macula.\n==== Refs\n1 Terelak-Borys B. Skonieczna K. Grabska-Liberek I. Ocular ischemic syndrome—a systematic review Medical Science Monitor 2012 18 8 RA138 RA144 2-s2.0-84866071372 22847215 \n2 Mendrinos E. Machinis T. G. Pournaras C. J. Ocular Ischemic Syndrome Survey of Ophthalmology 2010 55 1 2 34 10.1016/j.survophthal.2009.02.024 2-s2.0-71649085133 19833366 \n3 Osman Saatci A. Ayhan Z. Durmaz Engin C. Simultaneous intravitreal ranibizumab and dexamethasone implant administration at the same setting in eyes with severe diabetic macular edema Open Journal of Ophthalmology 2016 6 2 112 118 10.4236/ojoph.2016.62016 \n4 Marticorena J. Romano V. Gómez-Ulla F. Sterile endophthalmitis after intravitreal injections Mediators of Inflammation 2012 2012 6 928123 10.1155/2012/928123 \n5 Glading J. A. Lake S. Craig J. E. Supramaniam D. Delayed onset panuveitis following intravitreal aflibercept injection BMJ Case Reports 2014 2014 10.1136/bcr-2013-202515 \n6 Hahn P. Kim J. E. Stinnett S. Aflibercept-related sterile inflammation Ophthalmology 2013 120 5 1100 1101.e5 10.1016/j.ophtha.2012.11.018 2-s2.0-84877750900 23642742 \n7 Goldberg R. A. Shah C. P. Wiegand T. W. Heier J. S. Noninfectious inflammation after intravitreal injection of aflibercept: clinical characteristics and visual outcomes American Journal of Ophthalmology 2014 158 4 733.e1 737.e1 10.1016/j.ajo.2014.06.019 2-s2.0-84908510760 24983791 \n8 Kim J. Y. You Y. S. Kwon O. W. Kim S. H. Sterile inflammation after intravitreal injection of aflibercept in a Korean population Korean Journal of Ophthalmology 2015 29 5 325 330 10.3341/kjo.2015.29.5.325 26457038 \n9 Fine H. F. Roth D. B. Shah S. P. Haque T. Wheatley H. M. Frequency and characteristics of intraocular inflammation after aflibercept injection Retina 2015 35 4 681 686 10.1097/IAE.0000000000000398 2-s2.0-84926150914 25394166 \n10 Hahn P. Chung M. M. Flynn H. W. Jr. Postmarketing analysis of aflibercept-related sterile intraocular inflammation JAMA Ophthalmology 2015 133 4 421 426 10.1001/jamaophthalmol.2014.5650 2-s2.0-84928252920 25590968 \n11 Roth D. B. Chieh J. Spirn M. J. Green S. N. Yarian D. L. Chaudhry N. A. Noninfectious endophthalmitis associated with intravitreal triamcinolone injection Archives of Ophthalmology 2003 121 9 1279 1282 10.1001/archopht.121.9.1279 2-s2.0-0141499061 12963610 \n12 Nelson M. L. Tennant M. T. S. Sivalingam A. Regillo C. D. Belmont J. B. Martidis A. Infectious and presumed noninfectious endophthalmitis after intravitreal triamcinolone acetonide injection Retina 2003 23 5 686 691 10.1097/00006982-200310000-00014 2-s2.0-0142244629 14574256 \n13 Özkiriş A. Erkiliç K. Complications of intravitreal injection of triamcinolone acetonide Canadian Journal of Ophthalmology 2005 40 1 63 68 10.1016/S0008-4182(05)80119-X 2-s2.0-16344389598 15825532 \n14 Moshfeghi D. M. Kaiser P. K. Bakri S. J. Presumed sterile endophthalmitis following intravitreal triamcinolone acetonide injection Ophthalmic Surgery Lasers and Imaging 2005 36 1 24 29 2-s2.0-19944432858 \n15 Fong A. H. Chan C. K. Presumed sterile endophthalmitis after intravitreal triamcinolone (Kenalog)—more common and less benign than we thought? Asia-Pacific Journal of Ophthalmology 2017 6 1 45 49 10.1097/apo.0000000000000194 28161929 \n16 Yeung C. K. Chan K. P. Chan C. K. M. Pang C. P. Lam D. S. C. Cytotoxicity of triamcinolone on cultured human retinal pigment epithelial cells: comparison with dexamethasone and hydrocortisone Japanese Journal of Ophthalmology 2004 48 3 236 242 10.1007/s10384-003-0053-8 2-s2.0-2542467968 15175915 \n17 Kai W. Yanrong J. Xiaoxin L. Vehicle of triamcinolone acetonide is associated with retinal toxicity and transient increase of lens density Graefe's Archive for Clinical and Experimental Ophthalmology 2006 244 9 1152 1159 10.1007/s00417-005-0251-9 2-s2.0-33747640491 \n18 Carrero J. L. Barcia M. G. Flores I. P. Sterile endophthalmitis after benzyl alcohol-filtered triamcinolone acetonide injection Archives of Ophthalmology 2008 126 1 142 143 10.1001/archophthalmol.2007.20 2-s2.0-38349073483 18195239 \n19 Bakri S. J. Edwards A. O. Couch S. M. Noninfectious endophthalmitis occurring after intravitreal Triesence injection Retinal Cases & Brief Reports 2009 3 3 316 318 10.1097/icb.0b013e318199b086 25389596 \n20 Jonas J. B. Kreissig I. Degenring R. Intravitreal triamcinolone acetonide for treatment of intraocular proliferative, exudative, and neovascular diseases Progress in Retinal and Eye Research 2005 24 5 587 611 10.1016/j.preteyeres.2005.01.004 2-s2.0-21944444230 16005407 \n21 Yoon S. J. Rhee D. Y. Marx J. L. Anatomic and visual outcomes of noninfectious endophthalmitis after intravitreal triamcinolone American Journal of Ophthalmology 2009 147 6 1031 1036 10.1016/j.ajo.2008.12.034 2-s2.0-67349247525 19268893\n\n",
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"title": "Bilateral Severe Sterile Inflammation with Hypopyon after Simultaneous Intravitreal Triamcinolone Acetonide and Aflibercept Injection in a Patient with Bilateral Marked Rubeosis Associated with Ocular Ischemic Syndrome.",
"title_normalized": "bilateral severe sterile inflammation with hypopyon after simultaneous intravitreal triamcinolone acetonide and aflibercept injection in a patient with bilateral marked rubeosis associated with ocular ischemic syndrome"
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"abstract": "BACKGROUND\nFlolan (iFLO) and Veletri (iVEL) are 2 inhaled epoprostenol formulations. There is no published literature comparing these formulations in critically ill patients with refractory hypoxemia.\n\n\nOBJECTIVE\nTo compare efficacy, safety, and cost outcomes in patients who received either iFLO or iVEL for hypoxic respiratory failure.\n\n\nMETHODS\nThis was a retrospective, single-center analysis of adult, mechanically ventilated patients receiving iFLO or iVEL for improvement in oxygenation. The primary end point was the change in the PaO2/FiO2 ratio after 1 hour of pulmonary vasodilator therapy. Secondary end points assessed were intensive care unit (ICU) length of stay (LOS), hospital LOS, duration of study therapy, duration of mechanical ventilation, mortality, incidence of adverse events, and cost.\n\n\nRESULTS\nA total of 104 patients were included (iFLO = 52; iVEL = 52). More iFLO patients had acute respiratory distress syndrome compared with the iVEL group (61.5 vs 34.6%; P = 0.01). There was no difference in the change in the PaO2/FiO2 ratio after 1 hour of therapy (33.04 ± 36.9 vs 31.47 ± 19.92; P = 0.54) in the iFLO and iVEL groups, respectively. Patients who received iVEL had a shorter duration of mechanical ventilation (P < 0.001) and ICU LOS (P < 0.001) but not hospital LOS (P = 0.86) and duration of therapy (P = 0.36). No adverse events were attributed to pulmonary vasodilator therapy, and there was no difference in cost.\n\n\nCONCLUSIONS\nWe found no difference between iFLO and iVEL when comparing the change in the PaO2/FiO2 ratio, safety, and cost in hypoxic, critically ill patients. There were differences in secondary outcomes, likely a result of differences in underlying indication for inhaled epoprostenol.",
"affiliations": "Cleveland Clinic, Cleveland, OH, USA torbich@ccf.org.;Brigham and Women's Hospital, Boston, MA, USA.;Brigham and Women's Hospital, Boston, MA, USA.;Brigham and Women's Hospital, Boston, MA, USA.;Brigham and Women's Hospital, Boston, MA, USA.;Brigham and Women's Hospital, Boston, MA, USA.",
"authors": "Torbic|Heather|H|;Szumita|Paul M|PM|;Anger|Kevin E|KE|;Nuccio|Paul|P|;Lagambina|Susan|S|;Weinhouse|Gerald|G|",
"chemical_list": "D011725:Pyridines; D013777:Tetrazoles; D014665:Vasodilator Agents; C120582:tezosentan; D011464:Epoprostenol",
"country": "United States",
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"issue": "50(2)",
"journal": "The Annals of pharmacotherapy",
"keywords": "critical care; pharmacoeconomics; prostaglandins; respiratory failure; vasodilators",
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000280:Administration, Inhalation; D000328:Adult; D000368:Aged; D016638:Critical Illness; D011464:Epoprostenol; D005260:Female; D006801:Humans; D000860:Hypoxia; D007362:Intensive Care Units; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D011725:Pyridines; D012121:Respiration, Artificial; D012128:Respiratory Distress Syndrome; D012131:Respiratory Insufficiency; D012189:Retrospective Studies; D013777:Tetrazoles; D013997:Time Factors; D014665:Vasodilator Agents",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "106-12",
"pmc": null,
"pmid": "26668204",
"pubdate": "2016-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical and Economic Impact of Formulary Conversion From Inhaled Flolan to Inhaled Veletri for Refractory Hypoxemia in Critically Ill Patients.",
"title_normalized": "clinical and economic impact of formulary conversion from inhaled flolan to inhaled veletri for refractory hypoxemia in critically ill patients"
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"abstract": "IL-17 antagonism is among the most potent treatments for psoriasis. Generally safe, new onset and exacerbations of inflammatory bowel disease may occur in association with IL-17 therapy. We describe a patient with long-standing history of psoriasis and psoriatic arthritis in whom asymptomatic Crohn's disease was identified during treatment with secukinumab. The patient underwent an elective colonoscopy for colorectal cancer screening which revealed inflammation and multiple ulcers in the terminal ileum suggestive of Crohn's disease. While the patient did not have any gastrointestinal symptoms, he was diagnosed as having asymptomatic Crohn's disease. Given the association of inflammatory bowel disease with secukinumab treatment, secukinumab was discontinued. Although in this patient, Crohn's disease was identified during treatment with secukinumab, a direct causal relationship cannot be assumed. Medications that are effective for both psoriasis and inflammatory bowel disease may be a good choice in patients with psoriasis who have comorbid Crohn's disease or develop inflammatory bowel disease during treatment with another biologic.",
"affiliations": "Center for Dermatology Research, Department of Dermatology, Wake Forest School of Medicine, Winston-Salem, NC, USA.;Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, USA.;Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, USA.;Department of Internal Medicine, Section of Gastroenterology, Wake Forest School of Medicine, Winston-Salem, NC, USA.;Center for Dermatology Research, Department of Dermatology, Wake Forest School of Medicine, Winston-Salem, NC, USA.",
"authors": "Haidari|Wasim|W|;Al-Naqshabandi|Sarah|S|;Ahn|Christine S|CS|;Bloomfeld|Richard S|RS|;Feldman|Steven R|SR|",
"chemical_list": null,
"country": "England",
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"doi": "10.1177/2050313X19893580",
"fulltext": "\n==== Front\nSAGE Open Med Case RepSAGE Open Med Case RepSCOspscoSAGE Open Medical Case Reports2050-313XSAGE Publications Sage UK: London, England 10.1177/2050313X1989358010.1177_2050313X19893580JCMS Case ReportAsymptomatic Crohn’s disease identified in a patient being treated\nwith secukinumab: A case report Haidari Wasim 1Al-Naqshabandi Sarah 2Ahn Christine S 2Bloomfeld Richard S 3Feldman Steven R 1241 Center for Dermatology Research,\nDepartment of Dermatology, Wake Forest School of Medicine, Winston-Salem, NC,\nUSA2 Department of Pathology, Wake Forest\nSchool of Medicine, Winston-Salem, NC, USA3 Department of Internal Medicine, Section\nof Gastroenterology, Wake Forest School of Medicine, Winston-Salem, NC, USA4 Department of Social Sciences &\nHealth Policy, Wake Forest School of Medicine, Winston-Salem, NC, USAWasim Haidari, Center for Dermatology\nResearch, Department of Dermatology, Wake Forest School of Medicine, Medical\nCenter Boulevard, Winston-Salem, NC 27157-1071, USA. Email:\nwh374@georgetown.edu6 12 2019 2019 7 2050313X19893580© The Author(s) 20192019SAGE PublicationsThis article is distributed under the terms of the Creative Commons\nAttribution-NonCommercial 4.0 License (http://creativecommons.org/licenses/by-nc/4.0/) which\npermits non-commercial use, reproduction and distribution of the work\nwithout further permission provided the original work is attributed as\nspecified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).IL-17 antagonism is among the most potent treatments for psoriasis. Generally\nsafe, new onset and exacerbations of inflammatory bowel disease may occur in\nassociation with IL-17 therapy. We describe a patient with long-standing history\nof psoriasis and psoriatic arthritis in whom asymptomatic Crohn’s disease was\nidentified during treatment with secukinumab. The patient underwent an elective\ncolonoscopy for colorectal cancer screening which revealed inflammation and\nmultiple ulcers in the terminal ileum suggestive of Crohn’s disease. While the\npatient did not have any gastrointestinal symptoms, he was diagnosed as having\nasymptomatic Crohn’s disease. Given the association of inflammatory bowel\ndisease with secukinumab treatment, secukinumab was discontinued. Although in\nthis patient, Crohn’s disease was identified during treatment with secukinumab,\na direct causal relationship cannot be assumed. Medications that are effective\nfor both psoriasis and inflammatory bowel disease may be a good choice in\npatients with psoriasis who have comorbid Crohn’s disease or develop\ninflammatory bowel disease during treatment with another biologic.\n\nPsoriasisbiologicinflammatory bowel diseaseCrohn’s diseasecover-dateJanuary-December 2019typesetterts1\n==== Body\nIntroduction\nDermatologists and patients with plaque psoriasis have enjoyed the dramatic\nimprovement in outcomes, thanks to a number of biologic treatments. IL-17 antagonism\nis among the most potent treatments for psoriasis. Generally safe, new onset and\nexacerbations of inflammatory bowel disease (IBD) can occur in psoriasis patients\nreceiving IL-17 therapy.1 We describe a patient with long-standing history of psoriasis and psoriatic\narthritis (PsA) in whom asymptomatic Crohn’s disease (CD) was identified during\ntreatment with secukinumab.\n\nCase report\nThe subject is a 69-year-old male who was diagnosed with psoriasis and PsA over\n45 years ago. Throughout this time period, patient’s psoriasis has been treated with\na variety of medications, including methotrexate, etanercept and adalimumab,\nsupplemented with intermittent dexamethasone as needed for arthritis pain; each\nworked well though appeared to become less effective with time. The patient was then\ntreated with secukinumab for a year and a half, with excellent control of both the\npsoriasis and PsA. The psoriasis was essentially 100% clear, and the joint pain had\nresolved to the point that the intermittent dexamethasone was rarely needed. There\nwas no apparent side effect of the secukinumab.\n\nThe patient underwent an elective colonoscopy for colorectal cancer screening in\nFebruary 2019, which revealed inflammation and multiple ulcers in the terminal\nileum, suggestive of CD with a normal-appearing colon (Figure 1). Terminal ileum biopsies revealed\nchronic active ileitis, which is seen in CD; however, there were no granulomas, no\ncrypt abscesses and no evidence of dysplasia or malignancy (Figure 2). While the patient did not have any\ngastrointestinal symptoms, he was diagnosed as having asymptomatic CD. Given the\nassociation of IBD with secukinumab, secukinumab was discontinued and the patient\nwas started on ustekinumab. It was later switched to guselkumab because the\npsoriasis and joint pain had recurred. No follow-up colonoscopy was done.\n\nFigure 1. Endoscopy of the terminal ileum. (a) The black arrows show multiple ulcers\nwith regular borders on edematous mucosa seen in the terminal ileum of the\npatient. (b) The blue arrows show edematous erythematous mucosa with\nnodularity in patient’s terminal ileum. (c) Endoscopy of healthy terminal\nileum from another patient being shown for comparison.\n\nFigure 2. Histopthology of the ileal mucosa biopsy. (a) Histopathology of the ileal\nmucosa demonstrates there is preservation of the crypt architecture with the\npresence of mucin depletion and reactive epithelial changes. The lamina\npropria contains increased numbers of inflammatory cells (lymphocytes and\nplasma cells) as shown by the blue arrows. (b) On higher magnification,\nneutrophils are seen superficially with superficial cryptitis (neutrophils\ninfiltrating the crypt epithelium) without crypt abscesses and active\ninflammation as shown by the black arrows.\n\nDiscussion\nPsoriasis is a T-cell-mediated immune disease characterized by increased keratinocyte\nproliferation leading to the formation of well-demarcated erythematous plaques with scaling.2 CD and ulcerative colitis (UC) are parts of the spectrum of IBD. All three\nconditions result from immune dysregulation due to genetic predisposition and\nenvironmental assaults. The anatomical and functional integrity of the tissue\nenvironment barriers is compromised in the skin of psoriasis patients and intestinal\nlumen of IBD patients.3 Psoriasis and IBD are linked epidemiologically as well as genetically. In a\npopulation-based nationwide study in Korea, psoriasis patients had a higher risk of\nIBD than did the general population.4 A meta-analysis of genome-wide association studies recognized seven\nsusceptibility loci shared by psoriasis and CD in addition to the four already\nestablished common psoriasis and CD risk loci.3 There is also an association between PsA and IBD.5,6\n\nIn addition to the shared epidemiologic and genetic links, these conditions share\nsome therapies. Tumor necrosis factor (TNF) inhibitors adalimumab and infliximab are\neffective for plaque psoriasis and IBD.7 Ustekinumab, an anti-p40 IL-12/23 humanized monoclonal antibody, is effective\nfor psoriasis and was approved in 2016 by Health Canada and US Food and Drug\nAdministration (FDA) for the treatment of moderate to severe active CD (not for\nUC).8,9\n\nIL-17 inhibition, highly effective for psoriasis, was expected to improve IBD.\nHowever, in controlled trials of patients with active CD, the placebo groups did\nbetter than the groups receiving anti-IL-17 (secukinumab) and anti-IL17 receptor\n(brodalumab) antibodies.10,11 In a retrospective analysis of pooled data from 21 clinical\ntrials, the exposure-adjusted incidence rate for UC and CD was 0.13 and 0.05 per 100\npatient-years, respectively.12 One case report described a patient with rapid onset of fulminant IBD after a\nsingle infusion of secukinumab, although the authors acknowledged that the patient\nmight have developed IBD even without secukinumab infusion, considering the\npatient’s positive family history.13\n\nAlthough in this patient CD was incidentally found during secukinumab therapy, a\ndirect causal relationship cannot be assumed. The patient had previously been on\nadalimumab, which may have been keeping underlying IBD under control. The ulcers and\ninflammation may have been present long before treatment with secukinumab, as CD may\nbe asymptomatic. Endoscopically or histologically detected inflammation occurs in a\nmajority of IBD patients whose disease is clinically in remission.14 Without experiencing any gastrointestinal symptoms, patients may not have any\ntesting to detect the IBD.\n\nThe overall incidence of IBD in psoriasis patients treated with secukinumab appears\nrare and does not appear to increase over time. However, caution should be exercised\nin patients with IBD and possibly in patients with family history of IBD.\nMedications that are effective for both psoriasis and IBD may be a good choice in\npatients with psoriasis who have comorbid CD or who develop IBD during treatment\nwith another biologic.\n\nDeclaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect\nto the research, authorship, and/or publication of this article: S.R.F. has\nreceived research, speaking and/or consulting support from a variety of\ncompanies, including Galderma, GSK/Stiefel, Almirall, Leo Pharma, Boehringer\nIngelheim, Mylan, Celgene, Pfizer, Valeant, Abbvie, Samsung, Janssen, Lilly,\nMenlo, Merck, Novartis, Regeneron, Sanofi, Novan, Qurient, National Biological\nCorporation, Caremark, Advance Medical, Sun Pharma, Suncare Research, Informa,\nUpToDate and National Psoriasis Foundation. He is the founder and majority owner\nof www.DrScore.com and the founder and part owner of Causa\nResearch, a company dedicated to enhancing patients’ adherence to treatment.\nW.H., S.A.-N., C.S.A. and R.S.B. have no conflicts to disclose.\n\nFunding: The author(s) received no financial support for the research, authorship and/or\npublication of this article.\n\nInformed consent: All investigators ensure that the planning conduct and reporting of human\nresearch are in accordance with the Helsinki Declaration as revised in 2013. The\npatient provided written informed consent granting permission for patient\ninformation and images to be published.\n==== Refs\nReferences\n1 \nKamata M Tada Y. \nSafety of biologics in psoriasis . J\nDermatol \n2018 ; 45 (3 ):\n279 –286 .29226369 \n2 \nDas D Akhtar S Kurra S , et al\nEmerging role of immune cell\nnetwork in autoimmune skin disorders: an update on pemphigus, vitiligo and\npsoriasis . Cytokine Growth Factor Rev \n2019 ; 43 :\n35 –44 .\n3 \nVlachos C Gaitanis G Katsanos K , et al\nPsoriasis and inflammatory\nbowel disease: links and risks . Psoriasis \n2016 ; 6 :\n73 –92 .29387596 \n4 \nLee JY Kang S Bae JM , et al\nPsoriasis increases the risk\nof concurrent inflammatory bowel disease: a population-based nationwide\nstudy in Korea . Indian J Dermatol Venereol\nLeprol \n2019 ; 85 (2 ):\n145 –152 .30058564 \n5 \nManos CK Xiao R Brandon TG , et al\nRisk factors for arthritis\nand the development of comorbid cardiovascular and metabolic disease in\nchildren with psoriasis . Arthritis\nRheumatol \n2017 ; 69 (Suppl. 10 ).\nhttps://acrabstracts.org/abstract/risk-factors-for-arthritis-and-the-development-of-comorbid-cardiovascular-and-metabolic-disease-in-children-with-psoriasis/\n(accessed 22 September 2019 ).\n6 \nCharlton R Green A Shaddick G , et al\nRisk of uveitis and\ninflammatory bowel disease in people with psoriatic arthritis: a\npopulation-based cohort study . Ann Rheum\nDis \n2018 ; 77 (2 ):\n277 –280 .29092855 \n7 \nAdegbola SO Sahnan K Warusavitarne J , et al\nAnti-TNF therapy in Crohn’s\ndisease . Int J Mol Sci \n2018 ; 19 (8 ):\n2244 .\n8 \nAggeletopoulou I Assimakopoulos SF Konstantakis C , et al\nInterleukin 12/interleukin\n23 pathway: biological basis and therapeutic effect in patients with Crohn’s\ndisease . World J Gastroenterol \n2018 ; 24 (36 ):\n4093 –4103 .30271076 \n9 \nGhosh S Gensler LS Yang Z , et al\nUstekinumab safety in\npsoriasis, psoriatic arthritis, and Crohn’s disease: an integrated analysis\nof phase II/III clinical development programs . Drug\nSaf \n2019 ; 46 :\n751 –768 .\n10 \nHueber W Sands BE Lewitzky S , et al\nSecukinumab, a human\nanti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease:\nunexpected results of a randomised, double-blind placebo-controlled\ntrial . Gut \n2012 ; 61 (12 ):\n1693 –1700 .22595313 \n11 \nTargan SR Feagan B Vermeire S , et al\nA randomised, double blind,\nplacebo-controlled phase 2 study of brodalumab in patients with moderate to\nsevere Crohn’s disease . Am J Gastroenterol \n2016 ; 111 (11 ):\n1599 –1607 .27481309 \n12 \nSchreiber S Colombel JF Feagan BG , et al\nIncidence rates of\ninflammatory bowel disease in patients with psoriasis, psoriatic arthritis\nand ankylosing spondylitis treated with secukinumab: a retrospective\nanalysis of pooled data from 21 clinical trials . Ann\nRheum Dis \n2019 ; 78 (4 ):\n473 –479 .30674475 \n13 \nWang J Bhatia A Krugliak Cleveland N , et al\nRapid onset of inflammatory\nbowel disease after receiving secukinumab infusion .\nACG Case Rep J \n2018 ; 5 : e56 .30105273 \n14 \nBaars JE Nuij VJ Oldenburg B , et al\nMajority of patients with\ninflammatory bowel disease in clinical remission have mucosal\ninflammation . Inflamm Bowel Dis \n2012 ; 18 (9 ):\n1634 –1640 .22069022\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2050-313X",
"issue": "7()",
"journal": "SAGE open medical case reports",
"keywords": "Crohn’s disease; Psoriasis; biologic; inflammatory bowel disease",
"medline_ta": "SAGE Open Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101638686",
"other_id": null,
"pages": "2050313X19893580",
"pmc": null,
"pmid": "31839950",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "29226369;30271076;30674475;30058564;30065229;29387596;27481309;22069022;29092855;30739254;30773437;22595313;30105273",
"title": "Asymptomatic Crohn's disease identified in a patient being treated with secukinumab: A case report.",
"title_normalized": "asymptomatic crohn s disease identified in a patient being treated with secukinumab a case report"
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"companynumb": "NVSC2019US084687",
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"abstract": "Bevacizumab (BV) monotherapy leads to compensatory upregulation of multiple signaling pathways, resulting in mTOR activation. We evaluated combining BV and everolimus (EV), an mTOR kinase inhibitor, to circumvent BV-resistance in women with recurrent or persistent ovarian, fallopian tube or primary peritoneal cancer (OC).\n\n\n\nEligible OC patients had measurable (RECIST1.1) or detectable disease, 1-3 prior regimens, performance status (PS) 0-2, and no prior m-TOR inhibitor. All patients received BV 10 mg/kg IV every 2wks. Patients were randomized (1:1) to oral EV (10 mg daily) or placebo stratified by platinum-free interval (PFI), measurable disease and prior BV. Primary endpoint was progression-free survival (PFS); secondary endpoints included safety and response.\n\n\n\n150 patients were randomized to BV with (n = 75) and without (n = 75) EV. Arms were well-balanced for age (median 63: range 28-92), PS (0: 73%, 1-2: 27%), prior regimens (1: 37%, 2: 47%, 3: 16%), prior BV (11%), PFI (<6mos: 65%) and measurable disease (81%). The BV + EV vs BV median PFS was 5.9 vs 4.5 months (hazard ratio [HR] 0.95 (95% CI, 0.66-1.37, p = 0.39)). Median OS was 16.6 vs 17.3 months (HR 1.16 (95% CI, 0.72-1.87, p = 0.55). Objective measurable responses were higher with BV + EV (22% vs 12%). Study removal due to toxicity was higher with BV + EV (29% vs 12%). Toxicity (≥grade 3) from BV + EV were \"other GI (mucositis)\" (23 vs 1%) and \"metabolic/nutrition\" (19 vs. 7%); common ≥ grade 2 toxicities with BV + EV were cytopenia, nausea, fatigue and rash.\n\n\n\nThe combination regimen (BV + EV) did not significantly reduce the hazard of progression or death relative to BV and was associated with higher rates of adverse events and study discontinuation when compared to BV alone.",
"affiliations": "Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, United States of America. Electronic address: teww@mskcc.org.;NRG Oncology, Clinical Trial Development Division, Biostatistics & Bioinformatics, Roswell Park, Buffalo, NY 14263, United States of America. Electronic address: msill@gogstats.org.;Department of Gynecologic Oncology, The Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States of America. Electronic address: joan-walker@ouhsc.edu.;Dept. of Obstetrics/Gynecology, Division of Gynecology Oncology, Duke University Medical Center, Durham, NC 27710, United States of America. Electronic address: secor002@mc.duke.edu.;Cancer Research for the Ozarks-Cox Health, Ferrell_Duncan Clinic GYN-ONC, Springfield, MO 65807, United States of America. Electronic address: albert.bonebrake@coxhealth.com.;Indiana University Medical Center, Cancer Pavilion - Section of GYN Oncology, Indianapolis, IN 46202, United States of America. Electronic address: jschilde@iupui.edu.;Women and Infants Hospital, Program in Women's Oncology, Providence, RI 02905, United States of America. Electronic address: astuckey@wihri.org.;University of Wisconsin, Obstetrics & Gynecology, Division of Gyn/Oncology, Madison, WI 53792, United States of America. Electronic address: lwrice@wisc.edu.;The Division of Gynecologic Oncology, University of California, Irvine Medical Center, Orange, CA 92868, United States of America. Electronic address: ktewari@uci.edu.;Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, United States of America. Electronic address: aghajanc@mskcc.org.",
"authors": "Tew|William P|WP|;Sill|Michael W|MW|;Walker|Joan L|JL|;Secord|Angeles Alvarez|AA|;Bonebrake|Albert J|AJ|;Schilder|Jeanne M|JM|;Stuckey|Ashley|A|;Rice|Laurel|L|;Tewari|Krishnansu S|KS|;Aghajanian|Carol A|CA|",
"chemical_list": "D000068258:Bevacizumab; D000068338:Everolimus",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ygyno.2018.08.027",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0090-8258",
"issue": "151(2)",
"journal": "Gynecologic oncology",
"keywords": "Bevacizumab; Everolimus; Ovarian cancer; Targeted therapy",
"medline_ta": "Gynecol Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D000077216:Carcinoma, Ovarian Epithelial; D018572:Disease-Free Survival; D004311:Double-Blind Method; D000068338:Everolimus; D005185:Fallopian Tube Neoplasms; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009375:Neoplasms, Glandular and Epithelial; D010051:Ovarian Neoplasms; D010534:Peritoneal Neoplasms",
"nlm_unique_id": "0365304",
"other_id": null,
"pages": "257-263",
"pmc": null,
"pmid": "30177462",
"pubdate": "2018-11",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural",
"references": "10379858;10419737;10901370;15026475;15208673;16443261;17363557;17634556;18024863;18024865;18165643;20368560;21720365;21752435;22204724;22204725;22529265;24637997;24687829;24742900;26731724;27217446;28438473;7973224",
"title": "Randomized phase II trial of bevacizumab plus everolimus versus bevacizumab alone for recurrent or persistent ovarian, fallopian tube or peritoneal carcinoma: An NRG oncology/gynecologic oncology group study.",
"title_normalized": "randomized phase ii trial of bevacizumab plus everolimus versus bevacizumab alone for recurrent or persistent ovarian fallopian tube or peritoneal carcinoma an nrg oncology gynecologic oncology group study"
} | [
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"abstract": "Hemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by severe hyperinflammation due to an overwhelming ineffective immune response to different triggers. Most important symptoms are fever, hepatosplenomegaly and cytopenias. Biochemical signs include elevated ferritin, hypertriglyceridemia and low fibrinogen. Hemophagocytosis in the bone marrow is a hallmark of this syndrome. Based on the pathogenetic mechanism, it can be classified into primary (inherited) or secondary (acquired) HLH. We report, to our knowledge, the first case of acquired hemophagocytic syndrome that arose in a 20-year-old man affected by synovial sarcoma as a complication during chemotherapy.",
"affiliations": "Medical Oncology, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), University of Verona, P.le L.A Scuro 10, 37134 Verona, Italy; Medical Oncology, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), University of Verona, P.le L.A Scuro 10, 37134 Verona, Italy.;Medical Oncology, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), University of Verona, P.le L.A Scuro 10, 37134 Verona, Italy; Medical Oncology, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), University of Verona, P.le L.A Scuro 10, 37134 Verona, Italy.;Medical Oncology, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), University of Verona, P.le L.A Scuro 10, 37134 Verona, Italy; Medical Oncology, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), University of Verona, P.le L.A Scuro 10, 37134 Verona, Italy.;Medical Oncology, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), University of Verona, P.le L.A Scuro 10, 37134 Verona, Italy; Medical Oncology, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), University of Verona, P.le L.A Scuro 10, 37134 Verona, Italy.;Medical Oncology, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), University of Verona, P.le L.A Scuro 10, 37134 Verona, Italy; Medical Oncology, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), University of Verona, P.le L.A Scuro 10, 37134 Verona, Italy.;Medical Oncology, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), University of Verona, P.le L.A Scuro 10, 37134 Verona, Italy; Medical Oncology, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), University of Verona, P.le L.A Scuro 10, 37134 Verona, Italy.;Medical Oncology, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), University of Verona, P.le L.A Scuro 10, 37134 Verona, Italy; Medical Oncology, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), University of Verona, P.le L.A Scuro 10, 37134 Verona, Italy.;Medical Oncology, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), University of Verona, P.le L.A Scuro 10, 37134 Verona, Italy; Medical Oncology, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), University of Verona, P.le L.A Scuro 10, 37134 Verona, Italy.;Medical Oncology, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), University of Verona, P.le L.A Scuro 10, 37134 Verona, Italy; Medical Oncology, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), University of Verona, P.le L.A Scuro 10, 37134 Verona, Italy.;Medical Oncology, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), University of Verona, P.le L.A Scuro 10, 37134 Verona, Italy; Medical Oncology, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), University of Verona, P.le L.A Scuro 10, 37134 Verona, Italy.;Department of Pathology & Diagnostic, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), University of Verona, Verona, Italy; Department of Pathology & Diagnostic, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), University of Verona, Verona, Italy.;Department of Medicine, Section of Hematology & Bone Marrow Transplant Unit, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), University of Verona, Verona, Italy; Department of Medicine, Section of Hematology & Bone Marrow Transplant Unit, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), University of Verona, Verona, Italy.;Medical Oncology, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), University of Verona, P.le L.A Scuro 10, 37134 Verona, Italy; Medical Oncology, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), University of Verona, P.le L.A Scuro 10, 37134 Verona, Italy.;Medical Oncology, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), University of Verona, P.le L.A Scuro 10, 37134 Verona, Italy; Medical Oncology, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), University of Verona, P.le L.A Scuro 10, 37134 Verona, Italy.",
"authors": "Ciccarese|Chiara|C|;Ferrara|Roberto|R|;Fantinel|Emanuela|E|;Zecchetto|Camilla|C|;Simionato|Francesca|F|;Grego|Elisabetta|E|;Ortolani|Silvia|S|;Caccese|Mario|M|;Bimbatti|Davide|D|;Cingarlini|Sara|S|;Brunelli|Matteo|M|;Andreini|Angelo|A|;Tortora|Giampaolo|G|;Massari|Francesco|F|",
"chemical_list": null,
"country": "England",
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"doi": "10.4155/fso.15.27",
"fulltext": "\n==== Front\nFuture Sci OAFuture Sci OAFSOFuture Science OA2056-5623Future Science Ltd London, UK 10.4155/fso.15.27Case ReportAcquired hemophagocytic syndrome in a patient with synovial sarcoma: a case report Ciccarese, Ferrara, Fantinel et al.Acquired hemophagocytic syndrome in a patient with synovial sarcoma: a case reportCiccarese Chiara \n1\nFerrara Roberto \n1\nFantinel Emanuela \n1\nZecchetto Camilla \n1\nSimionato Francesca \n1\nGrego Elisabetta \n1\nOrtolani Silvia \n1\nCaccese Mario \n1\nBimbatti Davide \n1\nCingarlini Sara \n1\nBrunelli Matteo \n2\nAndreini Angelo \n3\nTortora Giampaolo \n1\nMassari Francesco *\n1\n1 Medical Oncology, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), University of Verona, P.le L.A Scuro 10, 37134 Verona, Italy2 Department of Pathology & Diagnostic, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), University of Verona, Verona, Italy3 Department of Medicine, Section of Hematology & Bone Marrow Transplant Unit, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), University of Verona, Verona, Italy*Author for correspondence: fmassari79@gmail.com11 2015 01 11 2015 1 4 FSO29© C Ciccarese et al.2015This work is licensed under a Creative Commons Attribution 4.0 License\nHemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by severe hyperinflammation due to an overwhelming ineffective immune response to different triggers. Most important symptoms are fever, hepatosplenomegaly and cytopenias. Biochemical signs include elevated ferritin, hypertriglyceridemia and low fibrinogen. Hemophagocytosis in the bone marrow is a hallmark of this syndrome. Based on the pathogenetic mechanism, it can be classified into primary (inherited) or secondary (acquired) HLH. We report, to our knowledge, the first case of acquired hemophagocytic syndrome that arose in a 20-year-old man affected by synovial sarcoma as a complication during chemotherapy.\n\nThe importance of this case report resides mainly in the difficulty of identifying a rare syndrome, as the hemophagocytic lymphohistiocytosis is, which can gather and justify several unspecific clinical and biochemical signs and symptoms. Hardly, prolonged fever, hepatosplenomegaly and a lasted cytopenia arising in a patients with solid tumor (a synovial sarcoma in our case) during chemotherapy, not directly attributable and not fully justifiable by infections, cytotoxic treatment or by the cancer itself, lead clinicians assuming the hemophagocytosis as a possible etiology. Therefore, describing a peculiar case, which promptly responded to corticosteroid therapy, can help to bring about an early diagnosis and set quickly an adequate treatment so as to change the patient's prognosis.\n\nKeywords: \nchemotherapyhemophagocytic lymphohistiocytosis syndromesynovial sarcoma\n==== Body\nFigure 1. \nCytological evidence of hemophagocytosis.\n\nHemophagocytosis is clearly a ‘dynamic’ process of disruption on red blood cell by histiocytes. Hysto-cytological examination of the bone marrow is just a ‘static’ picture of a single phase of the hemophagocytic process. In this figure, the hemosiderin inside the macrophages represents the end stage of hemophagocytosis, when the external membrane of red blood cell has already been disrupted.\n\nHemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome characterized by severe hyperinflammation due to an overwhelming ineffective immune response to different triggers [1]. Cardinal symptoms are fever, hepatosplenomegaly and cytopenias. Biochemical signs include elevated ferritin, hypertriglyceridemia and low fibrinogen. Hemophagocytosis in the bone marrow is a hallmark of this syndrome (Box 1). Based on the pathogenetic mechanism, it can be classified into primary (inherited) or secondary (acquired) HLH [2]. Impaired function of NK cells and macrophages, as well as cytotoxic T lymphocytes deficiency, characterizes all forms of HLH. Genetic mutations leading to primary HLH impair the granule-dependent cytotoxic activity of lymphocytes [3]. Secondary forms are described in association with infections, autoimmune disorders, acquired immunodeficiency and malignancies, mainly lymphoproliferative diseases [4,5]. Solid tumors are seldom related to HLH [6–9]. Treatment should be started promptly in order to suppress the hyperinflammatory status. Steroids, immune-suppressive agents, cytotoxic drugs, biological response modifiers and stem-cell transplantation are available strategies, however, far from being curative in most cases [10].\n\nTo our knowledge, we report the first case of acquired hemophagocytic syndrome arose in a 20-year-old man affected by synovial sarcoma as a complication during chemotherapy. We hypothesize that an abnormal neoplastic production of cytokines, undetected infection, the iatrogenic immunosuppression status or the direct cytolytic effect of chemotherapy may have been the precipitating cofactor.\n\nCase presentation\nA 20-year-old man, affected by synovial sarcoma of the left buttock with pulmonary metastases since October 2013, was treated with doxorubicin and ifosfamide as first-line chemotherapy. After two courses of doxorubicin and ifosfamide, complicated by febrile neutropenia despite primary prophylactic G-CSF support but with a partial response of the disease on CT scan revaluation, the patient received single-agent chemotherapy with high-dose ifosfamide (14 g/m2 continuous infusion for 14 days). The 13th day of ifosfamide infusion the patient was hospitalized for fever and severe mucositis and diarrhea (grade 4 according to CTCAE v4.03).\n\nLaboratory tests revealed low counts in all blood cell types; the hemoglobin nadir was 6.6 g/dl, the white blood cell count was 180/mmc, with severe neutropenia (absolute neutrophil count <10), and the platelet nadir was 5000/mmc. Furthermore, the C-reactive protein (PCR) was significantly augmented, without a concomitant rise of procalcitonin. The serum ferritin level was increased to 19,500 ng/ml. The clinical examination showed the presence of hepatomegaly, with no laboratory evidence of hepatic dysfunction, a maculopapular erythematous rash spread from the trunk to the extremities, and a severe oral mucositis. Lymphadenopathies were not detectable.\n\nAt the beginning, the pancytopenia was ascribed to chemotherapy myelotoxicity. The patient was therefore supported with periodic packed red blood cells and platelets transfusions and with G-CSF. Considering the presence of febrile neutropenia, possible sources of infections were excluded through a chest X-ray, urine cultures, blood cultures from central venous catheter and peripheral vein. In any case, a broad-spectrum antibiotic therapy was set up, initially with piperacillin/tazobactam, daptomycin and, given the diarrhea, metronidazole. The persistence of fever and the appearance of a parenchymal lung lesion at a monitoring chest x-ray moved us to replace antibiotic therapy with meropenem, vancomycin and levofloxacin, with no clinical improvement nor defervescence.\n\nFifteen days after admission, fever and pancytopenia still persisted. The sole chemotherapy could not be the only cause. A bone marrow aspiration and biopsy were performed, with cytological evidence of hemophagocytosis (Figure 1). The histologic pattern confirmed the presence of bone marrow aplasia, with rare macrophages containing hemosiderin deposits. Neoplastic bone marrow infiltration was excluded.\n\nThe patient received intravenous gammaglobulin infusions for immunomodulatory purposes, with insignificant effects on hematopoiesis.\n\nCollaterally, due to the prolonged neutropenia, antiviral (acyclovir) and antifungal (posaconazole) therapies were introduced as prophylaxis. There were no findings of active viral infection (i.e., Cytomegalovirus – IgM and IgG antibodies and PRC, Epstein-Barr virus - viral capsid antigens (VCA) IgG, VCA IgM, and EBV nuclear antigen (EBNA)-1 IgG antibodies, Parvovirus B19 - anti-B19 IgM and IgG antibodies with western blot and B19 DNA with PCR, Herpesvirus-6 and 7- with PCR) that could justify the bone marrow aplasia. The patient's clinical condition worsened. Although the state of consciousness of the patient was never altered, even during peaks of fever, appeared persistent cough and dyspnea for modest efforts. Moreover, 18 days after admission, the serum positivization assay of beta-D-glucan and Aspergillus antigen suggested the onset of a fungal infection. Therefore, the pulmonary status was investigated through a high-resolution CT scan, with evidence of a large lung cavity resembling the typical ‘fungus ball’. Thus, the patient started antifungal therapy with amphotericin B.\n\nAt this point, the main problem was the assessment of the fine balance between the potential benefit of steroid therapy on hematopoiesis and its detrimental effect on fungal infection. Considering the resumption of the bone marrow activity as a priority, for both the magnitude of blood transfusion needs and its crucial role in facilitating the lung infection resolution, we started corticosteroid therapy (dexamethasone 8 mg intravenously). Surprisingly, 2 days after corticosteroid infusions white blood cells began to rise, reaching normal values after 6 days of steroid therapy. The platelet count showed a trend of slower growth.\n\nThe antifungal therapy in combination with the resumption of the immune system efficacy resulted in a progressive clinical, laboratoristic and radiological resolution of the infection. After 2 months, the patient was discharged.\n\nTo our knowledge this is the first case of acquired HLH in a patient with synovial sarcoma during chemotherapy treatment.\n\nWhich was the precipitating factor in the case reported is difficult to define. Probably, the coexistence of an overwhelming neoplastic production of cytokines, an unrecognized fungal infection, the iatrogenic immune suppression due to chemotherapy or a direct cytolytic effect of chemotherapy could have contributed.\n\nIfosfamide is a structural synthetic analog of cyclophosphamide, and thus a nitrogen mustard-like alkylating agent. After hepatic microsomal activation, biologically active alkylated metabolites interact with DNA to form covalent bonds. Myelosuppression is dose-related and dose-limiting. It consists primarily in leukopenia and, to a lesser extent, piastrinopenia. At ifosfamide dosage of 10–12 g/m2/cycle, leukopenia is almost the rule. Myelosuppression is usually reversible, the nadir is reached after 8–14 days, with recovery in 18–20 days. In the present case, the persistent severe pancytopenia with no evidence of bone marrow recovery could not be ascribed exclusively to the myelosuppressive effect of ifosfamide. Alkylating agent-induced tumor cell lysis could instead have stimulated an immune response, resulting in HLH.\n\nIn our case, the clinical suspicion of an incoming complication that would justify the prolonged pancytopenia led to the diagnosis. Cytopenia, persistent fever, hepatomegaly, high levels of ferritin and the histological finding of hemophagocytosis were therefore ascribed to peculiar manifestations of acquired HLH.\n\nAs concerns the treatment, the peculiarity of our case also depends on the rapid onset of response to monotherapy with corticosteroids. Luckily, the use of immunosuppressive drugs was not necessary, avoiding therefore to aggravate active fungal pulmonary infection.\n\nConclusion\nIn conclusion, we report a noteworthy case of HLH secondary to chemotherapy for synovial sarcoma that achieved prompt remission with steroids, highlighting the importance to recognize a, albeit rare, correlation between HLH and solid tumors.\n\nBox 1. Diagnostic criteria for hemophagocytic lymphohistiocytosis used in the HLH-2004 trial†.\nA. Molecular diagnosis consistent with HLH: pathologic mutations of PRF1, UNC13D, Munc188–2, Rab27a, STX11, SH2D1A or BIRC4 or\n\nB. Five of the eight criteria listed below are fulfilled:\n\nFever ≥38.5°C\n\nHepatosplenomegaly\n\nCytopenias (affecting at least two of three lineages in the peripheral blood)\n\nHemoglobin <9 g/dl (in infants <4 weeks: hemoglobin <10 g/dl)\n\nPlatelets <100 × 103/ml\n\nNeutrophils <1 × 103/ml\n\nHypertriglyceridemia (fasting, >265 mg/dl) and/or hypofibrinogenemia (<150 mg/dl)\n\nHemophagocytosis in bone marrow, spleen, lymph nodes or liver\n\nLow or absent NK-cell activity\n\nFerritin >500 ng/ml‡\n\n\nElevated s CD25 (soluble IL-2 receptor α-chain)\n\n\n†Adapted from [11].\n\n\n‡Although the HLH-2004 protocol uses ferritin >500 ng/ml, ferritin >3000 ng/ml is suspect for HLH, and ferritin >10,000 ng/ml highly related to HLH [12].\n\nHLH: Hemophagocytic lymphohistiocytosis.\n\nExecutive summary\nHemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening, hyperinflammatory syndrome, peculiarly characterized by hemophagocytosis in the bone marrow, and clinically marked by fever, hepatosplenomegaly and pancytopenia.\n\nInhered and acquired forms can be distinguished. Different triggers have been identified as possible etiologic agents, seldom including solid tumors.\n\nWe reported the first case of acquired HLH in a patient with synovial sarcoma during chemotherapy treatment.\n\nThe neoplastic production of cytokines, an unrecognized fungal infection, the iatrogenic immune suppression due to chemotherapy, or a direct cytolytic effect of chemotherapy can be listed as contributing etiological factors.\n\nThe peculiarity of our case also depends on the rapid onset of response to monotherapy with corticosteroids.\n\n\nFinancial & competing interests disclosure\n\n\nSupported by a grant of the Italian Association for Cancer Research (AIRC-IG 11930; AIRC 5per mille 12214). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.\n\nNo writing assistance was utilized in the production of this manuscript.\n\n\nInformed consent disclosure\n\n\nThe authors state that they have obtained verbal and written informed consent from the patient/patients for the inclusion of their medical and treatment history within this case report.\n\n\nOpen Access\n\n\nThis work is licensed under the Creative Commons Attribution 4.0 License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/\n==== Refs\nReferences\n1 Janka GE Hemophagocytic syndromes Blood Rev. 21 5 245 253 2007 17590250 \n2 George MR Hemophagocytic lymphohistiocytosis: review of etiologies and management J. Blood Med. 5 69 86 2014 24966707 \n3 de Saint Basile G Ménasché G Fischer A Molecular mechanisms of biogenesis and exocytosis of cytotoxic granules Nat. Rev. Immunol. 10 8 568 579 2010 20634814 \n4 Rouphael NG Talati NJ Vaughan C Cunningham K Moreira R Gould C Infections associated with haemophagocytic syndrome Lancet Infect. Dis. 7 12 814 822 2007 18045564 \n5 Atteritano M David A Bagnato G Haemophagocytic syndrome in rheumatic patients. A systematic review Eur. Rev. Med. Pharmacol. Sci. 16 10 1414 1424 2012 23104659 \n6 Urban C Lackner H Schwinger W Beham-Schmid C Fatal hemophagocytic syndrome as initial manifestation of a mediastinal germ cell tumor Med. Pediatr. Oncol. 40 4 247 249 2003 12555254 \n7 Sakai T Shiraki K Deguchi M Hepatocellular carcinoma associated with hemophagocytic syndrome Hepatogastroenterology 48 41 1464 1466 2001 11677988 \n8 Aryal MR Badal M Giri S Aryal S Haemophagocytic lymphohistiocytosis mimicking septic shock after the initiation of chemotherapy for squamous cell carcinoma of the neck BMJ Case Rep. 2013 pii: bcr2013009651 2013 \n9 Molad Y Stark P Prokocimer M Joshua H Pinkhas J Sidi Y Hemophagocytosis by small cell lung carcinoma Am. J. Hematol. 36 2 154 156 1991 1849348 \n10 Jordan MB Allen CE Weitzman S Filipovich AH McClain KL How I treat hemophagocytic lymphohistiocytosis Blood 118 15 4041 4452 2011 21828139 \n11 Henter JI Carlson LA Söder O Nilsson-Ehle P Elinder G Lipoprotein alterations and plasma lipoprotein lipase reduction in familial hemophagocytic lymphohistiocytosis Acta Paediatr. Scand. 80 6–7 675 681 1991 1867086 \n12 Allen CE Yu X Kozinetz CA McClain KL Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis Pediatr. Blood Cancer 50 6 1227 1235 2008 18085676\n\n",
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"title": "Acquired hemophagocytic syndrome in a patient with synovial sarcoma: a case report.",
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"abstract": "We have read with great interest the articles regarding cutaneous manifestations in Coronavirus Disease 2019 (COVID-19) infection. Studies showed 20.4% of COVID-19 patients developed cutaneous manifestations. COVID-19 causes vascular endothelial injury, vasculitis and prothrombotic state which might be the underlying cause of hemorrhagic cutaneous manifestations, disseminated intravascular coagulation (DIC), and multiple organ failures. To date, hemorrhagic cutaneous manifestations reported are chilblain-like lesion, purpura to ecchymosis, livedo reticularis, and dry gangrene. We present a case of ecchymosis in COVID-19-positive ICU hospitalized patient.",
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"title": "Ecchymosis in critical coronavirus disease 2019 (COVID-19) patient in Tangerang, Indonesia: a case report.",
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"abstract": "BACKGROUND\nSARS-CoV-2 pandemic has posed formidable public health and clinical challenges. The use of immunosuppressive agents, such as high dose corticosteroids and cytokine inhibitors (e.g., Tocilizumab) has been suggested to contrast the hyperinflammatory process involved in the pathogenesis of the severe disease, with conflicting evidence. Among the drawbacks of immunosuppressive therapy, the risk of reactivation of latent infections, including parasitic infestations, is to be considered.\n\n\nMETHODS\nWe report a case of a 59-year-old Italian patient treated with high dose intravenous dexamethasone and two intravenous doses of Tocilizumab for interstitial bilateral pneumonia associated with SARS-CoV-2 infection who developed itching, abdominal pain, and an increased eosinophil count. Stool examination confirmed the presence of S. stercoralis larvae. The patient was treated with a 4-day course of Ivermectin with full recovery.\n\n\nCONCLUSIONS\nWe report the first case of S. stercoralis infection following an 11-day treatment with high-dose steroids and Tocilizumab for severe COVID-19. Clinicians should be aware of the risk of strongyloidiasis as a complication of the treatment for severe COVID-19.",
"affiliations": "Specialist Consultation Service ASST Spedali Civili; University Division of Infectious and Tropical Diseases, University of Brescia, ASST Spedali Civili Hospital, Brescia, Italy. v.marchese@unibs.it.;University Department of Infectious and Tropical Diseases, University of Brescia, ASST Spedali Civili Hospital, Brescia, Italy.;University Division of Infectious and Tropical Diseases, ASST Spedali Civili Hospital, Brescia, Italy.;University Division of Infectious and Tropical Diseases, ASST Spedali Civili Hospital, Brescia, Italy.;University Division of Infectious and Tropical Diseases, ASST Spedali Civili Hospital, Brescia, Italy.;University Division of Infectious and Tropical Diseases, University of Brescia, ASST Spedali Civili, Brescia, Italy.;University Division of Infectious and Tropical Diseases, University of Brescia, ASST Spedali Civili Hospital, Brescia, Italy.",
"authors": "Marchese|Valentina|V|http://orcid.org/0000-0002-5221-1614;Crosato|Verena|V|;Gulletta|Maurizio|M|;Castelnuovo|Filippo|F|;Cristini|Graziella|G|;Matteelli|Alberto|A|;Castelli|Francesco|F|",
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"fulltext": "\n==== Front\nInfection\nInfection\nInfection\n0300-8126\n1439-0973\nSpringer Berlin Heidelberg Berlin/Heidelberg\n\n32910321\n1522\n10.1007/s15010-020-01522-4\nCase Report\nStrongyloides infection manifested during immunosuppressive therapy for SARS-CoV-2 pneumonia\nhttp://orcid.org/0000-0002-5221-1614\nMarchese Valentina v.marchese@unibs.it\n\n1\nCrosato Verena 2\nGulletta Maurizio 3\nCastelnuovo Filippo 3\nCristini Graziella 3\nMatteelli Alberto 4\nCastelli Francesco 5\n1 grid.7637.5 0000000417571846 Specialist Consultation Service ASST Spedali Civili; University Division of Infectious and Tropical Diseases, University of Brescia, ASST Spedali Civili Hospital, Brescia, Italy\n2 grid.7637.5 0000000417571846 University Department of Infectious and Tropical Diseases, University of Brescia, ASST Spedali Civili Hospital, Brescia, Italy\n3 grid.412725.7 University Division of Infectious and Tropical Diseases, ASST Spedali Civili Hospital, Brescia, Italy\n4 grid.7637.5 0000000417571846 University Division of Infectious and Tropical Diseases, University of Brescia, ASST Spedali Civili, Brescia, Italy\n5 grid.7637.5 0000000417571846 University Division of Infectious and Tropical Diseases, University of Brescia, ASST Spedali Civili Hospital, Brescia, Italy\n10 9 2020\n10 9 2020\n2021\n49 3 539542\n28 7 2020\n1 9 2020\n© The Author(s) 2020\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.\nBackground\n\nSARS-CoV-2 pandemic has posed formidable public health and clinical challenges. The use of immunosuppressive agents, such as high dose corticosteroids and cytokine inhibitors (e.g., Tocilizumab) has been suggested to contrast the hyperinflammatory process involved in the pathogenesis of the severe disease, with conflicting evidence. Among the drawbacks of immunosuppressive therapy, the risk of reactivation of latent infections, including parasitic infestations, is to be considered.\n\nCase presentation\n\nWe report a case of a 59-year-old Italian patient treated with high dose intravenous dexamethasone and two intravenous doses of Tocilizumab for interstitial bilateral pneumonia associated with SARS-CoV-2 infection who developed itching, abdominal pain, and an increased eosinophil count. Stool examination confirmed the presence of S. stercoralis larvae. The patient was treated with a 4-day course of Ivermectin with full recovery.\n\nDiscussion\n\nWe report the first case of S. stercoralis infection following an 11-day treatment with high-dose steroids and Tocilizumab for severe COVID-19. Clinicians should be aware of the risk of strongyloidiasis as a complication of the treatment for severe COVID-19.\n\nKeywords\n\nStrongyloides stercoralis\nTocilizumab\nSARS-CoV-2\nImmunosuppression\nissue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2021\n==== Body\nBackground\n\nThe recent emergence of SARS-CoV-2 and its rapid spread throughout all continents has become a global concern [1]. Many studies have recently been conducted to identify the molecular pathway leading to alveolar damage in moderate and severe Coronavirus disease 2019 (COVID-19), and have shown the pivotal role of the hyperinflammatory response of the patients’ immune system to the virus in determining alveolar destruction [2]. This is the rationale for the use of corticosteroids, to counteract respiratory failure in severely ill patients, along with oxygen supply [3]. Clinical observational studies have described an improvement in clinical symptoms and oxygenation after steroid administration in patients with severe COVID-19 [4–7]. Moreover, one randomized clinical trial has been recently published to support a survival benefit (the RECOVERY trial) [8]. This controlled, open-label randomized trial provides evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in hospitalized patients with COVID-19 who are receiving oxygen supply, but not among those receiving no respiratory support. On the other hand, IL-6 has been implicated in the pathogenesis of the disease, causing what is known as “cytokine release syndrome” (CRS), contributing to the development of ARDS. Tocilizumab, an IL-6 inhibitor that has been approved for the treatment of rheumatoid arthritis, has been suggested to reduce ARDS-related complications in patients affected by COVID-19 [9, 10].\n\nPrevious experiences with tocilizumab suggest an increased risk of opportunistic and bacterial infection similar to anti-TNF-α agents. When using this drug, continuous clinical monitoring is recommended, as secondary infections might arise [11].\n\nStrongyloidiasis is a parasitic disease widely distributed in tropical and subtropical regions [12]. It is mainly caused by Strongyloides stercoralis (seldom by other Strongyloides species), a soil-transmitted helminth that spread primarily through contaminated soil The presence of this helminth has been well documented in some temperate countries, especially in the past, like the Mediterranean basin [13].\n\nRhabditiform larvae are eliminated through the stool in soil, where they can develop either infective filariform larvae directly, or free-living adult male and female worms, which mate and develop eggs, rhabditiform larvae and eventually infective filariform larvae. Infective filariform (L3) larvae penetrate the human host skin and migrate to the small intestine, where they become adult female worms, which produce eggs via parthenogenesis and new rhabditiform larvae. These can either be eliminated through stool or can become infective filariform larvae, penetrating either the intestinal mucosa or the skin of the perianal area, resulting in autoinfection [14]. By this peculiar auto-infective cycle untreated cases can generate persistent, lifelong infections, and represent a risk factor for a potentially fatal hyperinfection syndrome or disseminated infection [15].\n\nSo far, only a few reports describe exacerbation of S. stercoralis infection in patients treated with either tocilizumab or anti TNF-α agents [16, 17].\n\nCase report\n\nA 59-year-old woman born in Southern Italy was admitted to our ward in March 2020 after experiencing malaise, nausea, vomiting and fever lasting about a week. Chest x-ray showed bilateral basal interstitial pneumonia and SARS-CoV-2 RT-PCR in a oropharyngeal/nasal swab resulted positive. Since arterial pO2 was 57 mmHg, she was started on high-flow supplemental oxygen support. The patient reported chronic treatment with low dose prednisone for adult Still’s disease since 2010 and atenolol for hypertension.\n\nTreatment with hydroxychloroquine, lopinavir/ritonavir, and dexamethasone was started together with enoxaparin prophylaxis. On the 5th day of hospitalization due to severe hypoxia and worsening of respiratory performance, she underwent non-invasive mechanical ventilation with continuous positive airway pressure (CPAP), which was continued for a total of 11 days. On day 7th she was treated with two doses of tocilizumab 8 mg/kg 12 h apart. Dexamethasone treatment was given at the dose of 20 mg/day for 5 days, followed by 10 mg/day for other 6 days. During the hospitalization, she presented an episode of atrial fibrillation, which was successfully reverted by amiodarone, and hyperglycemia, for which she started insulin-based treatment, later switched to oral hypoglycemic agents. Overall her clinical condition gradually improved, and she completed oxygen weaning on day 27th of hospitalization.\n\nOn day 25th her eosinophil absolute count (EAC) increased up to 5540 cell/µL and the patient reported abdominal pain and itching. Stool examination revealed the presence of rhabditiform larvae of S. stercoralis, while IFAT serology tested positive at a titre of 1:640. A 4-day oral treatment with ivermectin (200 mcg/kg) was administered, with a rapid decrease of eosinophil cell count and symptom improvement. She was discharged and a follow-up visit 1 month later was scheduled to check EAC, serology for S. stercoralis and stool examination.\n\nThe patient did not develop fever or worsening clinical condition concomitant to EAC rising. She denied travelling to tropical or subtropical areas and revealed recent moving to Lombardia region from Calabria region (Southern Italy). She reported repeated episodes of diffuse itching in the last 10 years, treated with topical steroids with partial improvement.\n\nDiscussion\n\nTo date, no case of strongyloidiasis related to severe COVID-19 treatment has been reported. Nevertheless, based on the experiences from the use of steroids and tocilizumab in other diseases, it is conceivable that exacerbation of S. stercoralis infestation may occur [18]. Efficacy of immunosuppressive treatments for severe COVID-19 is still debated. In particular for tocilizumab, a recent meta-analysis did not show any additional benefit for patients with severe COVID-19 [19]. The authors concluded that further recommendations on tocilizumab should wait results from on-going clinical trials, due to the low quality of evidence of the available studies. Nevertheless, despite the promising preliminary data of RECOVERY trial on steroid administration [8], some concerns have been raised about the applicability of these results in different settings, such as in low-income, African countries [20]. Authors highlighted the risk of harms rather than benefits from steroid administration as a consequence of the different epidemiology of other infectious diseases, like tuberculosis or strongyloidiasis (which may be reactivated or worsened).\n\nStrongyloidiasis is mainly an asymptomatic or mildly symptomatic disease [21], often only accompanied by a moderate increased EAC. In a recent study conducted in Northern Italy the prevalence of infection was 8% in Italian patients with EAC ≥ 500 cells/µL, especially in those born before 1947 and originating from rural areas surrounding the Po river, regardless of symptoms. The prevalence of strongyloidiasis was even higher (17%) in immigrants originating from endemic areas with eosinophilia [13]. Our patient had only recently moved to Lombardy: her 10-year history of itching suggests that she might have acquired the infection in Southern Italy.\n\nIn case of immunosuppression, strongyloidiasis can determine an hyperinfection syndrome or disseminated infection, with fatality rates up to 70–100% [15]. In Strongyloides hyperinfection syndrome an acceleration in the parasite life cycle leads to excessive reproduction rates within the traditional reproductive sites of the worm (skin, guts and lungs). The number of larvae increases in stools and/or sputum along with clinical manifestations to the respiratory, gastrointestinal system and peritoneum. Disseminated strongyloidiasis is a severe infection which results from massive dissemination to body districts the parasite does not normally reach and colonise, such as the liver, heart, brain and the urinary tract [22].\n\nHyperinfection or disseminated strongyloidiasis are rarely reported in patients treated with tocilizumab. To date, only one case report described the onset of haemorragic alveolitis following combined steroid and tocilizumab treatment [17], while sporadic cases following anti TNF-α or high dose corticosteroid treatments have been reported [16, 23].\n\nGiven these high fatality rates, a screening process should be performed when using such therapies in patients with risk of exposure to Strongyloides, and, if diagnostic test is not available, pre-emptive treatment with ivermectin should be considered [24]. The use of Tocilizumab for COVID-19 is limited to a short-term treatment course, which includes a few doses (generally 2 or 3). If compared to the long treatment course which is licensed for rheumatological diseases, the risk for opportunistic disease reactivation should be limited, though no specific studies have yet been conducted.\n\nOur patient did not present increased EAC on admission, which suggests that the worsening of patient’s strongyloidiasis was associated with the use of tocilizumab and high-dose corticosteroids. Our patient did not develop an hyperinfection syndrome or a disseminated infection, possibly due to the rapid detection of the infection and its prompt treatment. It is also possible that the leukocyte formula alterations in the course of COVID-19 could have masked a pre-existing mild hypereosinophilia, as a consequence of the hyperinflammatory response to SARS-CoV-2 infection.\n\nA dedicated strategy based on epidemiological risk stratification has been recently proposed to prevent Strongyloides hyperinfection/disseminated infection for COVID-19 patients undergoing steroids [25]. In inpatient clinical settings, presumptive ivermectin treatment is proposed for at-risk patients who initiate or are candidates for steroids, as well as in case of invasive gram-negative rod infection while waiting for diagnostic tests. Even in outpatient setting, in presence of risk factor for strongyloidiasis, a presumptive treatment (usually one dose) should be considered, if it is not contraindicated and serology is not available.\n\nIn confirmed uncomplicated infection the efficacy of a single-dose treatment has been well established [26], longer treatment being suggested in hyperinfection/dissemination [27]. In our case the underlying immunosuppressive treatment prompted us to adopt a treatment longer than that proposed for uncomplicated infection.\n\nIn conclusion, we report the first case of strongyloidiasis following high-dose steroid and tocilizumab treatment for severe COVID-19. Risk assessment for strongyloidiasis should be performed for people who live or have visited areas, where the organism is endemic. Similarly, we suggest considering this helminth in case of unexplained appearance of hypereosinophilia. When a prompt diagnosis is not feasible, due to the urgency of treatment and the risk of fatal outcome either for COVID-19 or Strongyloides hyperinfection/dissemination syndrome, empirical pre-emptive single-dose ivermectin therapy must be considered.\n\nAuthor contributions\n\nVM, VC, MG, F Castelnuovo, CG, AM, F Castelli drafted the text; VM and VC performed data analysis and literature research; VM, MG contributed to the conception and design of the manuscript; F Castelnuovo and GC contributed to the acquisition of data; FC and AM substantively revised the text.\n\nFunding\n\nOpen access funding provided by Università degli Studi di Brescia within the CRUI-CARE Agreement. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\n\nCompliance with ethical standards\n\nConflict of interest\n\nAll authors had no financial or other conflicts of interest to disclose.\n\nEthics declarations\n\nInformed consent was obtained from the subject.\n==== Refs\nReferences\n\n1. Rothan HA Byrareddy SN The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak J Autoimmun 2020 109 102433 10.1016/j.jaut.2020.102433 32113704\n2. Chi Z Zhao W Jia-Wen L Hong Z Gui-Qiang W Cytokine release syndrome in Severe COVID-19: Interleukin-6 Receptor Antagonist Tocilizumab May Be the Key to Reduce Mortality Int J Antimicrob Agents. 2020 55 105954 10.1016/j.ijantimicag.2020.105954 32234467\n3. Veronese N Demurtas J Yang L Tonelli R Barbagallo M Lopalco P Use of Corticosteroids in coronavirus disease 2019 Pneumonia: a systematic review of the literature Front Med 2020 7 170 10.3389/fmed.2020.00170\n4. Zhou W Liu Y Tian D Wang C Wang S Cheng J Potential benefits of precise corticosteroids therapy for severe 2019-nCoV pneumonia Signal Transduct Target Ther. 2020 10.1038/s41392-020-0127-9 33376237\n5. Wang Y Jiang W He Q Wang C Wang B Zhou P A retrospective cohort study of methylprednisolone therapy in severe patients with COVID-19 pneumonia Signal Transduct Target Ther. 2020 10.1038/s41392-020-0158-2 33911071\n6. Li R Tian J Yang F Lv L Yu J Sun G Clinical characteristics of 225 patients with COVID-19 in a tertiary Hospital near Wuhan China J Clin Virol 2020 127 104363 10.1016/j.jcv.2020.104363 32298988\n7. Wu C Chen X Cai Y Xia J Zhou X Xu S Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 Pneumonia in Wuhan China JAMA Intern Med 2020 180 934 943 10.1001/jamainternmed.2020.0994 32167524\n8. Horby P Wei SL Dexamethasone in hospitalized patients with Covid-19—preliminary report N Engl J Med 2020 10.1056/nejmoa2021436 33031652\n9. Toniati P Piva S Cattalini M Garrafa E Regola F Castelli F Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: a single center study of 100 patients in Brescia, Italy Autoimmunity Rev 2020 19 102568 10.1016/j.autrev.2020.102568 32376398\n10. Guaraldi G Meschiari M Cozzi-Lepri A Milic J Tonelli R Menozzi M Tocilizumab in patients with severe COVID-19: a retrospective cohort study Lancet Rheumatol 2020 2 e474 e484 10.1016/S2665-9913(20)30173-9 32835257\n11. Winthrop KL Mariette X Silva JT Benamu E Calabrese LH Dumusc A ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Soluble immune effector molecules [II]: agents targeting interleukins, immunoglobulins and complement factors) Clin Microbiol Infect 2018 24 S21 40 10.1016/j.cmi.2018.02.002 29447987\n12. Greaves D Coggle S Pollard C Aliyu SH Moore EM Strongyloides stercoralis infection BMJ (Online) 2013 347 f4610 10.1136/bmj.f4610\n13. Buonfrate D Baldissera M Abrescia F Bassetti M Caramaschi G Giobbia M Epidemiology of Strongyloides stercoralis in northern Italy: results of a multicentre case–control study, February 2013 to July 2014 Eurosurveillance 2016 21 30310 10.2807/1560-7917.ES.2016.21.31.30310\n14. WHO | Strongyloidiasis. https://www.who.int/intestinal_worms/epidemiology/strongyloidiasis/en/. Accessed 21 Aug 2020.\n15. Mejia R Nutman TB Screening, prevention, and treatment for hyperinfection syndrome and disseminated infections caused by Strongyloides stercoralis Curr Opin Infect Dis 2012 25 458 463 10.1097/QCO.0b013e3283551dbd 22691685\n16. Downey C Serious infection during etanercept, infliximab and adalimumab therapy for rheumatoid arthritis: a literature review Int J Rheumatic Dis 2016 19 536 550 10.1111/1756-185X.12659\n17. Mafort TT Reis LVT Faria LF Pinto BM Silva RV Miranda CS Alveolar hemorrhage secondary to infection by strongyloides stercoralis in immunosuppressed patient—case report Am J Respir Crit Care Med 2017 195 A5586\n18. Buonfrate D Requena-Mendez A Angheben A Muñoz J Gobbi F Van Den Ende J Severe strongyloidiasis: a systematic review of case reports BMC Infect Dis. 2013 10.1186/1471-2334-13-78 23394259\n19. Lan SH Lai CC Huang HT Chang SP Lu LC Hsueh PR Tocilizumab for severe COVID-19: a systematic review and meta-analysis Int J Antimicrob Agents. 2020 10.1016/j.ijantimicag.2020.106103 32712333\n20. Brotherton H Usuf E Nadjm B Forrest K Bojang K Samateh AL Dexamethasone for COVID-19: data needed from randomised clinical trials in Africa Lancet Glob Heal 2020 10.1016/s2214-109x(20)30318-1\n21. Montes M Sawhney C Barros N Strongyloides stercoralis: there but not seen Curr Opin Infect Dis 2010 23 500 504 10.1097/QCO.0b013e32833df718 20733481\n22. Kassalik M, Moenkemueller K. Strongyloides stercoralis hyperinfection syndrome and disseminated disease. Gastroenterol Epatol. 2011;7.\n23. Fardet L Généreau T Cabane J Kettaneh A Severe strongyloidiasis in corticosteroid-treated patients Clin Microbiol Infect 2006 12 945 947 10.1111/j.1469-0691.2006.01443.x 16961629\n24. Requena-Méndez A Buonfrate D Gomez-Junyent J Zammarchi L Bisoffi Z Muñoz J Evidence-based guidelines for screening and management of strongyloidiasis in non-endemic countries Am J Trop Med Hyg 2017 97 645 652 10.4269/ajtmh.16-0923 28749768\n25. Stauffer WM Alpern JD Walker PF COVID-19 and dexamethasone. A potential strategy to avoid steroid-related strongyloides hyperinfection JAMA 2020 10.1001/jama.2020.13170 32761166\n26. Buonfrate D Salas-Coronas J Muñoz J Maruri BT Rodari P Castelli F Multiple-dose versus single-dose ivermectin for Strongyloides stercoralis infection (Strong Treat 1 to 4): a multicentre, open-label, phase 3, randomised controlled superiority trial Lancet Infect Dis 2019 19 1181 1190 10.1016/S1473-3099(19)30289-0 31558376\n27. CDC | Parasites-Strongyloides - Resources for Health Professionals. 2020. https://www.cdc.gov/parasites/strongyloides/health_professionals/index.html. Accessed 21 Aug 2020\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0300-8126",
"issue": "49(3)",
"journal": "Infection",
"keywords": "Immunosuppression; SARS-CoV-2; Strongyloides stercoralis; Tocilizumab",
"medline_ta": "Infection",
"mesh_terms": "D000818:Animals; D061067:Antibodies, Monoclonal, Humanized; D000977:Antiparasitic Agents; D000086382:COVID-19; D003907:Dexamethasone; D005243:Feces; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007559:Ivermectin; D000085343:Latent Infection; D008875:Middle Aged; D000086402:SARS-CoV-2; D017171:Strongyloides stercoralis; D013322:Strongyloidiasis; D016896:Treatment Outcome",
"nlm_unique_id": "0365307",
"other_id": null,
"pages": "539-542",
"pmc": null,
"pmid": "32910321",
"pubdate": "2021-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "33376237;33911071;32298988;32167524;33031652;22691685;23394259;32712333;16961629;32761166;31558376",
"title": "Strongyloides infection manifested during immunosuppressive therapy for SARS-CoV-2 pneumonia.",
"title_normalized": "strongyloides infection manifested during immunosuppressive therapy for sars cov 2 pneumonia"
} | [
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"abstract": "Acute myeloid leukemia (AML) with intrachromosomal amplification of chromosome 21 (iAMP21) is rare and has not been well characterized. We report 13 patients, 7 men and 6 women, with a median age of 65 years. Eleven patients presented with AML with myelodysplasia-related changes, and two patients had therapy-related AML. Cytopenias were detected in all patients (11 pancytopenia and two bi-lineage cytopenia). Myelodysplastic changes were observed in all 11 patients with adequate cells to evaluate. Myelofibrosis was present in ten patients. All patients had a complex karyotype, including abnormalities of chromosomes 5, 7, 17, and hsr(21)(q22), and ten patients showed TP53 deletion and/or mutation. Eleven patients received AML-based chemotherapy, one of whom also received hematopoietic stem cell transplant. By the end of the last follow-up, eight patients died with median survival of 3.2 months, four patients were alive with persistent AML, and one was in complete remission. The median overall survival was 6 months for all patients. We conclude that AML with iAMP21 is often associated with cytopenias, myelodysplasia, a complex karyotype, TP53 mutation/deletion, and a poor prognosis despite current therapies.",
"affiliations": "Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.;Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.;Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.;Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.;Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.;Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.;Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.;Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.;Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.;Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. gtang@mdanderson.org.",
"authors": "Xie|Wei|W|http://orcid.org/0000-0003-1815-7666;Xu|Jie|J|http://orcid.org/0000-0001-9163-3898;Hu|Shimin|S|http://orcid.org/0000-0001-7110-3814;Li|Shaoying|S|http://orcid.org/0000-0002-6857-0523;Wang|Wei|W|;Cameron Yin|C|C|;Toruner|Gokce|G|;Tang|Zhenya|Z|http://orcid.org/0000-0002-8079-9945;Medeiros|L Jeffrey|LJ|;Tang|Guilin|G|",
"chemical_list": "C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53",
"country": "United States",
"delete": false,
"doi": "10.1038/s41379-020-0494-3",
"fulltext": null,
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"issn_linking": "0893-3952",
"issue": "33(7)",
"journal": "Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc",
"keywords": null,
"medline_ta": "Mod Pathol",
"mesh_terms": "D059786:Abnormal Karyotype; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002891:Chromosomes, Human, Pair 21; D005260:Female; D005784:Gene Amplification; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016159:Tumor Suppressor Protein p53",
"nlm_unique_id": "8806605",
"other_id": null,
"pages": "1389-1397",
"pmc": null,
"pmid": "32034282",
"pubdate": "2020-07",
"publication_types": "D016428:Journal Article",
"references": "8609706;16079113",
"title": "iAMP21 in acute myeloid leukemia is associated with complex karyotype, TP53 mutation and dismal outcome.",
"title_normalized": "iamp21 in acute myeloid leukemia is associated with complex karyotype tp53 mutation and dismal outcome"
} | [
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"companynumb": "US-CELGENEUS-USA-20200703677",
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"activesubstancename": "PACLITAXEL"
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... |
{
"abstract": "Underlying lung disease, especially asthma, has recently been found to be associated with a higher risk of hospitalization with coronavirus disease 2019 (COVID-19) infection. Inhaled corticosteroids (ICS) are the most commonly used controller medications in patients with asthma. It is unclear whether ICS use increases the risk for severe COVID-19 infection. At the current time, asthma organizations are still recommending the continued use of ICS and other asthma medications to minimize the risk of uncontrolled asthma. However, for patients with asthma and who have recovered from COVID-19 infection, the timing of resumption of asthma therapy is equally uncertain. Pulmonary function testing and exhaled oral nitric oxide testing are aerosol-generating procedures and are currently being severely restricted at most health-care facilities. We presented a case of a patient with cough-variant asthma who developed severe COVID-19 associated acute respiratory distress syndrome with the need for intubation and prolonged mechanical ventilation. We highlighted the potential utility of using COVID-19 RNA detection as well as immunoglobulin G antibody testing to help guide the timing of resumption of asthma therapy.",
"affiliations": "From the Division of Allergic Disease, Mayo Clinic, Rochester, Minnesota; and.;From the Division of Allergic Disease, Mayo Clinic, Rochester, Minnesota; and.;Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota.",
"authors": "Joshi|Avni Y|AY|;Mullakary|Roshini M|RM|;Iyer|Vivek N|VN|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D015415:Biomarkers",
"country": "United States",
"delete": false,
"doi": "10.2500/aap.2020.41.200044",
"fulltext": null,
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"issn_linking": "1088-5412",
"issue": "41(4)",
"journal": "Allergy and asthma proceedings",
"keywords": null,
"medline_ta": "Allergy Asthma Proc",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D000465:Algorithms; D001249:Asthma; D000073640:Betacoronavirus; D015415:Biomarkers; D000086382:COVID-19; D018352:Coronavirus Infections; D019468:Disease Management; D006801:Humans; D008297:Male; D058873:Pandemics; D011024:Pneumonia, Viral; D012129:Respiratory Function Tests; D000086402:SARS-CoV-2; D016896:Treatment Outcome",
"nlm_unique_id": "9603640",
"other_id": null,
"pages": "296-300",
"pmc": null,
"pmid": "32605700",
"pubdate": "2020-07-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment of coronavirus disease 2019 in a patient with asthma.",
"title_normalized": "successful treatment of coronavirus disease 2019 in a patient with asthma"
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"companynumb": "US-TEVA-2020-US-1829797",
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"activesubstancename": "LOPINAVIR\\RITONAVIR"
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"abstract": "Clear cell carcinoma of the ovary has shown an exceedingly chemo-resistant phenotype, especially in cases that are recurrent or refractory to previous therapy. Also, progression-free survival was less than 6 months, even in the patients that achieved response when they were treated with conventional anti-cancer cytotoxic agents. We present a case with recurrent and refractory ovarian clear cell carcinoma that achieved complete remission using a combination of bevacizumab, trabectedin and oxaliplatin. The progression-free interval of the patient is over 30 months, and she is still receiving the combination therapy without toxicities of more than grade 2.",
"affiliations": "Department of Obstetrics and Gynecology, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan. mastkn@ndmc.ac.jp",
"authors": "Takano|Masashi|M|;Ikeda|Yuji|Y|;Kudoh|Kazuya|K|;Kita|Tsunekazu|T|;Sasaki|Naoki|N|;Kikuchi|Yoshihiro|Y|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D004149:Dioxoles; D009944:Organoplatinum Compounds; D044005:Tetrahydroisoquinolines; D000077150:Oxaliplatin; D000068258:Bevacizumab; D000077606:Trabectedin",
"country": "Australia",
"delete": false,
"doi": "10.1111/j.1447-0756.2012.02047.x",
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"issue": "39(4)",
"journal": "The journal of obstetrics and gynaecology research",
"keywords": null,
"medline_ta": "J Obstet Gynaecol Res",
"mesh_terms": "D018262:Adenocarcinoma, Clear Cell; D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D004149:Dioxoles; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D009364:Neoplasm Recurrence, Local; D009944:Organoplatinum Compounds; D010051:Ovarian Neoplasms; D000077150:Oxaliplatin; D012074:Remission Induction; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin",
"nlm_unique_id": "9612761",
"other_id": null,
"pages": "872-5",
"pmc": null,
"pmid": "23167774",
"pubdate": "2013-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Complete remission of recurrent ovarian clear cell carcinoma by chemotherapy with bevacizumab, trabectedin and oxaliplatin.",
"title_normalized": "complete remission of recurrent ovarian clear cell carcinoma by chemotherapy with bevacizumab trabectedin and oxaliplatin"
} | [
{
"companynumb": "JP-WATSON-2014-09655",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRABECTEDIN"
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... |
{
"abstract": "BACKGROUND\nInfrequent but serious postoperative complications following inflatable penile prosthesis (IPP) insertion include infection, malfunction, and bleeding. Although prior publications report methods to reduce immediate postoperative bleeding, there is little in the literature concerning the etiology, diagnosis, imaging, and management of delayed bleeding after IPP insertion.\n\n\nOBJECTIVE\nThe aim of the study was to review cases of delayed postoperative bleeding following IPP insertion in a large single-surgeon series.\n\n\nMETHODS\nWe carried out a retrospective chart review of 600 patients implanted with a Coloplast Titan IPP with One-Touch Release pump by a single surgeon, and analyzed cases of delayed postoperative bleeding.\n\n\nMETHODS\nThe main outcome measure was an analysis of the incidence, causes, diagnostic methods, treatment, and final outcome of these cases.\n\n\nRESULTS\nThree out of 600 consecutive patients (0.5%) developed a delayed (defined as >5 days postoperative) hematoma following IPP insertion. All patients presented postoperatively with a swollen surgical site, and all were evaluated with a pelvic computed tomography scan to completely define the extent of the hematoma. Two patients developed a delayed hematoma because of excessive physical activity; the remaining patient bled because of premature administration of enoxaparin sodium (Lovenox) by his cardiologist. All three patients were successfully treated with hospital admission, intravenous antibiotics, wound exploration, hematoma evacuation, and antibiotic washout. All three IPPs were successfully salvaged; none developed peri-prosthetic infection.\n\n\nCONCLUSIONS\nThe incidence of delayed postoperative hematoma following IPP surgery was 0.5% in our series of 600 cases. All cases were successfully managed with intravenous antibiotics, hematoma evacuation, and antibiotic washout. Because of the low incidence of this complication, definitive statements concerning prevention and management cannot be made. However, we now recommend avoiding postoperative anticoagulants for at least 5 days if possible, and avoiding vigorous physical activity for at least 3 weeks.",
"affiliations": "Department of Urology, Drexel University College of Medicine, Philadelphia, PA, USA.",
"authors": "Garber|Bruce B|BB|;Bickell|Michael|M|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "Netherlands",
"delete": false,
"doi": "10.1111/jsm.12728",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1743-6095",
"issue": "12(1)",
"journal": "The journal of sexual medicine",
"keywords": "Inflatable Penile Prosthesis; Penile Prosthesis Complications; Penile Prosthesis Hematoma",
"medline_ta": "J Sex Med",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D007172:Erectile Dysfunction; D006406:Hematoma; D006801:Humans; D008297:Male; D008875:Middle Aged; D017060:Patient Satisfaction; D010409:Penile Diseases; D010410:Penile Erection; D019935:Penile Implantation; D015917:Penile Prosthesis; D019106:Postoperative Hemorrhage; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States",
"nlm_unique_id": "101230693",
"other_id": null,
"pages": "265-9",
"pmc": null,
"pmid": "25349141",
"pubdate": "2015-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Delayed postoperative hematoma formation after inflatable penile prosthesis implantation.",
"title_normalized": "delayed postoperative hematoma formation after inflatable penile prosthesis implantation"
} | [
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"companynumb": "US-CIPLA LTD.-2020US08893",
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"occurcountry": "US",
"patient": {
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{
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"activesubstancename": "ENOXAPARIN"
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{
"abstract": "Tumour rupture is a strong predictor of poor outcome in gastrointestinal stromal tumours (GISTs) of the stomach and small intestine. The objective was to determine whether tumour genotype was associated with risk of rupture.\n\n\n\nRupture was classified according to the definition proposed by the Oslo Sarcoma Group. Since January 2000, data were registered retrospectively for all patients at Oslo University Hospital undergoing surgery for localized GIST of the stomach or small intestine. Tumour genotype was analysed by Sanger sequencing.\n\n\n\nTwo hundred and nine patients with mutation data available were identified. Tumour rupture occurred in 37 patients. Among the 155 patients with KIT exon 11 mutations, an increased risk of rupture was observed with a deletion or insertion-deletion (25 of 86, 29 per cent) compared with substitutions (5 of 50, 10 per cent) or duplications/insertions (2 of 19, 11 per cent) (P = 0·014). Notably, rupture occurred in 17 of 46 tumours (37 per cent) with deletions involving codons 557 and 558 (del557/558) versus 15 of 109 (13·8 per cent) with other exon 11 mutations (P = 0·002). This association was confined to gastric tumours: 12 of 34 (35 per cent) with del557/558 ruptured versus six of 77 (8 per cent) with other exon 11 mutations (P = 0·001). In multivariable logistic regression analysis, del557/558 and tumour size were associated with an increased likelihood of tumour rupture, but mitotic count was not.\n\n\n\nGastric GISTs with KIT exon 11 deletions involving codons 557 and 558 are at increased risk of tumour rupture. This high-risk feature can be identified in the diagnostic evaluation and should be included in the assessment when neoadjuvant imatinib treatment is considered.",
"affiliations": "Department of Oncology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.;Department of Pathology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.;Department of Oncology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.;Department of Oncology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.;Department of Abdominal and Paediatric Surgery, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.;Department of Oncology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.;Department of Pathology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.;Department of Abdominal and Paediatric Surgery, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.",
"authors": "Boye|K|K|0000-0002-5552-6283;Berner|J-M|JM|;Hompland|I|I|;Bruland|Ø S|ØS|;Stoldt|S|S|;Sundby Hall|K|K|;Bjerkehagen|B|B|;Hølmebakk|T|T|0000-0003-2461-9089",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/bjs.10743",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1323",
"issue": "105(2)",
"journal": "The British journal of surgery",
"keywords": null,
"medline_ta": "Br J Surg",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004252:DNA Mutational Analysis; D005260:Female; D005770:Gastrointestinal Neoplasms; D046152:Gastrointestinal Stromal Tumors; D020022:Genetic Predisposition to Disease; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020360:Neoadjuvant Therapy; D009664:Norway; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D012421:Rupture; D012422:Rupture, Spontaneous; D055815:Young Adult",
"nlm_unique_id": "0372553",
"other_id": null,
"pages": "e169-e175",
"pmc": null,
"pmid": "29341147",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Genotype and risk of tumour rupture in gastrointestinal stromal tumour.",
"title_normalized": "genotype and risk of tumour rupture in gastrointestinal stromal tumour"
} | [
{
"companynumb": "NO-MYLANLABS-2019M1055971",
"fulfillexpeditecriteria": "1",
"occurcountry": "NO",
"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IMATINIB MESYLATE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nThe aim of the present study was to evaluate the outcomes of proton beam therapy (PBT) concurrently combined with chemotherapy consisting of cisplatin and 5-fluorouracil for esophageal cancer.\n\n\nMETHODS\nForty consecutive patients (stage I in 16 patients, II in 9 and III in 15) treated between 2008 and 2012 were evaluated. A total dose of 60 Gray equivalents (GyE) in 30 fractions was delivered, and an additional boost of 4-10 GyE was given when residual tumors were suspected. The median follow-up time was 24 months (range=7-66 months).\n\n\nRESULTS\nNo cardio-pulmonary toxicities of grade 3 or higher were observed. Recurrences were observed in 16 patients, and the 2-year rates of disease-specific survival and locoregional control were 77% and 66%, respectively.\n\n\nCONCLUSIONS\nIrrespective of the small sample size and short follow-up time of the study, proton beam therapy combined with chemo therapy seems to be feasible for esophageal cancer.",
"affiliations": "Department of Radiation Oncology, University of Tsukuba, Faculty of Medicine, Ibaraki, Japan hishikawa@pmrc.tsukuba.ac.jp.;Department of Radiation Oncology, University of Tsukuba, Faculty of Medicine, Ibaraki, Japan.;Department of Gastroenterology, University of Tsukuba, Faculty of Medicine, Ibaraki, Japan.;Department of Gastroenterology, University of Tsukuba, Faculty of Medicine, Ibaraki, Japan.;Gastroenterological and Hepatobiliary Surgery, University of Tsukuba, Faculty of Medicine, Ibaraki, Japan.;Gastroenterological and Hepatobiliary Surgery, University of Tsukuba, Faculty of Medicine, Ibaraki, Japan.;Gastroenterological and Hepatobiliary Surgery, University of Tsukuba, Faculty of Medicine, Ibaraki, Japan.;Department of Radiation Oncology, University of Tsukuba, Faculty of Medicine, Ibaraki, Japan.;Department of Radiation Oncology, University of Tsukuba, Faculty of Medicine, Ibaraki, Japan.;Department of Radiation Oncology, University of Tsukuba, Faculty of Medicine, Ibaraki, Japan.;Department of Radiation Oncology, University of Tsukuba, Faculty of Medicine, Ibaraki, Japan.;Department of Radiation Oncology, University of Tsukuba, Faculty of Medicine, Ibaraki, Japan.;Department of Radiation Oncology, University of Tsukuba, Faculty of Medicine, Ibaraki, Japan.",
"authors": "Ishikawa|Hitoshi|H|;Hashimoto|Takayuki|T|;Moriwaki|Toshikazu|T|;Hyodo|Ichinosuke|I|;Hisakura|Katsuji|K|;Terashima|Hideo|H|;Ohkohchi|Nobuhiro|N|;Ohno|Toshiki|T|;Makishima|Hirokazu|H|;Mizumoto|Masashi|M|;Ohnishi|Kayoko|K|;Okumura|Toshiyuki|T|;Sakurai|Hideyuki|H|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "35(3)",
"journal": "Anticancer research",
"keywords": "Proton beam therapy; concurrent chemoradiotherapy; esophageal cancer; late toxicity; survival",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000368:Aged; D059248:Chemoradiotherapy; D004938:Esophageal Neoplasms; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009017:Morbidity; D009364:Neoplasm Recurrence, Local; D061766:Proton Therapy",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "1757-62",
"pmc": null,
"pmid": "25750339",
"pubdate": "2015-03",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Proton beam therapy combined with concurrent chemotherapy for esophageal cancer.",
"title_normalized": "proton beam therapy combined with concurrent chemotherapy for esophageal cancer"
} | [
{
"companynumb": "JP-BAUSCH-BL-2014-006531",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
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"drugadditional": null,
... |
{
"abstract": "A case of severe and irreversible pancytopenia secondary to acute primary cytomegalovirus infection in an immunocompetent woman is described. The patient presented with thrombocytopenia, lymphopenia, anemia, and abnormal liver function tests. Treatment with corticosteroids and intravenous immunoglobulin was ineffective in reconstituting hemopoiesis. The patient developed severe sepsis and eventually expired.",
"affiliations": "15th Department of Medicine, Division of Infectious Diseases, Evangelismos General Hospital, 45-47 Ipsilantou street, Athens, Greece. mkoukoulaki@gmail.com",
"authors": "Koukoulaki|Maria|M|;Ifanti|Georgia|G|;Grispou|Eirini|E|;Papastamopoulos|Vassilios|V|;Chroni|Georgia|G|;Diamantopoulos|Emmanouil|E|;Skoutelis|Athanasios|A|",
"chemical_list": "D005938:Glucocorticoids; D016756:Immunoglobulins, Intravenous; D011239:Prednisolone",
"country": "Brazil",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1413-8670",
"issue": "14(2)",
"journal": "The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases",
"keywords": null,
"medline_ta": "Braz J Infect Dis",
"mesh_terms": "D003586:Cytomegalovirus Infections; D017809:Fatal Outcome; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007121:Immunocompetence; D016756:Immunoglobulins, Intravenous; D008875:Middle Aged; D010198:Pancytopenia; D011239:Prednisolone; D018805:Sepsis; D012720:Severity of Illness Index",
"nlm_unique_id": "9812937",
"other_id": null,
"pages": "180-2",
"pmc": null,
"pmid": "20563446",
"pubdate": "2010",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fulminant pancytopenia due to cytomegalovirus infection in an immunocompetent adult.",
"title_normalized": "fulminant pancytopenia due to cytomegalovirus infection in an immunocompetent adult"
} | [
{
"companynumb": "GR-AMGEN-GRCSP2020146055",
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"occurcountry": "GR",
"patient": {
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "GANCICLOVIR"
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... |
{
"abstract": "Hemorrhagic cholecystitis -- a rare cause of hemobilia and melena -- is an atypical presentation of calculous cholecystitis, associated with significant morbidity and mortality. A 75-year-old woman with multiple comorbidities, who was undergoing dual antiplatelet therapy, presented with symptoms of acute cholecystitis. Two days later, she developed melena and symptoms of obstructive jaundice. Following radiological evaluation, a diagnosis of hemorrhagic cholecystitis was made. The patient was managed conservatively with IV antibiotics and blood transfusion in the initial period (clopidogrel was withheld); an interval cholecystectomy was performed six weeks later. Hemorrhagic cholecystitis is a rare complication of acute cholecystitis, and its diagnosis is challenging as it mimics various other hepatopancreaticobiliary diseases. Management options include early surgery or conservative management at the initial stage, followed by interval cholecystectomy.",
"affiliations": "General Surgery, Faculty of Medicine, University of Jaffna, Jafffna, LKA.;General Surgery, Teaching Hospital Jaffna, Jaffna, LKA.;Radiology, Base Hospital, Point Pedro, LKA.",
"authors": "Gobishangar|Sreekanthan|S|;Shelton|John|J|;Jenil|Anton A|AA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.16385",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.16385\nGastroenterology\nHemorrhagic Cholecystitis: A Rare Cause of Melena\nMuacevic Alexander\nAdler John R\nGobishangar Sreekanthan 1\nShelton John 2\nJenil Anton A 3\n1 General Surgery, Faculty of Medicine, University of Jaffna, Jafffna, LKA\n2 General Surgery, Teaching Hospital Jaffna, Jaffna, LKA\n3 Radiology, Base Hospital, Point Pedro, LKA\nSreekanthan Gobishangar sgobishangar@univ.jfn.ac.lk\n14 7 2021\n7 2021\n13 7 e1638514 7 2021\nCopyright © 2021, Gobishangar et al.\n2021\nGobishangar 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/58930-hemorrhagic-cholecystitis-a-rare-cause-of-melena\nHemorrhagic cholecystitis -- a rare cause of hemobilia and melena -- is an atypical presentation of calculous cholecystitis, associated with significant morbidity and mortality. A 75-year-old woman with multiple comorbidities, who was undergoing dual antiplatelet therapy, presented with symptoms of acute cholecystitis. Two days later, she developed melena and symptoms of obstructive jaundice. Following radiological evaluation, a diagnosis of hemorrhagic cholecystitis was made. The patient was managed conservatively with IV antibiotics and blood transfusion in the initial period (clopidogrel was withheld); an interval cholecystectomy was performed six weeks later. Hemorrhagic cholecystitis is a rare complication of acute cholecystitis, and its diagnosis is challenging as it mimics various other hepatopancreaticobiliary diseases. Management options include early surgery or conservative management at the initial stage, followed by interval cholecystectomy.\n\nhemobilia\nmelena\nhemorrhagic cholecystitis\nantiplatelet\ninterval cholecystectomy\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\nIntroduction\n\nHemorrhagic cholecystitis is a rare cause of hemobilia and melena [1]. It is associated with significant morbidity and mortality due to delay in its diagnosis. Bleeding into the gallbladder could result from various causes, and the typical presentation of this rare problem only occurs in less than 25% of patients [2]. Therefore, diagnosing hemorrhagic cholecystitis is challenging, as it is often confused with the more common clinical diagnosis of acute cholecystitis [3]. There is no comprehensive study on the management of patients with hemorrhagic cholecystitis, and only case reports and series are available; no specific treatment guidelines exist. Here, we report a case of acute calculous hemorrhagic cholecystitis with melena. The patient had a rare presentation, and thus, her management differed from those reported in most available case reports.\n\nCase presentation\n\nA 75-year-old woman presented with a two-day history of fever and right upper quadrant abdominal pain. She had a history of diabetes and hypertension and had suffered a myocardial infarction four months prior, for which she was receiving dual antiplatelet therapy (aspirin 75 mg and clopidogrel 75 mg). On clinical examination, the patient was febrile, with a heart rate of 88 beats/min and blood pressure of 140/100 mmHg. There was tenderness on the right side of her abdomen, with a positive Murphy's sign. There were no palpable masses in the abdomen.\n\nOne day later, she developed yellowish discoloration of the sclera and melena. Her hemoglobin level was 7.1 g/dL. Other investigations revealed biochemical features of obstructive jaundice (alkaline phosphatase 517 U/L, bilirubin 156.6 µmol/L, direct bilirubin 152.4 µmol/L). Inflammatory marker levels were high (white cell count 16.3 × 109/L, C-reactive protein 61.3 mg/L), and INR was 1.4. She had no history of abdominal trauma or bleeding diathesis.\n\nTransabdominal ultrasonography (USG) revealed an avascular material of mixed echogenicity, in a distended gallbladder (Figure 1). Sonographic Murphy’s sign was positive. Non-contrast and IV contrast CT of the abdomen and pelvis showed a heterogeneous material, with a density almost equal to that of blood, filling the entire distended gall bladder, with no significant contrast enhancement in the arterial/venous phases (Figure 2). In addition, CT revealed a small gall stone. There was no biliary dilatation or active arterial bleeding in the biliary system. The patient was diagnosed with hemorrhagic cholecystitis.\n\nFigure 1 Transabodimal USG of the gallbladder.\n\nMixed echogenic materials and non-acoustic shadowing\n\nUSG, ultrasonography\n\n \n\nFigure 2 Axial cut of an abdominal CT with contrast.\n\nHeterogeneous material with a density almost equal to that of blood filling the entire distended gall bladder, with no significant contrast enhancement\n\nOn the day of admission, intravenous cefuroxime and metronidazole were initiated. On day 1, clopidogrel was withheld after the cardiologist’s opinion, and two pints of blood were transfused. On day 3, an esophagogastroduodenoscopy showed no bleeding from the upper gastrointestinal tract and a significant amount of bile in the duodenum. We arranged a multidisciplinary meeting with her physician and cardiologist and decided to continue conservative management unless her condition deteriorated. She responded well to antibiotics, and the melena resolved spontaneously on day 5 of admission. She was discharged after a week of conservative management and underwent laparoscopic cholecystectomy 6 weeks later. The gallbladder wall was thickened and showed some intramural thrombi with a single calculi (Figure 3). The patient had an uneventful postoperative period.\n\nFigure 3 Gross specimen of the gallbladder.\n\nThickened wall shows some residual intraluminal clots with a single calculus indicated by the white arrow\n\nThe histology of the gallbladder revealed features of acute on chronic cholecystitis with neither dysplasia nor malignancy. No complications were reported during the follow-up period of six months.\n\nAs it is a case report and it is not a clinical study or research, ethical approval was exempted. The patient was managed as it is, and no intervention was done for the publication. Written informed consent was obtained from the patient.\n\nDiscussion\n\nBleeding into the biliary tract, first described in 1945 by Sandblom, is caused by trauma [4]. Shah and Clegg first published about hemobilia due to hemorrhagic cholecystitis in 1979 [5]. Blood in the gall bladder lumen can be due to trauma, liver biopsy, hepatobiliary instrumentation, biliary tumor, parasite manifestation, aneurysm rupture into the biliary ducts, anticoagulation, or bleeding diathesis (renal failure and cirrhosis) [2, 6-7].\n\nIn hemorrhagic cholecystitis, inflammation occurs along the gallbladder wall, leading to mucosal injury and bleeding into the gallbladder lumen [7]. It commonly occurs in patients using antiplatelet (aspirin, cilostazol), nonsteroidal anti-inflammatory, anticoagulant, and steroidal drugs [8-10]. The literature shows that both calculous and acalculous cholecystitis can lead to hemorrhagic cholecystitis [11-12]. Cases of hemorrhagic cholecystitis present in many ways. Sometimes, the gallbladder distends with blood and perforates into the peritoneal cavity, leading to peritonitis, whereas at other times, blood clots may enter the common bile duct and cause obstructive jaundice; moreover, blood may enter the gastrointestinal tract and present as hematemesis or melena (hemobilia) [1].\n\nHemobilia is a rare presentation of hemorrhagic cholecystitis. Although upper abdominal pain, gastrointestinal tract bleeding, and jaundice (Quinke's triad) are typical characteristics of hemobilia, only 22% of cases have these features [2, 13]. Moreover, patients may have a fever with leukocytosis, and a positive Murphy’s sign [14]. Our patient presented with typical features of hemorrhagic cholecystitis. Blood entered the gastrointestinal tract and the patient had melena.\n\nAbdominal USG is the primary investigation in patients with acute cholecystitis. However, its usefulness in hemorrhagic cholecystitis is questionable. Therefore, diagnosis is made by contrast-enhanced CT. Typical CT findings include thickening of the gallbladder wall, distended gallbladder, and heterogeneous high-attenuation material within its lumen [15-16]. Extravasation of contrast material may be evident in the arterial phase of CT in actively bleeding patients [7]. In addition, endoscopic retrograde cholangiopancreatography (ERCP) is helpful in assessing hemobilia in some patients [17].\n\nAccording to the literature review of case reports, cholecystectomy is the gold standard treatment for hemorrhagic cholecystitis, and cholecystostomy is suitable in hemodynamically unstable and frail patients [18]. A retrospective analysis by Kim and Kim revealed that ERCP also plays a role in the initial management of biliary obstruction by removing blood clots from the common bile duct. Biliary drainage improves the condition in most cases [17]. However, this condition might be complicated by gallbladder perforation, thereby increasing morbidity and mortality [18]. Our patient was initially managed conservatively by withholding clopidogrel, administering IV antibiotics, and resuscitation with blood and IV fluids.\n\nConclusions\n\nIn a patient with melena and a typical presentation of hemobilia, hemorrhagic cholecystitis, although rare, should be considered as a differential diagnosis to avoid life-threatening complications. Early diagnosis with clinical and radiological assessment can significantly reduce morbidity and mortality. Although most patients with hemorrhagic cholecystitis can be treated with early cholecystectomy or ERCP, a few hemodynamically stable patients with no active bleeding can be managed conservatively in the initial stage, followed by interval cholecystectomy in six weeks.\n\nHuman Ethics\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study. Not Applicable issued approval Not Applicable. As it is a case report and it is not a clinical study or research, ethical approval was exempted. The patient was managed as it is, and no intervention was done for the publication. Written informed consent was obtained from the patient.\n==== Refs\nReferences\n\n1 Hemorrhagic cholecystitis in an elderly patient taking aspirin and cilostazol Case Rep Gastroenterol Morris DS Porterfield JR Sawyer MD 203 207 2 2008 21490889\n2 Hemorrhagic cholecystitis presenting as hemobilia Am J Gastroenterol Singh S Arora R Patil A 70 107 2012 https://journals.lww.com/ajg/Fulltext/2012/10001/Hemorrhagic_Cholecystitis_Presenting_as_Hemobilia_.162.aspx/.\n3 Hemorrhagic cholecystitis. Sonographic appearance and clinical presentation J Ultrasound Med Chinn DH Miller EI Piper N 313 317 6 1987 3302297\n4 Hemorrhage into the biliary tract following trauma; traumatic hemobilia Surgery Sandblom P 571 586 24 1948 https://pubmed.ncbi.nlm.nih.gov/18884132/ 18884132\n5 Haemorrhagic cholecystitis Br J Surg Shah VR Clegg JF 404 405 66 1979 466021\n6 Hemorrhagic cholecystitis simulating gallbladder carcinoma J Ultrasound Med Gremmels JM Kruskal JB Parangi S Kane RA 993 995 23 2004 15292572\n7 Hemorrhagic cholecystitis: report of a case Kor J Hepatobiliary Pancreat Surg Kwon JN 120 122 16 2012\n8 Atraumatic spontaneous hemorrhagic cholecystitis Proc (Bayl Univ Med Cent) Rahesh J Anand R Ciubuc J Athas V Brooks S Ronaghan C 107 108 34 2020 https://pubmed.ncbi.nlm.nih.gov/33456163/ 33456163\n9 Hemocholecyst. Report of a case associated with anticoagulation therapy Ohio State Med J Brawner J Trivedi H Sataline LR 1028 1030 62 1966 https://pubmed.ncbi.nlm.nih.gov/4166950/ 4166950\n10 Hemorrhagic cholecystitis: ultrasound and CT imaging findings - a retrospective case review series Emerg Radiol Ramírez Calderón JZ Martínez Chamorro E Ibáñez Sanz L Albillos Merino JC Borruel Nacenta S 613 620 28 2021 33464440\n11 Surgical case report-acalculous hemorrhagic cholecystitis J Surg Case Rep Leaning M 0 2021 2021\n12 [A case of spontaneous hemorrhagic cholecystitis without gallstone] Kor J Gastroenterol Heo TY An YY Lee JH Lee SW Kim YS Kang SB Lee DS 260 263 56 2010\n13 Haemorrhagic cholecystitis: an unusual cause of upper gastrointestinal bleeding BMJ Case Rep Hicks N 0 2014 2014\n14 Hemorrhagic cholecystitis Arch Surg Parekh J Corvera CU 202 204 145 2010 20157090\n15 Hemorrhagic cholecystitis as a complication of anticoagulant therapy: role of CT in its diagnosis Abdom Imaging Pandya R O'Malley C 652 653 33 2008 18629579\n16 Ultrasound and CT evaluation of emergent gallbladder pathology Radiol Clin North Am Bennett GL Balthazar EJ 1203 1216 42 2003 https://pubmed.ncbi.nlm.nih.gov/14661666/\n17 Etiology, clinical features, and endoscopic management of hemobilia: a retrospective analysis of 37 cases Kor J Gastroenterol Kim KH Kim TN 296 302 59 2012\n18 Haemorrhagic cholecystitis: a rare entity not to be forgotten BMJ Case Rep Ng ZQ Pradhan S Cheah K Wijesuriya R 0 2018 2018\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "13(7)",
"journal": "Cureus",
"keywords": "antiplatelet; hemobilia; hemorrhagic cholecystitis; interval cholecystectomy; melena",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e16385",
"pmc": null,
"pmid": "34306900",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports",
"references": "22544027;33456163;4166950;21490889;20157090;30244228;33796260;24443336;14661666;26388920;15292572;3302297;466021;18884132;20962563;18629579;33464440",
"title": "Hemorrhagic Cholecystitis: A Rare Cause of Melena.",
"title_normalized": "hemorrhagic cholecystitis a rare cause of melena"
} | [
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"companynumb": "LK-ACCORD-235121",
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"abstract": "OBJECTIVE\nThe results achieved in 44 patients with nonmetastatic peripheral neuroectodermal tumor (PNET) of bone treated with neoadjuvant chemotherapy are reported.\n\n\nMETHODS\nA six-drug regimen of chemotherapy (vincristine, doxorubicin, dactinomycin, cyclophosphamide, ifosfamide, and etoposide) was administered to all patients. Local treatment consisted of surgery in 20 patients, surgery followed by radiotherapy in 13, and radiotherapy only in 11.\n\n\nRESULTS\nAt a mean follow-up of 4.5 years (range, 2 to 7 years), 23 patients (52%) remain event-free, 20 have relapsed (45%), and one has died of chemotherapy-related toxicity. The 5-year event-free survival and overall survival were 54.2% and 62.7%, respectively. To assess the prognostic significance of neural differentiation in the family of Ewing's sarcoma, these results have been compared with the outcomes of 138 concomitant patients with typical Ewing's sarcoma (TES) who were treated according to the same protocol. Of these, 103 (75%) remained continuously event-free, 34 (24%) relapsed, and one died of chemotherapy-related toxicity. It follows that PNET patients treated with this chemotherapy regimen have a significantly worse prognosis than typical ES patients (5-year event-free survival, 54.2% v 70.6%, P <.012; 5-year overall survival, 62.7% v 78.3%, P <.002).\n\n\nCONCLUSIONS\nThe authors conclude that studies into new adjuvant therapy for Ewing's sarcoma modulated according to risk of relapse should also consider neural differentiation as a risk factor.",
"affiliations": "Departments of Chemotherapy and Pathology and Fifth Department of Orthopedic Surgery, Istituto Ortopedico Rizzoli, Bologna, Italy. chemioterapia@ior.it",
"authors": "Bacci|G|G|;Ferrari|S|S|;Bertoni|F|F|;Donati|D|D|;Bacchini|P|P|;Longhi|A|A|;Brach Del Prever|A|A|;Forni|C|C|;Rimondini|S|S|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D003609:Dactinomycin; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.2000.18.4.885",
"fulltext": null,
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"issn_linking": "0732-183X",
"issue": "18(4)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
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"title": "Neoadjuvant chemotherapy for peripheral malignant neuroectodermal tumor of bone: recent experience at the istituto rizzoli.",
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"abstract": "Takotsubo cardiomyopathy (TTC) is a transient condition that affects the myocardium and is seen mostly in post-menopausal women secondary to an emotional or physical stressor; however, certain drugs have been described as cause of this syndrome. We report the case of a young female with medication--induced TTC, who presented with cardiogenic shock as initial manifestation, treated successfully with extracorporeal membrane oxygenation (ECMO). To our knowledge, this is the first case in the literature describing the use of ECMO in cardiogenic shock due to medication-induced TTC.",
"affiliations": "Department of Medicine, Maimonides Medical Center, NY.;Department of Cardiology, Maimonides Medical Center, NY. Electronic address: doctorjacob@gmail.com.;Department of Cardiology, Maimonides Medical Center, NY.;Department of Cardiology, Maimonides Medical Center, NY.;Department of Cardiothoracic Surgery, Maimonides Medical Center, NY.;Department of Cardiology, Maimonides Medical Center, NY.",
"authors": "Rojas-Marte|Geurys|G|;John|Jinu|J|;Sadiq|Adnan|A|;Moskovits|Norbert|N|;Saunders|Paul|P|;Shani|Jacob|J|",
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"issue": "16(1)",
"journal": "Cardiovascular revascularization medicine : including molecular interventions",
"keywords": "ECMO; Takotsubo cardiomyopathy",
"medline_ta": "Cardiovasc Revasc Med",
"mesh_terms": "D000328:Adult; D004155:Diphenhydramine; D004562:Electrocardiography; D015199:Extracorporeal Membrane Oxygenation; D005260:Female; D006439:Hemodynamics; D006801:Humans; D007052:Ibuprofen; D020127:Recovery of Function; D012770:Shock, Cardiogenic; D054549:Takotsubo Cardiomyopathy; D013997:Time Factors; D016896:Treatment Outcome; D016277:Ventricular Function, Left",
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"title": "Medication-induced Takotsubo Cardiomyopathy presenting with cardiogenic shock-utility of extracorporeal membrane oxygenation (ECMO): case report and review of the literature.",
"title_normalized": "medication induced takotsubo cardiomyopathy presenting with cardiogenic shock utility of extracorporeal membrane oxygenation ecmo case report and review of the literature"
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"abstract": "OBJECTIVE\nThe objective of this study was to review the treatment outcomes of patients with secondary glaucoma in cases of autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV), a hereditary autoimmune uveitis due to mutations in CAPN5.\n\n\nMETHODS\nA retrospective, observational case series was assembled from ADNIV patients with secondary glaucoma. The main outcome measures were intraocular pressure (IOP), visual acuity, use of antiglaucoma medications, ocular surgeries, and adverse outcomes. Perimetry and optic disk optical coherence tomography (OCT) were also analyzed.\n\n\nRESULTS\nNine eyes of five ADNIV patients with secondary glaucoma were reviewed. Each received a fluocinolone acetonide (FA) implant for the management of posterior uveitis. Following implantation, no eyes developed neovascular glaucoma. Five eyes (in patients 1, 2, and 5) required Ahmed glaucoma valve surgery for the management of steroid-responsive glaucoma. Patient 2 also developed angle closure with iris bombe and underwent laser peripheral iridotomy. Patient 4 had both hypotony and elevated IOP that required periodic antiglaucoma medication in the FA-implanted eye. Patient 3 did not develop steroid-response glaucoma in either eye. Optic disk examinations were obscured by fibrosis and better assessed with OCT.\n\n\nCONCLUSIONS\nADNIV patients show combined mechanism secondary glaucoma best assessed by OCT of the optic disk. The FA implants have reduced uveitic and neovascular glaucoma. Nevertheless, IOP management remains complex due to steroid-response glaucoma, angle closure glaucoma, and hypotony.",
"affiliations": "Department of Ophthalmology and Visual Sciences; Omics Laboratory, University of Iowa, Iowa City, IA, USA.;Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India.;Department of Ophthalmology, Emory University School of Medicine, Atlanta, GA.;Department of Ophthalmology and Visual Sciences.;Department of Ophthalmology and Visual Sciences.;Department of Pediatrics, University of Iowa, Iowa City, IA.;Barbara and Donald Jonas Laboratory of Stem Cells and Regenerative Medicine and Bernard and Shirlee Brown Glaucoma Laboratory, Department of Pathology and Cell Biology, Institute of Human Nutrition, College of Physicians and Surgeons, Columbia University; Edward S Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY.;Retina Physicians & Surgeons, Inc., Dayton, OH, USA.;Department of Ophthalmology and Visual Sciences.;Department of Ophthalmology, Emory University School of Medicine, Atlanta, GA.;Department of Ophthalmology and Visual Sciences; Omics Laboratory, University of Iowa, Iowa City, IA, USA.",
"authors": "Cham|Abdourahman|A|;Bansal|Mayank|M|;Banda|Himanshu K|HK|;Kwon|Young|Y|;Tlucek|Paul S|PS|;Bassuk|Alexander G|AG|;Tsang|Stephen H|SH|;Sobol|Warren M|WM|;Folk|James C|JC|;Yeh|Steven|S|;Mahajan|Vinit B|VB|",
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"doi": "10.2147/OPTH.S103324",
"fulltext": "\n==== Front\nClin OphthalmolClin OphthalmolClinical OphthalmologyClinical Ophthalmology (Auckland, N.Z.)1177-54671177-5483Dove Medical Press 10.2147/OPTH.S103324opth-10-1187Original ResearchSecondary glaucoma in CAPN5-associated neovascular inflammatory vitreoretinopathy Cham Abdourahman 12Bansal Mayank 3Banda Himanshu K 4Kwon Young 1Tlucek Paul S 1Bassuk Alexander G 5Tsang Stephen H 67Sobol Warren M 8Folk James C 1Yeh Steven 4Mahajan Vinit B 121 Department of Ophthalmology and Visual Sciences2 Omics Laboratory, University of Iowa, Iowa City, IA, USA3 Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India4 Department of Ophthalmology, Emory University School of Medicine, Atlanta, GA5 Department of Pediatrics, University of Iowa, Iowa City, IA6 Barbara and Donald Jonas Laboratory of Stem Cells and Regenerative Medicine and Bernard and Shirlee Brown Glaucoma Laboratory, Department of Pathology and Cell Biology, Institute of Human Nutrition, College of Physicians and Surgeons, Columbia University7 Edward S Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY8 Retina Physicians & Surgeons, Inc., Dayton, OH, USACorrespondence: Vinit B Mahajan, Department of Ophthalmology and Visual Sciences, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA, Tel +1 319 467 5151, Fax +1 319 356 0363, Email mahajanlab@gmail.com2016 27 6 2016 10 1187 1197 © 2016 Cham et al. This work is published and licensed by Dove Medical Press Limited2016The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Objective\nThe objective of this study was to review the treatment outcomes of patients with secondary glaucoma in cases of autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV), a hereditary autoimmune uveitis due to mutations in CAPN5.\n\nPatients and methods\nA retrospective, observational case series was assembled from ADNIV patients with secondary glaucoma. The main outcome measures were intraocular pressure (IOP), visual acuity, use of antiglaucoma medications, ocular surgeries, and adverse outcomes. Perimetry and optic disk optical coherence tomography (OCT) were also analyzed.\n\nResults\nNine eyes of five ADNIV patients with secondary glaucoma were reviewed. Each received a fluocinolone acetonide (FA) implant for the management of posterior uveitis. Following implantation, no eyes developed neovascular glaucoma. Five eyes (in patients 1, 2, and 5) required Ahmed glaucoma valve surgery for the management of steroid-responsive glaucoma. Patient 2 also developed angle closure with iris bombe and underwent laser peripheral iridotomy. Patient 4 had both hypotony and elevated IOP that required periodic antiglaucoma medication in the FA-implanted eye. Patient 3 did not develop steroid-response glaucoma in either eye. Optic disk examinations were obscured by fibrosis and better assessed with OCT.\n\nConclusion\nADNIV patients show combined mechanism secondary glaucoma best assessed by OCT of the optic disk. The FA implants have reduced uveitic and neovascular glaucoma. Nevertheless, IOP management remains complex due to steroid-response glaucoma, angle closure glaucoma, and hypotony.\n\nKeywords\nADNIVCAPN5calpain-5fluocinolone acetonidesecondary glaucomauveitis\n==== Body\nIntroduction\nAutosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV) is an inherited autoimmune uveitis and neovascular vitreoretinal degeneration caused by mutations in the CAPN5 gene.1–3 CAPN5 is an intracellular protease expressed in the retina. The disease alleles appear to increase CAPN5 proteolytic activity,4 but molecular disease mechanisms remain to be elucidated. Inflammatory cells in the vitreous and anterior chamber, photoreceptor degeneration, vitreous hemorrhages, epiretinal membranes (ERMs), and proliferative iris and retinal neovascularization characterize ADNIV. Owing to intraocular fibrosis, there is further progression to tractional retinal detachment and eventual phthisis.1,2\n\nADNIV patients develop glaucoma secondary to uveitis, steroid response, and angle neovascularization. Autoimmune uveitis can lead to elevated intraocular pressure (IOP) and uveitic glaucoma due to obstruction of trabecular drainage by inflammatory infiltrates and proteinaceous materials.5 However, anti-inflammatory therapy with steroids can increase IOP and predispose ADNIV patients to steroid-induced glaucoma. ADNIV patients are also at risk for neovascular glaucoma. There is rubeotic and neovascular glaucoma in nearly half of ADNIV patients older than 60 years.1 Therefore, ADNIV patients have multiple risk factors for developing glaucoma. In late stages, some ADNIV eyes become hypotonous, which could accelerate phthisis. Given their common genetic defect, ADNIV patients provide a unique perspective on the management of uveitic glaucoma.\n\nManagement of glaucoma in ADNIV, especially in steroid responders, can be challenging given the competing interests of effective anti-inflammatory therapy and control of elevated IOP.6 ADNIV patients often receive fluocinolone acetonide (FA) implants for the management of chronic uveitis. Steroid-sparing agents have limited efficacy in ADNIV uveitis, and the FA implants obviate the need for long-term oral steroid therapy.7 Surgical management of uveitic glaucoma with glaucoma drainage devices has been described.8,9 In this series, we report on five patients with ADNIV-associated uveitis and describe their treatment outcomes.\n\nPatients and methods\nThe study was approved by the Institutional Review Board for Human Subjects Research and adhered to the tenets of the Declaration of Helsinki. All patients provided written informed consent. A retrospective case series was assembled from the charts of ADNIV patients (2001 to present) from the University of Iowa (four charts) and Emory University (one chart). Clinical examinations were performed by vitreoretinal and glaucoma specialists (authors). Genetic testing was performed as previously described.2 The FA implantation surgery was performed as previously described.10 The Ahmed glaucoma valve (AGV) implantation surgery was performed by standard methods. Patient 1 received AGV Model FP-7 and patient 2 and patient 5 received AGV Model S-2. The AGV implant was fixed to the globe 9 mm posterior to the limbus. The tube of the AGV was trimmed and inserted into the anterior chamber through a tract created with a 23-gage needle. The tube was well positioned with 1–2 mm visible in the anterior chamber. A donor scleral graft was used to secure the AGV implant to the host sclera.\n\nPatient 1\nA 49-year-old man with ADNIV was evaluated of recurrent uveitis and elevated IOP. He carried the CAPN5 p.L244P mutation. His uveitis was managed with topical steroids and subtenon’s triamcinolone acetate injections for 20 years. On examination, his best-corrected visual acuity (BCVA) was 20/50 OD and 20/1,000 OS. He was functionally monocular. His eye pressure measured as high as 45 mmHg OD and 25 mmHg OS, and it was refractory to a maximum treatment of dorzolamide–timolol, brimonidine, pilocarpine, and latanoprost. He could not tolerate methazolamide (oral carbonic anhydrase inhibitor). On anterior segment examination, his corneal thickness was 556 µm OD and 592 µm OS, and there was 2+ flare OU. On right eye gonioscopy, the angle was open with visible scleral spur. The angular approach was 40°, and the iris was flat with 1+ pigmentation of the trabecular meshwork. In the left eye, both the scleral spur and ciliary body were visible and the angular approach was 35° with 1+ pigmentation of the trabecular meshwork. He was pseudophakic OU. The posterior segment exam showed 2+ vitreous cells OU, vitreous opacities, and a 3+ ERM OD and 1+ ERM OS. He also had significant cystoid macular edema (CME) and inferior thinning of the optic disk OD (Figure 1A). He had significant media opacity, due to intraocular fibrosis and tractional retinal detachment, which obscured view of his optic disk OS (Figure 1B). There was 360° of diffuse pigmentary clumping OU without any retinal tears or detachment OD. These findings were consistent with early stage III ADNIV OD and stage IV ADNIV OS.\n\nOn Goldmann perimetry, the right eye showed diffuse constriction, superior > inferior (Figure 1C). In the left eye, he had extensive visual field losses with only an island of central and inferotemporal visual field remaining (Figure 1D). Stratus optic disk optical coherence tomography (OCT) showed no losses of retinal nerve fiber layer (RNFL) thickness OD, but severe losses were evident OS, especially in the nasal and temporal quadrants (Figure 1E–F).\n\nHe elected to undergo FA implantation OD for the management of his uveitis and CME. Given his history of steroid-induced ocular hypertension, it was decided to perform AGV (Model FP7) surgery, concurrent with the FA implantation. During his postoperative course, he did not require antiglaucoma medication OD. His BCVA improved to 20/50 by the second postoperative month, and his IOP remained <21 mmHg during 1-year of follow-up.\n\nPatient 2\nAt age 24, an ADNIV man with a CAPN5 p.R243L mutation underwent FA implantation OU for control of posterior uveitis, which stabilized his visual acuity at 20/30 OU. Over the next 3 years, however, his vision declined, due to photoreceptor degeneration and intraocular fibrosis, and his IOP steadily increased, even with the combination of dorzolamide–timolol, brimonidine, and latanoprost. He deferred replacement of the FA implants, which exhausted after ~2.5 years.\n\nAt age 27, he required AGV surgery OU for IOP control. His BCVA was 20/100 OD and 20/200 OS, and his IOP was 41 mmHg OD and 32 mmHg OS. His corneal thickness was 589 µm OD and 597 µm OS. On gonioscopy, the ciliary body was visible with the angular approach of 40° OU. The iris was flat with deep insertion, and there was no pigmentation in the trabecular meshwork. Posterior chamber intraocular lenses were well centered. On posterior examination, he had vitreous membrane attached to the optic nerve head OU and macular traction OS. The optic disk showed evidence of inferior thinning of the neuroretinal rim OD (Figure 2A and B). On Goldmann perimetry, he had significant superior visual field losses OD (Figure 2C) and mild superotemporal visual field constriction OS (Figure 2D).\n\nOne year after AGV surgery, his IOP was 25 mmHg OD and 20 mmHg OS. Because of ongoing intraocular fibrosis, common in ADNIV eyes, he suffered from pupillary block with iris bombe and acute angle-closure glaucoma OD. A laser peripheral iridotomy corrected this. With the addition of dorzolamide–timolol, brimonidine, and latanoprost OU, his IOP improved to 19 mmHg OD and 15 mmHg OS by postoperative year 2. At postoperative year 3, his IOP was 17 mmHg OD and 11 mmHg OS. His BCVA OD was 20/100, which was equal to his preoperative BCVA, but there was a moderate loss of acuity OS to 20/250.\n\nPatient 3\nA 36-year-old ADNIV woman with a CAPN5 p.R243L mutation was evaluated for chronic CME and uveitis. She was managed with methazolamide for chronic CME, and combination of subtenon’s triamcinolone acetate and prednisolone for uveitis. However, she continued to suffer from bouts of recurrent uveitis and underwent FA implantation OU. Her BCVA was 20/40 OD and 20/200 OS. Her IOP was 13 mmHg OD and 14 mmHg OS. Her angles were open, and there was 2+ flare with rare cells OU. Her posterior segment examination showed 1+ vitreous cells OU, peripheral retinal pigment epithelium changes OU, mild ERM OU, disk pallor OU (Figure 3A and B), CME OU, attenuated vessels OD (Figure 3A), and early neovascularization of the peripheral retina OS. Goldmann perimetry showed an intact visual field OD and mild superotemporal constriction OS (Figure 3C and D).\n\nTo control her uveitis and CME, she underwent FA implantation. After 6 months, her IOP increased to 24 mmHg OD. She was started on timolol OU, and her IOP OD improved to a mean of 16 for the next 2 years. Her IOP OS remained at a mean of 14. Her BCVA OD remained relatively stable for 2 years, but her left eye acuity began to decline due to intraocular fibrosis and retinal degeneration, eventually becoming prephthisical after 3 years.\n\nShe never required glaucoma surgery. Her interval OD Goldmann perimetry after 14 years showed severe constriction with a central scotoma (Figure 3E). Stratus optic disk OCT RNFL thickness showed mild thinning superiorly but was otherwise normal (Figure 3E, F, and G). This suggested that pigmentary degeneration was causing the visual field loss.\n\nPatient 4\nA 66-year-old ADNIV woman with a CAPN5 p.R243L mutation was treated with prednisolone for chronic iritis and required topical brimonidine–timolol for elevated IOP. On examination, her BCVA was 20/50 OD and 20/200 OS and her IOP was 20 mmHg OD and 10 mmHg OS. Her corneal thickness was 602 µm OD and 621 µm OS. She had 1+ cell and 1+ flare OU and bilateral pseudophakia. On posterior segment examination, she had dense vitreous hemorrhage OS, scattered retinal pigment epithelium clumps OU, markedly attenuated vessels OU, and optic disk pallor OU (Figure 4A and B). Goldmann perimetry showed severe bilateral visual field loss (Figure 4C and D). Stratus OCT RNFL thickness showed marked superior, nasal, and inferior thinning OU (Figure 4E and F).\n\nHer recurrent uveitis, CME, and vitreous hemorrhage OS were refractory to treatment with prednisolone, methotrexate, triamcinolone, and bevacizumab. At age 68, she underwent FA implantation in her left eye. One week postoperatively, her BCVA was 20/300 and her left eye was hypotonous with an IOP of 4 mmHg. Her brimonidine–timolol eye drop was withheld OS. By postoperative month 1, her IOP normalized to 18 mmHg OS, and between postoperative months 3–12, her IOP ranged between 7 and 14 mmHg. At postoperative month 15, her vision improved to 20/250; however, she had a recurrent hypotony OS with IOP <4 mmHg. Her IOP continued to fluctuate between 4 and 42 mmHg, sometimes necessitating topical antiglaucoma medication.\n\nAt age 69, she underwent FA implantation OD for chronic posterior uveitis. Preoperatively, her BCVA was 20/30 and her IOP was 13 mmHg OD. However, her IOP increased to 30 mmHg by postoperative week 6 and brimonidine–timolol was resumed. At postoperative month 5, her IOP increased to 32 mmHg OD and she was started on dorzolamide–timolol. One week later, her IOP dropped to 9 mmHg. Her IOP continued to fluctuate between 7 and 33 mmHg. The high IOPs were managed with intermittent use of topical antiglaucoma medication, and she has not required AGV surgery.\n\nPatient 5\nA 26-year-old woman with ADNIV carried a CAPN5 p.K250N mutation. Her bilateral intermediate uveitis was managed with topical steroids, subtenon’s triamcinolone acetate injections, intravitreal kenalog, and oral methotrexate for 3 years. However, she continued to have recalcitrant CME limiting her vision in both eyes. Her BCVA was 20/40 OD and 20/200 OS. IOP was 12 mmHg OU. Her corneal thickness was 584 µm OD and 581 µm OS. She had 1+ anterior chamber cells OU. Gonioscopy (Spaeth classification) of both eyes revealed scleral spur compressible to ciliary body band, 40° insertion, a regular and flat configuration of the peripheral iris, and minimal pigmentation of the trabecular meshwork. Peripheral anterior synechiae were noted OS. She had a 2+ nuclear sclerotic cataract OD and a 1+ nuclear sclerotic cataract/posterior subcapsular cataract OS. The posterior segment examination was significant for 2+ vitreous cell OU. Optic disks were pink and sharp, with a cup–disk ratio of 0.3 OU. Trace ERMs were present OU. The peripheral retinal had diffuse pigmentary clumping OU, without tears or detachments. She had snowballs in the inferior periphery. OCT revealed CME OU. She elected to undergo combined pars plana vitrectomy (PPV)/cataract extraction (CE)/intraocular lens (IOL)/fluocinolone acetonide (FA) implantation OS, with vision improving to 20/80.\n\nFive months after her surgery, her IOP measured 22 mmHg OD and 36 mmHg OS despite treatment with topical brimonidine, dorzolamide–timolol, latanoprost, and oral acetazolamide. Her left optic nerve had a pink neuroretinal rim OS (Figure 5A). Her Humphrey visual field (24-2) indicated inferior and superior arcuate defects OU, OS worse than OD (Figure 5B and C). She elected to undergo implantation of an AGV in her left eye for management of her glaucoma. During her postoperative course, she continued to require antiglaucoma drops in both eyes but was able to discontinue oral acetazolamide.\n\nAt the age of 29, she continued to have progression of her cataract and worsening CME OD. She underwent PPV/CE IOL/FA implantation in the right eye. IOP in the right eye measured 35 mmHg 1 month after her PPV despite maximum topical therapy. An AGV was implanted in the right eye. She was maintained on topical antiglaucoma medication with stable central acuity and glaucomatous findings noted on her visual fields for 3 years.\n\nDespite continued subtenon’s steroid injections OU, she continued to have CME in both eyes and underwent another PPV with a second FA implantation OU. She developed band keratopathy in both eyes, OD worse than OS. She underwent ethylene diamine tetraacetic acid chelation OD with improvement in her vision and symptoms.\n\nFive years after her last AGV surgery, her IOP was 5 mmHg OD and 9 mmHg OS. BCVA was 20/40 OD and 20/100 OS. Interval Humphrey visual field indicated progression of glaucomatous changes OU (Figure 5D and E).\n\nDiscussion\nUveitis is the fifth leading cause of vision loss in the developed world. It is often a chronic disease, and long-term steroid therapy increases likelihood of steroid-induced complications such as cataracts, infections, and glaucoma. About one-third of all eyes experience IOP elevation with steroid treatment, and inflammatory uveitis compounds this risk by diminishing trabecular outflow.5,11 Although uveitis can also cause aqueous hyposecretion, due to inflammation of the ciliary body, this IOP-lowering effect is usually overpowered by the increased resistance to trabecular drainage from inflammatory infiltrates and endothelial dysfunction. On balance, these processes often result in increased IOP and predispose patients to glaucoma.\n\nIn the setting of inflammatory uveitis, glaucoma can be secondary to steroid therapy, inflammation, or angle neovascularization. ADNIV patients are at risk of developing secondary glaucoma via all the three mechanisms, and they also develop intraocular fibrosis. Despite these significant risk factors, some ADNIV patients do not develop elevated IOP or glaucoma. In this series, patient 3 had normal appearing optic disks without evidence of glaucomatous change, despite >40 years of ADNIV-related pathology. Furthermore, her eye pressures were well controlled for up to 3 years following FA implantation. This suggests that a subset of patients may not develop complications of glaucoma, despite decades of ADNIV and steroid therapy. Furthermore, the exact genetic defect does not seem to make a difference, since glaucoma developed in all the three CAPN5 mutations varied between patients with the same genetic defect and between eyes.3,10,12 This supports the concept that there is significant phenotypic variance in ADNIV features.12\n\nADNIV uveitis generally fails management with topical steroids and steroid-sparing therapy. Oral prednisone at >10 mg/d usually causes too severe side effects to be used long term; therefore, ADNIV patients receive FA implants. Friedman et al13 reported that FA implant recipients were two to three times more likely to develop elevated IOP and require IOP-lowering therapy compared to patients receiving systemic steroid therapy.13 Furthermore, Bollinger et al14 also reported that 75% of patients with FA implants required IOP-lowering drops and almost half had IOP >30 mmHg within the first postoperative year. Additionally, 45% of patients receiving FA implants required glaucoma surgery by 36 months following FA implantation.15 Given the risks of elevated IOP and glaucoma associated with FA implantation and the baseline risk conferred by ADNIV itself, it is encouraging that some ADNIV patients – such as patient 3–might not develop glaucoma or steroid-induced ocular hypertension.\n\nNeovascular glaucoma was previously a major complicating factor in ADNIV patients, but we reported that FA implantation seems to have largely resolved this.10 In one instance, prior to FA implantation, ADNIV optic disk neovascularization had resolved following a course of oral prednisone and methotrexate. This is consistent with the findings of Sanislo et al16 regarding treatment of optic disk neovascularization with oral and periocular corticosteroids, and the FA implants are likely to have had a similar effect.10 The FA implants are also effective at controlling ADNIV uveitis;15 however, steroid-induced ocular hypertension is an emerging concern. This conundrum makes combined FA–AGV surgery particularly attractive. FA implantation and glaucoma valve surgery have been successfully performed in a single surgical session.8 Nonetheless, it is often difficult to determine in advance which ADNIV patients are likely to be steroid responders following FA implantation, and hence, good candidates for combined AGV–FA surgery.\n\nIOP fluctuation is challenging to manage in glaucoma patients. In our series, patient 4’s IOPs became very labile following FA implantation. The possible causes of hypotony include FA surgery, uveitis, and FA-associated hypotony. Bollinger et al14 reported that, following FA surgery, ~35% of patients developed hypotony (<5 mmHg). For this reason, some glaucoma surgeons avoid a large plate Baerveldt tube shunt (eg, Baerveldt 350) with no valve, which can lead to postoperative hypotony.\n\nThree multicenter clinical trials have demonstrated that FA implants are very effective at decreasing uveitis recurrence.15 However, steroid-induced IOP elevation, as described above, is a common complication of FA implantation.14 AGV implant is effective in treating uveitic glaucoma with few surgical complications.17 Elevated IOP in the early postoperative period may be due to AGV obstruction by fibrin, blood, iris, vitreous membranes, or silicone oil. In one study, this was observed in 11% of eyes following AGV implantation. The most common causes of blockage were iris tissues and fibrinous membranes followed by neovascular membrane and iridocorneal endothelial membrane.18 ADNIV patients can have an exuberant inflammatory response following intraocular surgery.7 Following AGV surgery, patient 2 still required topical therapy for IOP control. It is possible that his AGV implant become less functional due to fibrosis around the tube plate.7 Successful AGV surgery combined with adjunctive mitomycin C and fluorouracil has been reported by Alvarado et al.19 However, others have found no benefit of using adjunctive antifibrotic agents with tube shunts.20 At this point, we do not recommend adjunctive agents in ADNIV patients.\n\nConclusion\nADNIV is a complex hereditary autoimmune uveitis where disease management poses several challenges. In the past, severe progressive vision loss in ADNIV due to intraocular inflammation, neovascular glaucoma, and tractional retinal detachment made optic nerve monitoring less important, since these end-stage eyes rapidly became blind. The recent use of long-term steroid implants has delayed disease progression and controlled other aspects of ADNIV. This has made monitoring of glaucoma more important. The complex pathology of ADNIV and superimposed retinal degeneration makes interpretation of glaucoma studies challenging, and the use of OCT imaging in ADNIV may be more reliable than perimetry data and clinical examination. FA implants effectively control uveitis in ADNIV patients; however, they predispose patients to complications such as cataracts and steroid-response glaucoma. ADNIV patients with elevated IOP refractory to medical management were treated with AGV surgery. The findings from this series suggest that some ADNIV patients have good outcomes with combined FA–AGV surgery.\n\nAcknowledgments\nVBM was supported by the National Institutes of Health’s grants K08EY020530 and R01EY016822, the Doris Duke Charitable Foundation’s grant 2013103, and Research to Prevent Blindness, New York, NY, USA.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Patient 1.\n\nNotes: (A) OD optic disk image shows vertically oval cup with INF thinning of the NRR. (B) OS optic disk image with media haze and diffuse disk pallor. (C) OD Goldmann perimetry with diffuse constriction, SUP > INF. (D) OS Goldmann perimetry shows remaining island of central and inferotemporal visual field. (E) Stratus OCT RNFL thickness analysis OD shows no RNFL loss. (F) OS RNFL quadrant and analysis show severe losses (<1% of normative data) in the NAS and TEMP quadrants. OS RNFL clock hour analysis corroborates RNFL thickness findings. OD RNFL quadrant and clock hour analyses were both normal.\n\nAbbreviations: INF, inferior; NRR, neuroretinal rim; SUP, superior; OCT, optical coherence tomography; RNFL, retinal nerve fiber layer; NAS, nasal; TEMP, temporal; NA, not applicable; S, superior; N, nasal; T, temporal; I, inferior.\n\nFigure 2 Patient 2.\n\nNotes: (A) OD disk image showing fibrous membrane over disk with inferior thinning of NRR. There is no NVD. (B) OS optic disk appears hyperemic with dense fibrous membrane. There is no NVD. (C) OD Goldmann perimetry shows superior visual field loss. (D) OS Goldmann perimetry shows mild constriction of the superotemporal visual field.\n\nAbbreviations: NRR, neuroretinal rim; NVD, neovascularization of the disk.\n\nFigure 3 Patient 3.\n\nNotes: (A) OD optic disk has pink and regular NRR without peripapillary atrophy. (B) OS optic disk was similar with fibrous membrane and vessel sheathing. (C) Initial OD Goldmann perimetry with relatively intact visual field. (D) Initial OS Goldman perimetry with superotemporal constriction. (E) Interval OD Goldmann visual field after 14 years shows marked visual constriction with central scotoma (OS unavailable since the patient’s left eye became phthisical). (F) OD stratus OCT shows mild RNFL thinning superiorly, otherwise RNFL thickness is normal. (G) Normal RNFL quadrant and RNFL clock hour analyses OD.\n\nAbbreviations: NRR, neuroretinal rim; OCT, optical coherence tomography; RNFL, retinal nerve fiber layer; TEMP, temporal; SUP, superior; NAS, nasal; INF, inferior; NA, not applicable; S, superior; N, nasal; T, temporal; I, inferior.\n\nFigure 4 Patient 4.\n\nNotes: (A and B). Bilateral disk pallor with loss of disk capillaries and attenuation of major vessels, suggestive of optic atrophy. (C) Goldmann perimetry with severe visual field loss and preservation of central vision OD. (D) Goldmann perimetry with severe visual field loss and split fixation OS. (E) Stratus OCT RNFL thickness analysis OU showed marked SUP, NAS, and INF thinning (<1% of normal). (F) RNFL quadrant and clock hours were consistent with the RNFL thickness findings.\n\nAbbreviations: OCT, optical coherence tomography; RNFL, retinal nerve fiber layer; SUP, superior; NAS, nasal; INF, inferior; TEMP, temporal; NA, not applicable; S, superior; N, nasal; T, temporal; I, inferior.\n\nFigure 5 Patient 5.\n\nNotes: (A) OS optic disk has pink and regular NRR (OD examination was similar to OS examination). (B and C) Humphrey Visual Field 24-2 SITA-Standard protocol with superior and inferior arcuate defects OS > OD, and superior and inferior nasal step defects OU. (D and E) Interval Humphrey Visual Field 24-2 SITA-Standard protocol (obtained 6 years later) demonstrates glaucomatous progression with denser superior arcuate defects OU.\n\nAbbreviation: NRR, neuroretinal rim.\n==== Refs\nReferences\n1 Bennett SR Folk JC Kimura AE Russell SR Stone EM Raphtis EM Autosomal dominant neovascular inflammatory vitreoretinopathy Ophthalmology 1990 97 9 1125 1135 discussion 1126–1135 2234842 \n2 Mahajan VB Skeie JM Bassuk AG Calpain-5 mutations cause autoimmune uveitis, retinal neovascularization, and photoreceptor degeneration PLoS Genet 2012 8 10 e1003001 23055945 \n3 Bassuk AG Yeh S Wu S Structural modeling of a novel CAPN5 mutation that causes uveitis and neovascular retinal detachment PLoS One 2015 10 4 e0122352 25856303 \n4 Wert KJ Bassuk AG Wu WH CAPN5 mutation in hereditary uveitis: the R243L mutation increases calpain catalytic activity and triggers intraocular inflammation in a mouse model Hum Mol Genet 2015 24 16 4584 4598 25994508 \n5 Siddique SS Suelves AM Baheti U Foster CS Glaucoma and uveitis Surv Ophthalmol 2013 58 1 1 10 23217584 \n6 Sung VC Barton K Management of inflammatory glaucomas Curr Opin Ophthalmol 2004 15 2 136 140 15021226 \n7 Tlucek PS Folk JC Sobol WM Mahajan VB Surgical management of fibrotic encapsulation of the fluocinolone acetonide implant in CAPN5-associated proliferative vitreoretinopathy Clin Ophthalmol 2013 7 1093 1098 23785231 \n8 Malone PE Herndon LW Muir KW Jaffe GJ Combined fluocinolone acetonide intravitreal insertion and glaucoma drainage device placement for chronic uveitis and glaucoma Am J Ophthalmol 2010 149 5 800 806.e1 20189158 \n9 Ahmad ZM Hughes BA Abrams GW Mahmoud TH Combined posterior chamber intraocular lens, vitrectomy, Retisert, and pars plana tube in noninfectious uveitis Arch Ophthalmol 2012 130 7 908 913 22776928 \n10 Tlucek PS Folk JC Orien JA Stone EM Mahajan VB Inhibition of neovascularization but not fibrosis with the fluocinolone acetonide implant in autosomal dominant neovascular inflammatory vitreoretinopathy Arch Ophthalmol 2012 130 11 1395 1401 22777573 \n11 Kocabora MS Yilmazli C Taskapili M Gulkilik G Durmaz S Development of ocular hypertension and persistent glaucoma after intravitreal injection of triamcinolone Clin Ophthalmol 2008 2 1 167 171 19668401 \n12 Rowell HA Bassuk AG Mahajan VB Monozygotic twins with CAPN5 autosomal dominant neovascular inflammatory vitreoretinopathy Clin Ophthalmol 2012 6 2037 2044 23271883 \n13 Friedman DS Holbrook JT Ansari H Risk of elevated intraocular pressure and glaucoma in patients with uveitis: results of the multicenter uveitis steroid treatment trial Ophthalmology 2013 120 8 1571 1579 23601801 \n14 Bollinger KE Smith SD Prevalence and management of elevated intraocular pressure after placement of an intravitreal sustained-release steroid implant Curr Opin Ophthalmol 2009 20 2 99 103 19248312 \n15 Bollinger K Kim J Lowder CY Kaiser PK Smith SD Intraocular pressure outcome of patients with fluocinolone acetonide intravitreal implant for noninfectious uveitis Ophthalmology 2011 118 10 1927 1931 21652079 \n16 Sanislo SR Lowder CY Kaiser PK Corticosteroid therapy for optic disc neovascularization secondary to chronic uveitis Am J Ophthalmol 2000 130 6 724 731 11124290 \n17 Da Mata A Burk SE Netland PA Baltatzis S Christen W Foster CS Management of uveitic glaucoma with Ahmed glaucoma valve implantation Ophthalmology 1999 106 11 2168 2172 10571354 \n18 Huang MC Netland PA Coleman AL Siegner SW Moster MR Hill RA Intermediate-term clinical experience with the Ahmed glaucoma valve implant Am J Ophthalmol 1999 127 1 27 33 9932995 \n19 Alvarado JA Hollander DA Juster RP Lee LC Ahmed valve implantation with adjunctive mitomycin C and 5-fluorouracil: long-term outcomes Am J Ophthalmol 2008 146 2 276 284 18538300 \n20 Minckler DS Francis BA Hodapp EA Aqueous shunts in glaucoma: a report by the American Academy of Ophthalmology Ophthalmology 2008 115 6 1089 1098 18519069\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1177-5467",
"issue": "10()",
"journal": "Clinical ophthalmology (Auckland, N.Z.)",
"keywords": "ADNIV; CAPN5; calpain-5; fluocinolone acetonide; secondary glaucoma; uveitis",
"medline_ta": "Clin Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "101321512",
"other_id": null,
"pages": "1187-97",
"pmc": null,
"pmid": "27390515",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": "15021226;19668401;10571354;20189158;21652079;18538300;25994508;9932995;23601801;23217584;19248312;25856303;22777573;23055945;23271883;18519069;11124290;23785231;22776928;2234842",
"title": "Secondary glaucoma in CAPN5-associated neovascular inflammatory vitreoretinopathy.",
"title_normalized": "secondary glaucoma in capn5 associated neovascular inflammatory vitreoretinopathy"
} | [
{
"companynumb": "US-BAUSCH-BL-2016-020180",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHAZOLAMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "Adding a taxane to anthracycline-based adjuvant chemotherapy prolongs survival in node-positive early breast cancer. However, which is the preferable taxane in a dose-dense regimen remains unknown. We conducted a randomized study to compare the efficacy of dose-dense paclitaxel versus docetaxel following 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) as adjuvant chemotherapy in women with node-positive early breast cancer. Following surgery women with HER2-negative breast cancer and at least one infiltrated axillary lymph node were randomized to receive four cycles of FEC (700/75/700 mg/m(2)) followed by four cycles of either paclitaxel (175 mg/m(2)) or docetaxel (75 mg/m(2)). All cycles were administered every 14 days with G-CSF support. The primary endpoint was disease-free survival (DFS) at 3 years. Between 2004 and 2007, 481 women were randomized to paclitaxel (n = 241) and docetaxel (n = 240). After a median follow-up of 6 years, 51 (21%) and 48 (20%) women experienced disease relapse (p = 0.753) and there was no significant difference in DFS between the paclitaxel- and docetaxel-treated groups (3-year DFS 87.4 vs. 88.3%, respectively; median DFS not reached; p = 0.633). Toxicities were manageable, with grade 2-4 neutropenia in 21 versus 31% (p = 0.01), thrombocytopenia 0.8 versus 3.4% (p = 0.06), any grade neurotoxicity 17 versus 7.5% (p = 0.35) and onycholysis 4.9 versus 12.1% (p = 0.03) for patients receiving paclitaxel and docetaxel, respectively. There were no toxic deaths. Dose-dense paclitaxel versus docetaxel after FEC as adjuvant chemotherapy results in a similar 3-year DFS rate in women with axillary node-positive early breast cancer. Due to its more favorable toxicity profile, paclitaxel is the taxane of choice in this setting.",
"affiliations": "Hellenic Oncology Research Group (HORG), Lomvardou 55, 11470, Athens, Greece.",
"authors": "Saloustros|Emmanouil|E|;Malamos|Nikolaos|N|;Boukovinas|Ioannis|I|;Kakolyris|Stylianos|S|;Kouroussis|Charalampos|C|;Athanasiadis|Athanasios|A|;Ziras|Nikolaos|N|;Kentepozidis|Nikolaos|N|;Makrantonakis|Parisis|P|;Polyzos|Aristidis|A|;Christophyllakis|Charalampos|C|;Georgoulias|Vassilios|V|;Mavroudis|Dimitrios|D|",
"chemical_list": "D043823:Taxoids; D000077143:Docetaxel; D017239:Paclitaxel",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10549-014-3202-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-6806",
"issue": "148(3)",
"journal": "Breast cancer research and treatment",
"keywords": null,
"medline_ta": "Breast Cancer Res Treat",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D000077143:Docetaxel; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D008875:Middle Aged; D017239:Paclitaxel; D043823:Taxoids; D016896:Treatment Outcome",
"nlm_unique_id": "8111104",
"other_id": null,
"pages": "591-7",
"pmc": null,
"pmid": "25399229",
"pubdate": "2014-12",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "Dose-dense paclitaxel versus docetaxel following FEC as adjuvant chemotherapy in axillary node-positive early breast cancer: a multicenter randomized study of the Hellenic Oncology Research Group (HORG).",
"title_normalized": "dose dense paclitaxel versus docetaxel following fec as adjuvant chemotherapy in axillary node positive early breast cancer a multicenter randomized study of the hellenic oncology research group horg"
} | [
{
"companynumb": "GR-CIPLA LTD.-2014GR02281",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "EPIRUBICIN"
},
"drugadditional": null,
... |
{
"abstract": "Esophageal perforation is a rupture of the esophageal wall, caused by iatrogenesis in 56% of cases. Perforation of the esophagus remains a challenge, and its incidence has increased as the use of endoscopic procedures has become more frequent. We report a 54-year-old woman with esophageal perforation 8 days after kidney transplantation. She had received a gastrointestinal consultation prior to her transplantation. This report highlights the fact that perforation may occur after any organ transplantation, especially during the initial 2 weeks after transplantation, when mycophenolate mofetil and cyclosporine as well as and high doses of corticosteroid are administered. If there is a delay in passage and a swallowing difficulty, high doses of immunosuppressive drugs are likely to cause ulceration and perforation. Preventive strategies including intravenous steroids for the first 2 to 3 weeks and divided doses of pills should be considered for such patients.",
"affiliations": "Department of Surgery, Research Center for Improvement of Surgical Outcomes and Procedures, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran. al-ghorbani@sina.tums.ac.ir.",
"authors": "Amini|Manouchehr|M|;Ghorbani Abdehgah|Ali|A|;Molavi|Behnam|B|;Radmard|Amir Reza|AR|;Ali Askari|Ali|A|",
"chemical_list": "D013256:Steroids; D016572:Cyclosporine; D009173:Mycophenolic Acid",
"country": "Iran",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1735-8582",
"issue": "10(4)",
"journal": "Iranian journal of kidney diseases",
"keywords": null,
"medline_ta": "Iran J Kidney Dis",
"mesh_terms": "D016572:Cyclosporine; D004939:Esophageal Perforation; D005260:Female; D006801:Humans; D016030:Kidney Transplantation; D008875:Middle Aged; D009173:Mycophenolic Acid; D011183:Postoperative Complications; D013256:Steroids; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101316967",
"other_id": null,
"pages": "233-6",
"pmc": null,
"pmid": "27514772",
"pubdate": "2016-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Esophageal Perforation in a Patient With Kidney Transplantation.",
"title_normalized": "esophageal perforation in a patient with kidney transplantation"
} | [
{
"companynumb": "IR-CONCORDIA PHARMACEUTICALS INC.-E2B_00009498",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugad... |
{
"abstract": "OBJECTIVE\nAnti-cancer and immunosuppressive drugs often induce hepatitis B virus (HBV) reactivation, resulting in lethal hepatitis in the worst cases. It is to elucidate the clinical characteristics of the patients in our hospital, who underwent HBV-related examinations to help prevent HBV-associated hepatitis by reactivation during the two-year period after the announcement of new guidelines by the Ministry of Health, Labour and Welfare of Japan in January 2009.\n\n\nMETHODS\nWe enrolled 811 patients who were examined for HBs antigen, anti-HBc antibody, anti-HBs antibody and HBV DNA regarding HBV reactivation.\n\n\nRESULTS\nThe underlying diseases were hematological malignancies, followed by various other cancers, rheumatoid arthritis, Crohn's disease, and so on. The patients in their 60s showed the peak in the age distribution. The positive ratio of anti-HBc antibody was higher over the age of 40. The rate of reactivation was 7.7% in HBV carriers and 2.0% in the HBV-resolved patients. HBV reactivation occurred in two HBV carriers and four HBV-resolved patients. The three patients, showing hepatitis were two HBV carriers and one HBV-resolved patient without monitoring of HBV DNA, because their therapies started before announcement of the guidelines. In other three patients with reactivation from HBV-resolved infections, HBV DNA returned under detection by immediate administration of entecavir without following hepatitis.\n\n\nCONCLUSIONS\nThe patients at high risk of HBV reactivation were prevented from HBV-related hepatitis only by following the guideline. The screening for such patients and monitoring HBV DNA in the guideline are requisite to prevent HBV-related hepatitis.",
"affiliations": null,
"authors": "Matsuzaki|Tomoe|T|;Ohkubo|Kumiko|K|;Yuki|Makiko|M|;Kawashima|Hironobu|H|;Matsunaga|Akira|A|",
"chemical_list": "D000970:Antineoplastic Agents; D000998:Antiviral Agents; D015415:Biomarkers; D004279:DNA, Viral; D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens; D007166:Immunosuppressive Agents; C413685:entecavir; D006147:Guanine",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0047-1860",
"issue": "63(3)",
"journal": "Rinsho byori. The Japanese journal of clinical pathology",
"keywords": null,
"medline_ta": "Rinsho Byori",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D015415:Biomarkers; D002624:Chemistry, Clinical; D004279:DNA, Viral; D005260:Female; D006147:Guanine; D006509:Hepatitis B; D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens; D006515:Hepatitis B virus; D006748:Hospital Departments; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D008991:Monitoring, Physiologic; D017410:Practice Guidelines as Topic; D014775:Virus Activation",
"nlm_unique_id": "2984781R",
"other_id": null,
"pages": "297-304",
"pmc": null,
"pmid": "26524851",
"pubdate": "2015-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A Hospital-Based Analysis in the Department of Clinical Chemistry for the Patients with HBV Reactivation after Anti-Cancer or Immunosuppressive Therapy.",
"title_normalized": "a hospital based analysis in the department of clinical chemistry for the patients with hbv reactivation after anti cancer or immunosuppressive therapy"
} | [
{
"companynumb": "JP-PFIZER INC-2015192627",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nBeta-lactam hypersensitivity (HS) is suspected in 5-12% of the children, but proven in only 10-15% of those children, based on skin and challenge tests results. In contrast, 30-60% of patients with cystic fibrosis (CF) are diagnosed allergic to beta-lactams, based mainly on the clinical history of the patients.\n\n\nOBJECTIVE\nTo confirm or rule out a suspected beta-lactam HS in CF children and to determine the prevalences of suspected and confirmed beta-lactam HS in those children.\n\n\nMETHODS\nChildren with CF and suspected beta-lactam HS were explored by means of skin and challenge tests with the suspected and alternate beta-lactams. The results in CF children were compared with those reported in the literature in non- CF children.\n\n\nRESULTS\nEight of the 701 CF children followed in our center between 1990 and 2011 (1.14%), and 11 other children from other centers were explored for suspected beta-lactam HS. Beta-lactam HS was diagnosed in nine of these children (47.3%). Based on the results in the children followed in our center, the prevalence of beta-lactam HS was 0.71% (5/701) in CF children vs. a mean estimated prevalence of 1-1.5% in the general pediatric population.\n\n\nCONCLUSIONS\nOur results contrast with those of most previous studies. Although half of the CF children with suspected beta-lactam HS were truly allergic to beta-lactams, the general prevalence of beta-lactam HS in CF children was very low. This may result from tolerance induced by frequent and/or prolonged treatments with beta-lactams.",
"affiliations": "Department Pediatrics, Pulmonology and Allergy Service, Necker-Enfants Malades Hospital, Paris, France.",
"authors": "Matar|Rania|R|;Le Bourgeois|Muriel|M|;Scheinmann|Pierre|P|;de Blic|Jacques|J|;Ponvert|Claude|C|",
"chemical_list": "D047090:beta-Lactams",
"country": "England",
"delete": false,
"doi": "10.1111/pai.12154",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0905-6157",
"issue": "25(1)",
"journal": "Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology",
"keywords": "beta-lactam hypersensitivity; challenge tests; child; cystic fibrosis; skin tests",
"medline_ta": "Pediatr Allergy Immunol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D002648:Child; D003550:Cystic Fibrosis; D004342:Drug Hypersensitivity; D005260:Female; D006782:Hospitals, Special; D006801:Humans; D007108:Immune Tolerance; D008297:Male; D010372:Pediatrics; D015995:Prevalence; D012189:Retrospective Studies; D055815:Young Adult; D047090:beta-Lactams",
"nlm_unique_id": "9106718",
"other_id": null,
"pages": "88-93",
"pmc": null,
"pmid": "24237053",
"pubdate": "2014-02",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Beta-lactam hypersensitivity in children with cystic fibrosis: a study in a specialized pediatric center for cystic fibrosis and drug allergy.",
"title_normalized": "beta lactam hypersensitivity in children with cystic fibrosis a study in a specialized pediatric center for cystic fibrosis and drug allergy"
} | [
{
"companynumb": "FR-MYLANLABS-2015M1013379",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZTREONAM"
},
"drugadditional": null,
... |
{
"abstract": "In hospitalized coronavirus disease 2019 (COVID-19) patients, anticoagulation therapy is administered to prevent thrombosis. However, anticoagulation sometimes causes bleeding complications. We herein report two Japanese cases of severe COVID-19 in which spontaneous muscle hematomas (SMH) developed under therapeutic anticoagulation with unfractionated heparin. Although the activated partial prothrombin time was within the optimal range, contrast-enhanced computed tomography (CECT) revealed SMH in the bilateral iliopsoas muscles in both cases, which required emergent transcatheter embolization. Close monitoring of the coagulation system and the early diagnosis of bleeding complications through CECT are needed in severe COVID-19 patients treated with anticoagulants.",
"affiliations": "Department of Respiratory Medicine, Japanese Red Cross Medical Center, Japan.;Department of Respiratory Medicine, Japanese Red Cross Medical Center, Japan.;Department of Interventional Radiology, Japanese Red Cross Medical Center, Japan.;Department of Respiratory Medicine, Japanese Red Cross Medical Center, Japan.;Department of Respiratory Medicine, Japanese Red Cross Medical Center, Japan.;Department of Respiratory Medicine, Japanese Red Cross Medical Center, Japan.;Department of Respiratory Medicine, Japanese Red Cross Medical Center, Japan.;Department of Respiratory Medicine, Japanese Red Cross Medical Center, Japan.;Department of Respiratory Medicine, Japanese Red Cross Medical Center, Japan.;Department of Emergency and Critical Care Medicine, Japanese Red Cross Medical Center, Japan.;Department of Emergency and Critical Care Medicine, Japanese Red Cross Medical Center, Japan.;Department of Emergency and Critical Care Medicine, Japanese Red Cross Medical Center, Japan.;Department of Interventional Radiology, Japanese Red Cross Medical Center, Japan.;Department of Interventional Radiology, Japanese Red Cross Medical Center, Japan.;Department of Emergency and Critical Care Medicine, Japanese Red Cross Medical Center, Japan.;Department of Respiratory Medicine, Japanese Red Cross Medical Center, Japan.",
"authors": "Ito|Yu|Y|;Awano|Nobuyasu|N|;Uchiyama|Fumiya|F|;Inomata|Minoru|M|;Kuse|Naoyuki|N|;Tone|Mari|M|;Takada|Kohei|K|;Fujimoto|Kazushi|K|;Muto|Yutaka|Y|;Sagisaka|Shogo|S|;Maki|Kenro|K|;Yamashita|Ryuta|R|;Harada|Akinori|A|;Nishimura|Jun-Ichi|JI|;Hayashi|Munehiro|M|;Izumo|Takehiro|T|",
"chemical_list": "D000925:Anticoagulants; D006493:Heparin",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.7422-21",
"fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918\n1349-7235\nThe Japanese Society of Internal Medicine\n\n34433713\n10.2169/internalmedicine.7422-21\nCase Report\nSpontaneous Muscle Hematoma in Japanese Patients with Severe COVID-19 Treated with Unfractionated Heparin: Two Case Reports\nIto Yu 1\nAwano Nobuyasu 1\nUchiyama Fumiya 2\nInomata Minoru 1\nKuse Naoyuki 1\nTone Mari 1\nTakada Kohei 1\nFujimoto Kazushi 1\nMuto Yutaka 1\nSagisaka Shogo 3\nMaki Kenro 3\nYamashita Ryuta 3\nHarada Akinori 2\nNishimura Jun-ichi 2\nHayashi Munehiro 3\nIzumo Takehiro 1\n1 Department of Respiratory Medicine, Japanese Red Cross Medical Center, Japan\n2 Department of Interventional Radiology, Japanese Red Cross Medical Center, Japan\n3 Department of Emergency and Critical Care Medicine, Japanese Red Cross Medical Center, Japan\nCorrespondence to Dr. Yu Ito, yuito.steinway1994@gmail.com\n\n24 8 2021\n1 11 2021\n60 21 35033506\n24 2 2021\n12 7 2021\nCopyright © 2021 by The Japanese Society of Internal Medicine\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ The Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).\nIn hospitalized coronavirus disease 2019 (COVID-19) patients, anticoagulation therapy is administered to prevent thrombosis. However, anticoagulation sometimes causes bleeding complications. We herein report two Japanese cases of severe COVID-19 in which spontaneous muscle hematomas (SMH) developed under therapeutic anticoagulation with unfractionated heparin. Although the activated partial prothrombin time was within the optimal range, contrast-enhanced computed tomography (CECT) revealed SMH in the bilateral iliopsoas muscles in both cases, which required emergent transcatheter embolization. Close monitoring of the coagulation system and the early diagnosis of bleeding complications through CECT are needed in severe COVID-19 patients treated with anticoagulants.\n\nCOVID-19\nspontaneous muscle hematoma\ntherapeutic anticoagulation\nvascular dysfunction\nunfractionated heparin\n==== Body\npmcIntroduction\n\nSince the first report of a cluster of pneumonia in Wuhan, China, coronavirus disease 2019 (COVID-19) has rapidly spread worldwide (1). The spectrum of clinical manifestations of COVID-19 ranges from a fever, cough, and dyspnea to pneumonia, acute respiratory distress syndrome, and even respiratory failure (2). In addition, extrapulmonary complications, such as myocardial injury, arrhythmia, and acute renal injury, which sometimes result in death, have been reported (3).\n\nSince patients with severe COVID-19 have an increased risk of advancing to a hypercoagulable state, anticoagulation therapy is recommended for all hospitalized COVID-19 patients according to the National Heart, Lung, and Blood Institute guideline (4). However, whether low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) should be used for anticoagulation remains controversial (5,6). Recent studies have reported that anticoagulation with LMWH can cause bleeding complications, such as spontaneous muscle hematoma (SMH) (7-11). However, whether or not this hemorrhaging also occurs under anticoagulation with UFH and in individuals other than Caucasians, as reported, are unknown.\n\nWe herein report two Japanese patients who developed bilateral iliopsoas hematomas under therapeutic anticoagulation therapy with UFH and who required transcatheter arterial embolization (TAE) during treatment for severe COVID-19.\n\nCase Reports\n\nCase 1\n\nThis patient was a 48-year-old Japanese man with a medical history of asthma and diabetes mellitus. He was referred to our hospital with a fever, malaise, and cough that persisted for 1 week. On admission, his body weight was 71.5 kg, and his oxygen saturation was 92% under 5 L/min of oxygen provided by nasal cannula. The results of blood tests performed at admission are shown in Table.\n\nTable. Blood Test Findings at Admission and When Hematoma was Identified.\n\n\tCase 1\t\tCase 2\tReference range\t\nAdmission\tEvent*\tAdmission\tEvent*\t\nDays after COVID-19 onset\t7\t35\t\t8\t20\t\t\nCreatinine (mg/dL)\t0.60\t0.69\t\t1.18\t0.82\t0.65-1.07\t\nFerritin (ng/mL)\t806\t522\t\t1,567\t1,776\t50-200\t\nCRP (mg/dL)\t6.06\t13.80\t\t5.80\t1.56\t0.00-0.14\t\nWBC (/μL)\t6,660\t32,380\t\t9,020\t10,090\t3,700-8,000\t\nEosinophil (/μL)\t0\t80\t\t0\t110\t\t\nHemoglobin (g/dL)\t14.8\t7.5\t\t15.8\t13.4\t13.0-16.5\t\nPlatelet (104/μL)\t15.9\t20.6\t\t14.6\t28.3\t15.0-45.0\t\nPT (s)\t11.5\t13.8\t\t11.7\t13.4\t10.5-13.2\t\nPT-INR\t1.01\t1.23\t\t1.03\t1.19\t0.90-1.10\t\nAPTT (s)\t22.8\t58.6\t\t32.5\t40.0\t25.0-40.0\t\nD-dimer (μg/mL)\t3.9\t2.6\t\t0.5\t1.5\t0.0-1.0\t\n*Both samples were taken while unfractionated heparin was being administered.\n\nCOVID-19: coronavirus disease 2019, CRP: C-reactive protein, WBC: white blood cell, PT: prothrombin time, PT-INR: prothrombin time-international normalized ratio, APTT: activated partial thromboplastin time\n\nReal-time polymerase chain reaction (RT-PCR) of a nasopharyngeal swab detected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and he was diagnosed with severe COVID-19 (4). Remdesivir, dexamethasone (6 mg/day), and tocilizumab treatment was initiated, with the patient in a prone position for 16 h/day, but his respiratory failure did not improve. He was intubated on the 3rd day and underwent tracheostomy on the 15th day of hospitalization. Since his serum D-dimer level was elevated (4.0 μg/mL) on the 6th day, intravenous UFH was administered. UFH dose was increased to 32,000 U/day (18.6 U/kg/h) to keep his serum activated partial thromboplastin time (APTT) within 40-60 s. Bedside rehabilitation was initiated simultaneously.\n\nOn the 27th day of hospitalization, he presented with right lumbago, extension-based pain in the right lower leg, and numbness in the right thigh. Hypotension (81/59 mmHg) and remarkable anemia appeared on the 29th day (Table). Contrast-enhanced computed tomography (CECT) of the abdomen and pelvis revealed bilateral hematomas of the iliopsoas muscles and extravasation of contrast medium (Figure A, B). Intravenous UFH was immediately discontinued, and emergent TAE of the bilateral lumbar arteries was performed. The hematomas showed no evidence of further expansion after the procedure, and anemia and hypotension improved after transfusion and other supportive therapy. Anticoagulation was not resumed, but no apparent thrombosis has been identified. Rehabilitation was restarted, and he was discharged home on the 60th day of hospitalization.\n\nFigure. Radiological findings in two cases. Axial (A) and coronal sections (B) of the CECT arterial phase in Case 1 revealed bilateral iliopsoas hematomas (red arrows) and extravasation of contrast medium (blue arrow). Similarly, axial (C) and coronal sections (D) of the CECT equilibrium phase in Case 2 showed bilateral iliopsoas hematomas (orange arrows). CECT: contrast-enhanced computed tomography\n\nCase 2\n\nThis patient was a 60-year-old Japanese man with a medical history of diabetes mellitus, renal insufficiency, hypertension, and gastroesophageal reflex disease. After 1 week of a fever and cough, RT-PCR revealed SARS-CoV-2 positivity and dexamethasone (6 mg/day) treatment was initiated. He was referred to our hospital the following day, when his body weight was 71.6 kg and oxygen saturation was 93% under 15 L/min of oxygen provided by a reservoir mask. He was diagnosed with severe COVID-19 and promptly intubated. Results of blood tests performed at admission are shown in Table. Remdesivir and baricitinib were added to dexamethasone, with the patient maintained in a prone position. During intubation, 14,000 U/day (8.1 U/kg/h) of UFH was administered intravenously due to elevated D-dimer (3.8 μg/mL), and rehabilitation was started. He was extubated on the 8th day, and rehabilitation was intensified with the patient in a standing position.\n\nOn the 10th day of hospitalization, extension-based pain that was not relieved by painkillers appeared in the left lower leg. Hypotension (90/74 mmHg) appeared on the 13th day, but anemia only progressed slightly (Table). On the 13th day, CECT of the abdomen and pelvis identified bilateral iliopsoas hematomas (Figure C, D). Intravenous UFH was discontinued, and emergent TAE of the bilateral iliolumbar arteries and left iliac circumflex artery was performed. After a lack of further expansion of the hematomas was confirmed, he was discharged home with oxygen therapy on the 22nd day of hospitalization. No apparent thrombosis has been observed without anticoagulation therapy.\n\nDiscussion\n\nWe reported two Japanese cases of severe COVID-19 in which bilateral iliopsoas hematomas developed during the clinical course, both of which required emergent TAE. The patients complained of symptoms such as leg extension-based pain or numbness before CECT revealed hematomas, suggesting hemorrhaging due to arterial disruption. Previous literature reported iliopsoas hematoma in Caucasian patients with severe COVID-19 treated with LMWH (8-11). The data from the 11 Caucasian patients described in 4 references revealed unilateral hematoma, with 8 patients receiving therapeutic doses of heparin and 5 requiring TAE. However, to our knowledge, few reports have described bilateral iliopsoas hematomas or SMH in other races or patients treated with UFH as an anticoagulant (12). In patients with COVID-19, SMH is an important complication, regardless of race or the type of anticoagulant administered.\n\nA previous study indicated that known risk factors for SMH are cardiac or renal insufficiency, arteriosclerosis, hypertension, diabetes mellitus, and coagulation disorders, including when anticoagulants are used (13). Microtrauma of capillaries and muscles, such as in isometric muscle contraction, is believed to result in SMH development (14). In our cases, several reasons explained SMH occurrence. First, both of our patients had some risk factors of SMH: both had diabetes mellitus, and one had hypertension as well as renal insufficiency. Second, mobilization to a prone position and bedside rehabilitation can contribute to microvascular disruption and SMH (10). Another possible explanation for SMH was the tendency to bleed caused by UFH. However, in our cases, the targeted range of APTT was established at 40-60 s, and APTT was maintained within this optimal range in both cases when SMH developed. In one study, among patients treated with anticoagulation therapy who developed SMH, an overdose of anticoagulants occurred in approximately 30% (14). This suggests that the use of anticoagulants, even within the therapeutic range of APTT, can increase the risk for SMH.\n\nIn addition, it has been suggested that patients with COVID-19 are prone to bleeding due to various reasons. Disseminated intravascular coagulation (DIC) is frequently complicated with severe COVID-19, and enhanced-fibrinolytic-type DIC is particularly strongly associated with major bleeding (15). Thrombocytopenia is sometimes observed in patients with COVID-19 and is a predictor of bleeding complications (16). A previous study reported a case of acquired von Willebrand disease in a patient with COVID-19, suggesting that an abnormal platelet function may contribute to a bleeding tendency in some cases (17). Furthermore, histopathological mechanisms may cause arterial rupture in severe COVID-19. SARS-CoV-2 is known to cause inflammatory cell infiltration along the vessel surface, which results in vasculitis. This vascular dysfunction may cause spontaneous bleeding due to arterial vulnerability (18,19). A further pathological investigation and the accumulation of cases are needed to elucidate the mechanisms underlying bleeding complications in severe COVID-19.\n\nData on the use of anticoagulants at a therapeutic dose for severe COVID-19 patients are insufficient at present (4). Elevated serum D-dimer levels reflect a hypercoagulable state of COVID-19, so D-dimer may be a surrogate marker upon the introduction of anticoagulants at a therapeutic dose (16,20). However, as in our cases, patients who receive UFH within the optimal range of APTT can develop bleeding complications, such as SMH. In clinical practice, clinicians should recognize the tendency to bleed in COVID-19 patients, and careful monitoring of the coagulation system and adjustment of anticoagulants are necessary to prevent bleeding complications, especially when therapeutic doses of anticoagulants are administered. Furthermore, if COVID-19 patients under anticoagulation therapy experience symptoms, such as leg extension-based pain, numbness in the lower extremities, or the development of anemia and hypotension, CECT should be immediately considered in order to rule out SMH. Emergent angiography should be also performed in case circulatory instability or extravasation is identified by CECT (14). Furthermore, whether rehabilitation or early mobilization should be initiated under anticoagulant treatment requires further determination.\n\nIn conclusion, we reported two Japanese COVID-19 cases in which bilateral iliopsoas hematomas developed during the clinical course. Clinicians should pay attention to bleeding complications, such as SMH, in severe COVID-19 patients under anticoagulation therapy. Close monitoring of their symptoms and coagulation system and early CECT-based diagnosis are needed to prevent and detect SMH.\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Chan JF , Yuan S , Kok K-H , et al . A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet 395 : 514-523, 2020.31986261\n2. Macera M , Angelis GD , Sagnelli C , Coppola N ; Vanvitelli COVID-19 Group. Clinical presentation of COVID-19: case series and review of the literature. Int J Environ Res Public Health 17 : 5062, 2020.\n3. Gupta A , Madhavan MV , Sehgal K , et al . Extrapulmonary manifestations of COVID-19. Nat Med 26 : 1017-1032, 2020.32651579\n4. COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health [Internet]. [cited 2021 Jan 19]. Available from: https://www.covid19treatmentguidelines.nih.gov/.\n5. Thachil J , Tang N , Gando S , et al . ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost 18 : 1023-1026, 2020.32338827\n6. Thachil J , Tang N , Gando S , et al . Type and dose of heparin in Covid-19: reply. J Thromb Haemost 18 : 2063-2064, 2020.32329221\n7. Dorgalaleh A . Bleeding and bleeding risk in COVID-19. Semin Thromb Hemost 46 : 815-818, 2020.32512587\n8. Patel I , Akoluk A , Douedi S , et al . Life-threatening psoas hematoma due to retroperitoneal hemorrhage in a COVID-19 patient on enoxaparin treated with arterial embolization: a case report. J Clin Med Res 12 : 458-461, 2020.32655742\n9. Conti CB , Henchi S , Coppeta GP , Testa S , Grassia R . Bleeding in COVID-19 severe pneumonia: the other side of abnormal coagulation pattern? Eur J Intern Med 77 : 147-149, 2020.32414639\n10. Bargellini I , Cervelli R , Lunardi A , et al . Spontaneous bleedings in COVID-19 patients: an emerging complication. Cardiovasc Intervent Radiol 43 : 1095-1096, 2020.32419077\n11. Vergori A , Pianura E , Lorenzini P , et al ; ReCOVeRI Study Group. Spontaneous ilio-psoas haematomas (IPHs): a warning for COVID-19 inpatients. Ann Med 53 : 295-301, 2021.33491498\n12. Javid A , Kazemi R , Dehghani M , Bahrami Samani H . Catastrophic retroperitoneal hemorrhage in COVID-19 patients under anticoagulant prophylaxis. Urol Case Rep 36 : 101568, 2021.33520659\n13. Dohan A , Darnige L , Sapoval M , Pellerin O . Spontaneous soft tissue hematomas. Diagn Interv Imaging 96 : 789-796, 2015.26066549\n14. Dohan A , Sapoval M , Chousterman BG , di Primio M , Guerot E , Pellerin O . Spontaneous soft-tissue hemorrhage in anticoagulated patients: safety and efficacy of embolization. Am J Roentgenol 204 : 1303-1310, 2015.26001242\n15. Asakura H , Ogawa H . COVID-19-associated coagulopathy and disseminated intravascular coagulation. Int J Hematol 113 : 45-57, 2021.33161508\n16. Levi M , Thachil J , Iba T , Levy JH . Coagulation abnormalities and thrombosis in patients with COVID-19. Lancet Haematol 7 : e438-e440, 2020.32407672\n17. Hayakawa M , Takano K , Kayashima M , Kasahara K , Fukushima H , Matsumoto M . Management of a COVID-19 patient during ECMO: paying attention to acquired von Willebrand syndrome. J Atheroscler Thromb 28 : 396-401, 2021.33116032\n18. Becker RC . COVID-19-associated vasculitis and vasculopathy. J Thromb Thrombolysis 50 : 499-511, 2020.32700024\n19. Varga Z , Flammer AJ , Steiger P , et al . Endothelial cell infection and endotheliitis in COVID-19. Lancet 395 : 1417-1418, 2020.32325026\n20. Tang N , Li D , Wang X , Sun Z . Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 18 : 844-847, 2020.32073213\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "60(21)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "COVID-19; spontaneous muscle hematoma; therapeutic anticoagulation; unfractionated heparin; vascular dysfunction",
"medline_ta": "Intern Med",
"mesh_terms": "D000925:Anticoagulants; D000086382:COVID-19; D006406:Hematoma; D006493:Heparin; D006801:Humans; D007564:Japan; D009132:Muscles; D000086402:SARS-CoV-2",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "3503-3506",
"pmc": null,
"pmid": "34433713",
"pubdate": "2021-11-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "31986261;33520659;32325026;32073213;32700024;32512587;26001242;33116032;32655742;32329221;32338827;32419077;26066549;33491498;32651579;32407672;32674450;33161508;32414639",
"title": "Spontaneous Muscle Hematoma in Japanese Patients with Severe COVID-19 Treated with Unfractionated Heparin: Two Case Reports.",
"title_normalized": "spontaneous muscle hematoma in japanese patients with severe covid 19 treated with unfractionated heparin two case reports"
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"companynumb": "JP-BIOLOGICAL E. LTD-2120797",
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"activesubstancename": "HEPARIN SODIUM"
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"abstract": "Although severe flare of ulcerative colitis (UC) is uncommon, it significantly increases the risk of preterm delivery, low birth weight and other adverse fetal outcomes. It is critical to optimize aggressive medical treatment with both mother and fetal health. Here, we present a case of a 30-year-old woman with a severe flare of UC at the 16th gestational week. The diagnosis of extensive UC was established 8 years ago. From the time she was diagnosed, she had 5 moderate flares successfully treated with oral and topical mesalamine. The relapses of disease occurred due to poor adherence to maintenance therapy. The patient had a positive family history for UC and thrombophilia (factor V Leiden mutations). At the time of admission, she presented with 8-10 bloody diarrheas and moderate abdominal pain. She was afebrile with increased heart rate (96/min). Laboratory studies showed elevated C-reactive protein (CRP, 42 mg/l), fecal-calprotectin (7,223 μg/g), and anemia (hemoglobin 10.4 g/dl). Clostridium difficile and CMV infection were excluded. Intensive treatment with systemic steroids and low-molecular weight heparin was started. Three days later, no response to the therapy was observed (8 bloody stools, CRP 40 mg/l). According to emergency symptoms, rescue therapy with infliximab (IFX; 5 mg/kg standard induction protocol) was administered a week later. A partial clinical and laboratory response was achieved after the second dose of IFX (4 stools/day, CRP 12.2 mg/l and FCP 1,078 μg/g). The patient received the third and least doses of IFX at the 23rd gestational week. She continued on corticosteroids and mesalamine with chronically active moderate disease. IFX trough levels before the third dose were 20.6 μg/ml; antibodies to IFX were negative. The patient delivered trans-vaginally a healthy girl on the 36th gestational week (the newborn weight: 3,150 kg, APGAR score 9). No live vaccines were administrated to the newborn until 6 months of age.",
"affiliations": "Department of Gastroenterology, University Hospital Zvezdara, Belgrade, Serbia.",
"authors": "Protic|Marijana|M|;Markovic|Srdjan|S|;Tarabar|Dino|D|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D019804:Mesalamine; D000069285:Infliximab",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000449094",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0257-2753",
"issue": "35(1-2)",
"journal": "Digestive diseases (Basel, Switzerland)",
"keywords": null,
"medline_ta": "Dig Dis",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D003093:Colitis, Ulcerative; D018450:Disease Progression; D005260:Female; D006801:Humans; D000069285:Infliximab; D019804:Mesalamine; D011247:Pregnancy; D011248:Pregnancy Complications; D000067251:Symptom Flare Up",
"nlm_unique_id": "8701186",
"other_id": null,
"pages": "134-138",
"pmc": null,
"pmid": "28147377",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Case Report: Acute Flair of Ulcerative Colitis during Pregnancy Is Still a Major Problem.",
"title_normalized": "case report acute flair of ulcerative colitis during pregnancy is still a major problem"
} | [
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"companynumb": "RS-WARNER CHILCOTT-2017-000229",
"fulfillexpeditecriteria": "1",
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"patient": {
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{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "MESALAMINE"
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"drugadditional": null,
... |
{
"abstract": "Transarterial chemoembolization (TACE) is an important therapeutic option for patients with hepatocellular carcinoma (HCC). We discuss five patients with HCC and tuberculosis (TB) reactivation following TACE. Screening patients for latent TB infection at diagnosis of cirrhosis or HCC should be considered because of the immunosuppression inherent in both the diseases and their treatments.",
"affiliations": "From the Infectious Diseases Section, Medical Service, Veterans Affairs Medical Center , Washington, DC , USA.",
"authors": "Laake|Ann M|AM|;Liappis|Angelike P|AP|;Guy|Elizabeth|E|;Kerr|Gail|G|;Benator|Debra A|DA|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3109/00365548.2014.989540",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2374-4243",
"issue": "47(4)",
"journal": "Infectious diseases (London, England)",
"keywords": "Cirrhosis; hepatocellular carcinoma; transarterial chemoembolization; tuberculosis reactivation",
"medline_ta": "Infect Dis (Lond)",
"mesh_terms": "D000368:Aged; D006528:Carcinoma, Hepatocellular; D016461:Chemoembolization, Therapeutic; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D014376:Tuberculosis",
"nlm_unique_id": "101650235",
"other_id": null,
"pages": "267-70",
"pmc": null,
"pmid": "25688446",
"pubdate": "2015-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Tuberculosis reactivation in hepatocellular carcinoma: association with transarterial chemoembolization.",
"title_normalized": "tuberculosis reactivation in hepatocellular carcinoma association with transarterial chemoembolization"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/16/0065488",
"fulfillexpeditecriteria": "2",
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"drug": [
{
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"activesubstance": {
"activesubstancename": "ISONIAZID"
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... |
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"abstract": "Complex regional pain syndrome (CRPS) is a devastating posttraumatic neuroinflammatory condition with both autoinflammatory and autoimmune features, characterized by unrelenting severe pain and disability, with the majority of affected patients being unable to function socially or vocationally. Remission is more likely in children than adults, and if treatment is started early. Once established, there are no universally effective treatments, and these are desperately needed. A single limb is often involved, but there can be multi-limb spread, and systemic autonomic manifestations. We describe a case of long-standing CRPS with multi-limb spread and systemic autonomic features, controlled only with very high dose oral corticosteroids, which led to several complications. Multiple other treatment modalities failed or were insufficient to control the CRPS and allow tapering of the corticosteroids, but the patient had a dramatic response to hyperbaric oxygen therapy (HBOT), allowing a reduction in prednisone dose to just over the physiologic range. When symptoms started to increase several months later, a second course of HBOT treatments allowed reduction in prednisone dose into the physiologic range while still controlling CRPS symptoms. This case is unique in that it shows that HBOT can be effective in long-standing CRPS, both initially, and for subsequent flares, and adds to the evidence supporting HBOT as a potential treatment for this condition. Graphical Abstract HBOT effect on prednisone dose for symptom control.",
"affiliations": "Division of Clinical Immunology and Allergy, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada. binkleyk@smh.ca.;Department of Anesthesia and Pain Management, University Health Network, University of Toronto, Toronto, Ontario, Canada.",
"authors": "Binkley|Karen|K|;Katznelson|Rita|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s11481-019-09901-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1557-1890",
"issue": "15(1)",
"journal": "Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology",
"keywords": "Complex regional pain syndrome; Hyperbaric oxygen",
"medline_ta": "J Neuroimmune Pharmacol",
"mesh_terms": "D020918:Complex Regional Pain Syndromes; D005260:Female; D006801:Humans; D006931:Hyperbaric Oxygenation; D008875:Middle Aged; D016896:Treatment Outcome",
"nlm_unique_id": "101256586",
"other_id": null,
"pages": "1-6",
"pmc": null,
"pmid": "31838618",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": "28072713;23692303;31182576;26218942;24284843;20704676;30269438;25672366;30428789;15174218;26785976;29794285;25735985;16767061;21539489;26011726;16734515;25988526;24605121;21596875;22795247;11561147;30124090;29592784;26814238;17610454;28560010;27445607;24422915;22588663",
"title": "Successful Treatment of Long Standing Complex Regional Pain Syndrome with Hyperbaric Oxygen Therapy.",
"title_normalized": "successful treatment of long standing complex regional pain syndrome with hyperbaric oxygen therapy"
} | [
{
"companynumb": "CA-VALIDUS PHARMACEUTICALS LLC-CA-2020VAL000470",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BUMETANIDE"
},
"drugadd... |
{
"abstract": "A 19-year-old female was seen at the emergency department following an auto-intoxication. An oculogyric crisis (ogc) was observed, in the absence of other extrapyramidal symptoms (eps). In a second anamnesis, patient indicated that she had taken risperidone 3 mg (an atypical antipsychotic). This particular case description of an isolated ogc shows that care providers should be attentive to the occurrence of ogc, even if the most frequent eps are absent. This case also emphasizes the importance of a complete history in order to efficiently and timely guide the care provider to the correct diagnosis.",
"affiliations": null,
"authors": "van Renterghem|L|L|;Titeca|K|K|;Crunelle|C L|CL|;Geerts|P|P|;Matthys|F|F|",
"chemical_list": "D014150:Antipsychotic Agents; D018967:Risperidone",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0303-7339",
"issue": "61(9)",
"journal": "Tijdschrift voor psychiatrie",
"keywords": null,
"medline_ta": "Tijdschr Psychiatr",
"mesh_terms": "D014150:Antipsychotic Agents; D003937:Diagnosis, Differential; D004421:Dystonia; D005260:Female; D006801:Humans; D015835:Ocular Motility Disorders; D011618:Psychotic Disorders; D018967:Risperidone; D055815:Young Adult",
"nlm_unique_id": "0423731",
"other_id": null,
"pages": "649-653",
"pmc": null,
"pmid": "31560785",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Oculogyric crisis as an isolated extrapyramidal symptom of auto-intoxication with risperidone.",
"title_normalized": "oculogyric crisis as an isolated extrapyramidal symptom of auto intoxication with risperidone"
} | [
{
"companynumb": "BE-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-224554",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"dru... |
{
"abstract": "A 54-year-old man sought treatment at the ED for a productive cough with green phlegm of approximately 6 months' duration that was accompanied by a 10-pound weight loss, night sweats, and occasional subjective fevers. He had made several prior visits to the ED for the cough and was hospitalized 4 months earlier for similar symptoms, at which time he underwent a bronchoscopy with BAL and was discharged with antibiotics for presumed pneumonia. He did not report any itching, rashes, sinus infections, joint swelling, joint pain, or GI symptoms. His long-term medications included omeprazole and amlodipine. The patient had a past medical history of grade III follicular lymphoma for which he completed six cycles of bendamustine 4 years before presentation and had been in remission since. He was a never smoker, had a recent travel history to the Dominican Republic 8 months before admission, and had no recent sick contacts.",
"affiliations": "Department of Internal Medicine, Lenox Hill Hospital, New York, NY. Electronic address: zkattih@northwell.edu.;Department of Pulmonary and Critical Care Medicine, Lenox Hill Hospital, New York, NY.;Department of Pulmonary and Critical Care Medicine, Lenox Hill Hospital, New York, NY.;Prince Sultan Military Medical City, Riyadh, Saudi Arabia.;Department of Cardiovascular and Thoracic Surgery, Lenox Hill Hospital, New York, NY.;Department of Pulmonary and Critical Care Medicine, Lenox Hill Hospital, New York, NY.",
"authors": "Kattih|Zein|Z|;Mahajan|Akhilesh|A|;Birnbaum|Brian|B|;Aman|Abdulrahman|A|;Lazzaro|Richard S|RS|;Mina|Bushra|B|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.chest.2020.11.047",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-3692",
"issue": "159(4)",
"journal": "Chest",
"keywords": null,
"medline_ta": "Chest",
"mesh_terms": "D001706:Biopsy; D001980:Bronchi; D001988:Bronchiolitis; D001999:Bronchoscopy; D002908:Chronic Disease; D003371:Cough; D003937:Diagnosis, Differential; D004802:Eosinophilia; D006801:Humans; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D012141:Respiratory Tract Infections; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "0231335",
"other_id": null,
"pages": "e221-e224",
"pmc": null,
"pmid": "34022022",
"pubdate": "2021-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A 54-Year-Old Man With Chronic Cough and Recurrent Upper Respiratory Infection.",
"title_normalized": "a 54 year old man with chronic cough and recurrent upper respiratory infection"
} | [
{
"companynumb": "US-DEXPHARM-20210779",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OMEPRAZOLE"
},
"drugadditional": "3",
"d... |
{
"abstract": "We managed 6 cases of severe liver atrophy and failure associated with paclitaxel and bevacizumab combination therapy (PB therapy)for HER2-negative metastatic breast cancer. In this case-controlstudy, we examined the records of these 6 patients to investigate past treatment, medication history, and degree of atrophy, and compared their data with that of 67 patients without liver atrophy. The degree of the liver atrophy used SYNAPSE VINCENT®of the image analysis software. The results showed that patients with liver atrophy had a longer pretreatment period than those without liver atrophy(33.5 months vs 15.5 months), and they also experienced a longer median time to treatment failure with PB therapy than other patients(11 months vs 6 months). The ratio of individuals presenting with diffuse liver metastasis among patients with liver metastasis was 80% with liver atrophy, compared to 8% without liver atrophy. The degree of liver atrophy was an average of 67%in terms of volume ratio before/after PB therapy(57-82%). The individualwith the greatest extent of liver atrophy died of liver failure, not as a result of breast cancer progression. The direct causal link between bevacizumab and liver atrophy and failure is unclear, but the individuals in this study had a long previous history of treatment, and diffuse liver metastases may develop in patients undergoing long periods of PB therapy, which may also cause liver atrophy; therefore, the possibility of liver failure should be considered in such cases.",
"affiliations": "Dept. of Breast and Thyroid Surgery, Fukuyama City Hospital.",
"authors": "Yamamoto|Mari|M|;Ikeda|Masahiko|M|;Kubo|Shinichiro|S|;Tsukioki|Takahiro|T|;Nakamoto|Shougo|S|",
"chemical_list": "D000068258:Bevacizumab; D017239:Paclitaxel",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "43(7)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D001284:Atrophy; D000068258:Bevacizumab; D001943:Breast Neoplasms; D005260:Female; D006801:Humans; D008099:Liver; D017093:Liver Failure; D008113:Liver Neoplasms; D008875:Middle Aged; D017239:Paclitaxel",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "869-73",
"pmc": null,
"pmid": "27431631",
"pubdate": "2016-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Liver Atrophy and Failure Associated with Paclitaxel and Bevacizumab Combination Therapy for Metastatic Breast Cancer.",
"title_normalized": "liver atrophy and failure associated with paclitaxel and bevacizumab combination therapy for metastatic breast cancer"
} | [
{
"companynumb": "JP-ACCORD-042971",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
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"drugadditional": "3",
"druga... |
{
"abstract": "BACKGROUND\nMucosal melanoma is a rare and aggressive malignancy with poorer response compared with cutaneous melanoma. Prospective trials of immune checkpoint inhibitors in unresectable or metastatic mucosal melanoma have not been reported.\n\n\nOBJECTIVE\nThis phase II trial assessed the efficacy and safety of nivolumab monotherapy for unresectable or metastatic mucosal melanoma.\n\n\nMETHODS\nEligibility criteria were as follows: histological diagnosis of unresectable or metastatic mucosal melanoma; age ≥ 20 years; ECOG performance status 0 or 1; and with measurable lesions. Patients received nivolumab 2 mg/kg every 3 weeks. The primary endpoint was the response rate (RR) according to Response Evaluation Criteria in Solid Tumors version 1.1. The secondary endpoints were overall survival, progression-free survival, disease control rate, and toxicity.\n\n\nRESULTS\nTwenty patients were enrolled between December 2014 and July 2017. Two patients without measurable lesions and one patient with uveal melanoma were excluded from analysis of efficacy. The best overall RR was 23.5%. One patient achieved a complete response, three partial response, and five stable disease as their best response. The median progression-free survival was 1.4 months (95% CI 1.2-2.8). The median overall survival was 12.0 months (95% CI 3.5 to not reached). The 1-year overall survival was 50.0% (95% CI 25.9-70.0%). Treatment-related adverse events of grades 3 or 4 occurred in 15% (3/20) of the patients. Grade 3 adverse events were resolved by corticosteroid treatment.\n\n\nCONCLUSIONS\nAlthough this trial met the primary endpoint, the RR was still unsatisfactory. Therefore, further treatment development is required.",
"affiliations": "Department of Medical Oncology, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. excell@hkg.odn.ne.jp.;Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Clinical Oncology, Aichi Cancer Center Hospital, 54 Kawahara-choSakyo-ku, ShogoinKyoto, 606-8507, Japan.;Division of Gastrointestinal Oncology, Shizuoka Cancer Center, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Medical Oncology, Kobe City Medical Center General Hospital, 54 Kawahara-choSakyo-ku, ShogoinKyoto, 606-8507, Japan.;Department of Respirology, Chiba University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.;Division of Gastrointestinal Medical Oncology, National Cancer Center Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Clinical Oncology, Aichi Cancer Center Hospital, 54 Kawahara-choSakyo-ku, ShogoinKyoto, 606-8507, Japan.",
"authors": "Nomura|Motoo|M|http://orcid.org/0000-0002-5967-0610;Oze|Isao|I|;Masuishi|Toshiki|T|;Yokota|Tomoya|T|;Satake|Hironaga|H|;Iwasawa|Shunichiro|S|;Kato|Ken|K|;Andoh|Masashi|M|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000077594:Nivolumab",
"country": "Japan",
"delete": false,
"doi": "10.1007/s10147-020-01618-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-9625",
"issue": "25(5)",
"journal": "International journal of clinical oncology",
"keywords": "Immune checkpoint inhibitor; Metastatic melanoma; Mucosal melanoma",
"medline_ta": "Int J Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000074322:Antineoplastic Agents, Immunological; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D009092:Mucous Membrane; D000077594:Nivolumab; D000077982:Progression-Free Survival; D011446:Prospective Studies; D012878:Skin Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "9616295",
"other_id": null,
"pages": "972-977",
"pmc": null,
"pmid": "31938955",
"pubdate": "2020-05",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Multicenter prospective phase II trial of nivolumab in patients with unresectable or metastatic mucosal melanoma.",
"title_normalized": "multicenter prospective phase ii trial of nivolumab in patients with unresectable or metastatic mucosal melanoma"
} | [
{
"companynumb": "JP-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-009077",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddi... |
{
"abstract": "HMG-CoA reductase inhibitors (statins) are one of the most widely used medications in the primary care setting, and like any medications they have many side effects. The common ones include myalgias and rare ones include dermatomyositis. Here we present the case of atorvastatin-induced dermatomyositis with an unfortunate progression. This mandates a low threshold for first contact doctors to screen their patients for new-onset muscle weakness and rash after starting a statin recently, like our patient who had started atorvastatin several months before. This case adds to the previously reported cases and provides further evidence for statins being triggers of immune-mediated disease. The appropriate management of this condition requires a collaborative effort involving clinical judgment, laboratory testing, and imaging.",
"affiliations": "Radiology, Brookwood Baptist Medical Center, Birmingham, USA.;Radiology, Louisiana State University Health Sciences Center Shreveport, Shreveport, USA.;Internal Medicine, Brookwood Baptist Medical Center, Birmingham, USA.",
"authors": "Gutierrez|Edgar|E|;Faraji|Mehdi|M|;Pacheco|Lauren|L|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.7387",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.7387\nDermatology\nInternal Medicine\nRadiology\nWeak Knees: A Case of Atorvastatin-induced Dermatomyositis\nMuacevic Alexander Adler John R Gutierrez Edgar 1 Faraji Mehdi 2 Pacheco Lauren 3 \n1 \nRadiology, Brookwood Baptist Medical Center, Birmingham, USA \n\n2 \nRadiology, Louisiana State University Health Sciences Center Shreveport, Shreveport, USA \n\n3 \nInternal Medicine, Brookwood Baptist Medical Center, Birmingham, USA \n\nMehdi Faraji mfaraj@lsuhsc.edu\n24 3 2020 \n3 2020 \n12 3 e73879 3 2020 24 3 2020 Copyright © 2020, Gutierrez et al.2020Gutierrez 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/28971-weak-knees-a-case-of-atorvastatin-induced-dermatomyositisHMG-CoA reductase inhibitors (statins) are one of the most widely used medications in the primary care setting, and like any medications they have many side effects. The common ones include myalgias and rare ones include dermatomyositis. Here we present the case of atorvastatin-induced dermatomyositis with an unfortunate progression. This mandates a low threshold for first contact doctors to screen their patients for new-onset muscle weakness and rash after starting a statin recently, like our patient who had started atorvastatin several months before. This case adds to the previously reported cases and provides further evidence for statins being triggers of immune-mediated disease. The appropriate management of this condition requires a collaborative effort involving clinical judgment, laboratory testing, and imaging.\n\nstatindermatomyositisweaknessmyopathyThe 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\nStatins are widely used lipid-lowering medications for the prevention of cardiovascular disease. Statins are generally well tolerated and safe, making them an excellent choice in therapy. However, there are common instances of statin-induced myalgias and rare instances of moderate-to-severe cases of statin-induced myopathies [1-6]. Statin-induced myopathy consists of a spectrum of disease conditions including polymyositis (PM), dermatomyositis (DM), and immune-mediated necrotizing myositis (IMNM). DM has been known to be an iatrogenic, autoimmune, and a paraneoplastic syndrome. Several previous cases of statin-induced DM have been reported in the literature with courses ranging from relatively benign to fatal [1]. We present the case of a patient with atorvastatin-induced DM. \n\nCase presentation\nA 49-year-old Caucasian male presents with a one-month history of progressively worsening dysphagia and proximal muscle weakness. Comorbidities include diabetes mellitus type 2 and hyperlipidemia. Home medications include semaglutide and atorvastatin. Two weeks prior to presentation, he noticed diffuse erythematous, circular plaques that appeared abruptly on his extremities, torso, back, and face. His primary care doctor discontinued the statin and referred him to gastroenterology and dermatology for dysphagia and rash, respectively. He underwent esophagogastroduodenoscopy for dysphagia showing esophageal stricture and was given a topical steroid cream for his rash. The patient was placed on oral prednisone therapy one week prior to arrival without symptom improvement. Due to worsening symptoms, he presented to our emergency department for further evaluation. Physical examination showed that the patient had 3/5 muscle strength at the shoulders and hips bilaterally. Other findings included heliotrope rash and Gottron’s papules (Figures 1, 2).\n\nFigure 1 Gottron's sign\nErythematous patch overlying the extensor surface of the left elbow (orange circle)\n\nFigure 2 Gottron’s papules\nErythematous papules/plaques seen on the extensor surfaces of the metacarpophalangeal joints (green ovals), proximal interphalangeal joints (yellow ovals), and distal interphalangeal joints (blue ovals) on the right and left hands\n\nInitial laboratory studies revealed elevated white blood cells at 29 (x10^9 cells/L), creatine kinase (CK, 6,000 mg/dL), myoglobin (12,000 ng/mL), aspartate aminotransferase (430 U/L), and alanine transaminase (700 U/L). Notable negative/normal laboratory values include C3, C4, antinuclear antibody, rheumatoid factor, hepatitis panel, antineutrophil cytoplasmic antibodies, anti-tissue transglutaminase (IgA/IgG), and myositis panel (including anti-Mi-2 and anti-Jo-1 autoantibodies).\n\nDuring his hospital course, he had persistent tachycardia and leukocytosis prompting a cardiac and infectious workup which came back normal. His treatment included one week of high-dose intravenous steroids and 20 mg oral prednisone thereafter, and a course of intravenous immunoglobulin. Despite treatment, he continued to have a rash with progressive proximal weakness and dysphagia as well as the development of head drop (neck muscle weakness). Malignancy workup was performed with contrast-enhanced CT scan of the head, chest, abdomen, and pelvis which were normal. Electromyography showed non-specific findings of myositis. MRI of the left lower extremity showed bilateral diffuse muscle enhancement on T1-weighted imaging with extensive muscle edema and evidence of fat stranding was seen (Figures 3, 4).\n\nFigure 3 MRI of the left hip\nFat-saturated post-contrast T1-weighted MRI of the left hip, showing an edematous signal within the rectus femoris (yellow arrow)\n\nFigure 4 MRI of the left hip\nFat-saturated post-contrast T1-weighted MRI of the left hip showing areas of intramuscular fat stranding and edematous signal within the semimembranosus muscles (yellow arrow)\n\nMuscle biopsy of the left vastus lateralis was consistent with necrotizing myopathy. At this point in time, the diagnosis of DM secondary to statin use was made. The patient was placed on prednisone 20 mg daily. Over the course of the next few months, the patient’s clinical course continued to deteriorate and he eventually required a percutaneous endoscopic gastrostomy tube and a wheelchair. He underwent subsequent readmission with high-dose intravenous steroids followed by high-dose oral steroid taper over the next several months. In the outpatient neurology setting, he was treated with regular rituximab infusions. Eight months after symptom onset, the patient was using a cane to walk and the severity of the skin rash was no better.\n\nDiscussion\nThis patient presented with classic features of DM, including proximal and symmetrical muscle weakness, Gottron’s papules, and heliotrope rash. MRI of muscle involvement showed characteristic findings of DM, including diffuse muscle enhancement on T1-weighted imaging suggesting fatty infiltration and diffuse bilateral muscle edema [1]. This patient had been on statin therapy for several months before presentation which is consistent with the timeline of most statin-induced myopathies [4]. Several statin-induced DM cases have been reported in previous literature [1-6].\n\nStatin-induced DM usually presents after months to years of previous statin therapy but can also present in the first few days [1]. Our patient had been on statin therapy for five months prior to symptom onset. This report presents a rare case of statin-induced DM with prominent necrosis seen on muscle biopsy. One could argue that this case presents a diagnosis of IMNM based on the muscle biopsy findings alone. However, IMNM presents with muscle involvement alone and would not explain the liver and skin findings in this patient, which can be seen in DM [2-4]. Additionally, the CK level findings in IMNM tend to be in excess of 10,000 U/L compared to our patient with CK levels around 5,000 U/L. The test for anti-HMGCR antibodies can be helpful in excluding the diagnosis of IMNM. However, the test for anti-HMGCR antibodies has a low positive predictive value making this test non-diagnostic. Hence, clinical correlation would still be required to make a diagnosis of IMNM [4].\n\nThis case adds to the previously reported cases and provides further evidence for statins being triggers of immune-mediated disease, although the exact mechanism is poorly understood. This case provides further evidence, and emphasizes the need for vigilance and close follow-up when assessing patients on statin therapy who present with proximal muscle weakness. The benefit of knowing the particular type of myopathy whether it be PM/DM/IMNM is of questionable clinical significance as there are no current treatment guidelines that would distinguish them at of the time of this report. However, most patients presenting with PM/DM-like symptoms undergo cancer screening, as to rule out a paraneoplastic syndrome.\n\nConclusions\nStatins are one of the most common medications that patients are on, and every good medical student knows about statin-induced myalgias, but statin-induced DM is also known to occur. DM presents with symmetrical muscle weakness, Gottron’s papules, and heliotrope rash with MRI finding of muscle edema and fatty infiltration. Muscle biopsy findings will include muscle necrosis. Patients on statin therapy presenting with proximal muscle weakness should have immediate intervention with cessation of the statin and aggressive immune suppression as complications of statin-induced DM can result in significant disability and sometimes even death. Our case report describes this unusual scenario with an unfortunate outcome; thus, it is important that the primary care, dermatological, and radiological communities are aware of these findings and complications from the disease. Hence, the appropriate management of this condition requires a collaborative effort involving clinical judgment, laboratory testing, and imaging.\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 Aggressive and fatal statin-induced dermatomyositis: a case report Oxf Med Case Rep Chemello RML Benvegnú AM Dallazem LND Chemello D 0 2017 2017 \n2 A novel autoantibody recognizing 200-kd and 100-kd proteins is associated with an immune-mediated necrotizing myopathy Arthritis Rheum Christopher-Stine L Casciola-Rosen LA Hong G Chung T Corse AM Mammen AL 2757 2766 62 2010 20496415 \n3 Myositis-specific autoantibodies: their clinical and pathogenic significance in disease expression Rheumatology (Oxford) Gunawardena H Betteridge ZE Mchugh NJ 607 612 48 2009 19439503 \n4 Statin-induced necrotizing myositis: a discrete autoimmune entity within the \"statin-induced myopathy spectrum\" Autoimmun Rev Hamann PD Cooper RG Mchugh NJ Chinoy H 1177 1181 12 2013 23851103 \n5 Myopathy with antibodies to the signal recognition particle: clinical and pathological features J Neurol Neurosurg Psychiatry Miller T Al-lozi MT Lopate G Pestronk A 420 428 73 2002 12235311 \n6 Simvastatin-induced dermatomyositis in a 50-year-old man BMJ Case Rep Zaraa IR Labbène I Mrabet D 0 2011 2011\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "12(3)",
"journal": "Cureus",
"keywords": "dermatomyositis; myopathy; statin; weakness",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e7387",
"pmc": null,
"pmid": "32337114",
"pubdate": "2020-03-24",
"publication_types": "D002363:Case Reports",
"references": "19439503;12235311;23851103;29255614;20496415;22700482",
"title": "Weak Knees: A Case of Atorvastatin-induced Dermatomyositis.",
"title_normalized": "weak knees a case of atorvastatin induced dermatomyositis"
} | [
{
"companynumb": "US-PFIZER INC-2020146786",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ATORVASTATIN CALCIUM"
},
"drugadditional": nul... |
{
"abstract": "OBJECTIVE\nTo report a case of Candida albicans keratitis after Descemet stripping with automated endothelial keratoplasty (DSAEK) due to fungal contamination of the donor cornea.\n\n\nMETHODS\nCase report.\n\n\nRESULTS\nA 73-year-old woman underwent phacoemulsification with intraocular lens (IOL) implantation and DSAEK with 1 week difference. Ten days after DSAEK surgery, the culture of the donor corneoscleral rim revealed Candida albicans contamination and a small whitish infiltrate was noted within the interface. Despite conservative treatment with oral and systemic voriconazole, the infection was present outside the interface and inside the anterior chamber. Hot penetrating keratoplasty (PKP) was performed and the infection was eradicated. However, due to uncontrolled high intraocular pressure, a new PKP had to be performed, the IOL was removed, and an Ahmed valve was implanted (by pars plana vitrectomy). The anterior cap of the same donor cornea was used to perform a tectonic superficial anterior lamellar keratoplasty and the recipient did not have any problem related to fungal infection.\n\n\nCONCLUSIONS\nThe diagnosis of fungal keratitis should be taken into account once a small infiltrate is seen in the interface of any kind of lamellar keratoplasty. It is not clear whether it is better to treat it conservatively or aggressively.",
"affiliations": "Corneal and external diseases department, Institute of Ophthalmology \"La Arruzafa\", Córdoba - Spain.",
"authors": "Villarrubia|Alberto|A|;Cano-Ortiz|Antonio|A|",
"chemical_list": "D000935:Antifungal Agents; D065819:Voriconazole",
"country": "United States",
"delete": false,
"doi": "10.5301/ejo.5000499",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1120-6721",
"issue": "24(6)",
"journal": "European journal of ophthalmology",
"keywords": null,
"medline_ta": "Eur J Ophthalmol",
"mesh_terms": "D000368:Aged; D000935:Antifungal Agents; D002177:Candidiasis; D003131:Combined Modality Therapy; D003320:Corneal Ulcer; D057111:Descemet Stripping Endothelial Keratoplasty; D015821:Eye Infections, Fungal; D005260:Female; D006801:Humans; D015948:Keratoplasty, Penetrating; D019654:Lens Implantation, Intraocular; D018918:Phacoemulsification; D012086:Reoperation; D014019:Tissue Donors; D065819:Voriconazole",
"nlm_unique_id": "9110772",
"other_id": null,
"pages": "964-7",
"pmc": null,
"pmid": "24966030",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Candida keratitis after Descemet stripping with automated endothelial keratoplasty.",
"title_normalized": "candida keratitis after descemet stripping with automated endothelial keratoplasty"
} | [
{
"companynumb": "ALCN2014ES006314",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
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"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE\\TOBRAMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "Lamotrigine is a commonly used agent for seizure control in epilepsy. There are limited data on the adverse effects of lamotrigine in overdose. We report a number of serious side-effects associated with a large overdose of lamotrigine. A 23-year-old female presented to the emergency department after taking an intentional overdose of 9.2 g of lamotrigine, 56 mg of chlorpheniramine, and 220 mg of citalopram. On admission, she had a reduced level of consciousness and electrocardiographic abnormalities; a widened QRS and a prolonged corrected QT (QTc) interval. Prompt treatment with early intubation, along with the use of magnesium for cardioprotection and administration of sodium bicarbonate may have aided in a quick recovery with a short intensive care stay and good outcome.",
"affiliations": "Acute Care Common Stem, University Hospitals of Leicester NHS Trust, Intensive Care Unit, Leicester Royal Infirmary, Leicester, United Kingdom. navinda@doctors.org.uk",
"authors": "Venkatraman|N|N|;O'Neil|D|D|;Hall|A P|AP|",
"chemical_list": "D000927:Anticonvulsants; D014227:Triazines; D015283:Citalopram; D002744:Chlorpheniramine; D017693:Sodium Bicarbonate; D000077213:Lamotrigine",
"country": "India",
"delete": false,
"doi": "10.4103/0022-3859.43516",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-3859",
"issue": "54(4)",
"journal": "Journal of postgraduate medicine",
"keywords": null,
"medline_ta": "J Postgrad Med",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000927:Anticonvulsants; D002744:Chlorpheniramine; D015283:Citalopram; D062787:Drug Overdose; D004562:Electrocardiography; D005260:Female; D006801:Humans; D000077213:Lamotrigine; D008133:Long QT Syndrome; D011041:Poisoning; D017693:Sodium Bicarbonate; D016896:Treatment Outcome; D014227:Triazines",
"nlm_unique_id": "2985196R",
"other_id": null,
"pages": "316-7",
"pmc": null,
"pmid": "18953153",
"pubdate": "2008",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"abstract": "BACKGROUND\nCytomegalovirus (CMV) is reported to have thrombogenic characteristics that activate factor X in vitro and stimulate the production of factor VIII and von Willebrand factor (vWF). Thrombosis associated with CMV infection is prevalent among immunocompromised patients and predominantly presents as a solitary large thrombus in the deep vein, pulmonary artery, splanchnic arteriovenous ducts, or other similar sites. Multiple thrombi, however, are rarely observed in such cases. Here, we report about an immunocompetent man with multiple microthrombi associated with CMV infection.\n\n\nMETHODS\nA 72-year-old Japanese man who complained of abdominal pain was hospitalized with multiple colonic stenosis. He was later diagnosed with CMV enterocolitis and treated with ganciclover from Day 27 post-admission. During hospitalization, the patient developed thrombi in his fingers. He was initially treated with anticoagulant therapy (rivaroxaban); however, the therapy was discontinued owing to a prolonged activated thromboplastin time and an elevated international normalized ratio of prothrombin time. Instead, vitamin K and fresh-frozen plasma were administered. Nevertheless, his coagulation profile remained abnormal. Eventually, he developed colonic perforation and had to undergo emergency surgery. An intraoperative specimen showed several microthrombi in the middle and small arteriovenous ducts of his small and large intestines. The patient's coagulopathy improved preoperatively, and his overall condition improved postoperatively. Since the activation of ADAMTS13 was reduced remarkably, the thrombotic tendency was determined to be a thrombotic microangiopathy-like condition owing to increased vWF. We could not attribute the coagulopathy to any other cause except CMV infection; therefore, we concluded that this was a case of multiple thrombosis associated with CMV.\n\n\nCONCLUSIONS\nWe present an extremely rare case of a patient with multiple thrombotic microangiopathy-like microthrombosis caused by CMV infection. Our findings suggest that CMV infection may be considered as a differential diagnosis for immunocompetent individuals who present with thrombosis of unspecified cause.",
"affiliations": "Department of Internal Medicine, Hyogo Prefectural Tamba Medical Center, 2002-7 Iso, Hikami-cho, Tamba, 669-3495, Japan.;Department of Internal Medicine, Hyogo Prefectural Tamba Medical Center, 2002-7 Iso, Hikami-cho, Tamba, 669-3495, Japan. smile.kenzaka@jichi.ac.jp.;Department of Internal Medicine, Hyogo Prefectural Tamba Medical Center, 2002-7 Iso, Hikami-cho, Tamba, 669-3495, Japan.;Division of Community Medicine and Career Development, Kobe University Graduate School of Medicine, 2-1-5, Arata-cho, Hyogo-ku, Kobe, Hyogo, 652-0032, Japan.;Division of Medical Oncology/Hematology, Department of Medicine, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan.;Department of Internal Medicine, Hyogo Prefectural Tamba Medical Center, 2002-7 Iso, Hikami-cho, Tamba, 669-3495, Japan.",
"authors": "Kamatani|Kaisei|K|;Kenzaka|Tsuneaki|T|http://orcid.org/0000-0002-3120-6605;Sugimoto|Ryu|R|;Kumabe|Ayako|A|;Kitao|Akihito|A|;Akita|Hozuka|H|",
"chemical_list": "D000925:Anticoagulants; D000998:Antiviral Agents; D000069552:Rivaroxaban; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human; D015774:Ganciclovir",
"country": "England",
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"doi": "10.1186/s12879-021-06230-4",
"fulltext": "\n==== Front\nBMC Infect Dis\nBMC Infect Dis\nBMC Infectious Diseases\n1471-2334\nBioMed Central London\n\n6230\n10.1186/s12879-021-06230-4\nCase Report\nMultiple thrombosis associated with Cytomegalovirus enterocolitis in an immunocompetent patient: a case report\nKamatani Kaisei 1\nhttp://orcid.org/0000-0002-3120-6605\nKenzaka Tsuneaki smile.kenzaka@jichi.ac.jp\n\n12\nSugimoto Ryu 1\nKumabe Ayako 23\nKitao Akihito 4\nAkita Hozuka 1\n1 Department of Internal Medicine, Hyogo Prefectural Tamba Medical Center, 2002-7 Iso, Hikami-cho, Tamba, 669-3495 Japan\n2 grid.31432.37 0000 0001 1092 3077 Division of Community Medicine and Career Development, Kobe University Graduate School of Medicine, 2-1-5, Arata-cho, Hyogo-ku, Kobe, Hyogo 652-0032 Japan\n3 Department of General Medicine, Toyooka Public Hospital, 1094, Tobera, Toyooka, Hyogo 668-8501 Japan\n4 grid.31432.37 0000 0001 1092 3077 Division of Medical Oncology/Hematology, Department of Medicine, Kobe University Graduate School of Medicine, Kobe, 650-0017 Japan\n5 6 2021\n5 6 2021\n2021\n21 53018 12 2020\n24 5 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nCytomegalovirus (CMV) is reported to have thrombogenic characteristics that activate factor X in vitro and stimulate the production of factor VIII and von Willebrand factor (vWF). Thrombosis associated with CMV infection is prevalent among immunocompromised patients and predominantly presents as a solitary large thrombus in the deep vein, pulmonary artery, splanchnic arteriovenous ducts, or other similar sites. Multiple thrombi, however, are rarely observed in such cases. Here, we report about an immunocompetent man with multiple microthrombi associated with CMV infection.\n\nCase presentation\n\nA 72-year-old Japanese man who complained of abdominal pain was hospitalized with multiple colonic stenosis. He was later diagnosed with CMV enterocolitis and treated with ganciclover from Day 27 post-admission. During hospitalization, the patient developed thrombi in his fingers. He was initially treated with anticoagulant therapy (rivaroxaban); however, the therapy was discontinued owing to a prolonged activated thromboplastin time and an elevated international normalized ratio of prothrombin time. Instead, vitamin K and fresh-frozen plasma were administered. Nevertheless, his coagulation profile remained abnormal. Eventually, he developed colonic perforation and had to undergo emergency surgery. An intraoperative specimen showed several microthrombi in the middle and small arteriovenous ducts of his small and large intestines. The patient’s coagulopathy improved preoperatively, and his overall condition improved postoperatively. Since the activation of ADAMTS13 was reduced remarkably, the thrombotic tendency was determined to be a thrombotic microangiopathy-like condition owing to increased vWF. We could not attribute the coagulopathy to any other cause except CMV infection; therefore, we concluded that this was a case of multiple thrombosis associated with CMV.\n\nConclusions\n\nWe present an extremely rare case of a patient with multiple thrombotic microangiopathy-like microthrombosis caused by CMV infection. Our findings suggest that CMV infection may be considered as a differential diagnosis for immunocompetent individuals who present with thrombosis of unspecified cause.\n\nKeywords\n\nCytomegalovirus\nThrombus\nADAMTS13\nThrombotic microangiopathy\nImmunocompetent\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nInfections caused by cytomegalovirus (CMV) are often asymptomatic; however, symptomatic manifestations of the infection vary from those of a mononucleosis-like syndrome to severe viral dissemination in immunocompromised patients [1]. Arteriovenous thrombosis is a rare complication of CMV infection and often presents as a solitary large thrombus in the deep veins, pulmonary arteries, or visceral arteriovenous ducts [1]. Multiple microthrombi consequent to CMV infection are rare, and only a few cases have been previously reported [2]. In addition, thrombosis associated with CMV infection often occurs in immunocompromised individuals [1] and has only recently been reported in immunocompetent patients [3].\n\nWe report the case of an immunocompetent patient who developed multiple microthrombosis subsequent to CMV colitis complicated with severe coagulation abnormalities.\n\nCase presentation\n\nThe patient is a 72-year-old man capable of independently performing activities of daily living. Regarding his medical history, he developed gastric ulceration at 18 years of age and underwent partial gastric resection. He was treated with rivaroxaban 10 mg / day for atrial fibrillation. Also, he regularly inhales formoterol fumarate for managing bronchial asthma. He used to smoke 20 cigarettes/day and drink more than three cups of sake between 20 and 65 years of age. He reported no positive history of food or drug allergy.\n\nApproximately 40 days before admission to our department, the patient developed pain in the lower left abdominal region. Eight days later, he visited a hospital where he underwent non-contrast computed tomography (CT) of the abdomen that showed multiple colonic stenosis. Colon cancer was suspected, and the patient was admitted to the facility immediately. The patient also had fever (38 °C) on admission and, therefore, underwent thoracoabdominal contrast-enhanced CT that showed pulmonary thromboembolism (Fig. 1). Therefore, the dose of rivaroxaban was increased from 10 mg/day to 30 mg/day on Day 14 (days numbered from day of admission at the first facility). Fig. 1 Thoracoabdominal contrast-enhanced CT on Day 14. The CT showed a contrast defect area in the main trunk of the left pulmonary artery\n\nThen, he underwent fasting treatment and received maintenance intravenous fluids. On Day 14 of hospitalization, he underwent colonoscopy that showed stenosis in the hepatic flexure of the transverse colon and a circumferential ulcer of the sigmoid colon. On administration of a contrast, a 55-mm stenosis was found in the transverse and descending colon (Fig. 2). Pathological examination of the stenosed colon tissue revealed intranuclear inclusion bodies and a positive immunostaining for anti-CMV antibodies and CMV antigens (CMV DNA viral load was not performed). Consequently, the patient was administered 5 mg/kg ganciclovir (GCV) every 12 h since Day 27. Although the patient’s abdominal pain was relieved by the treatment, the fever was not alleviated. Fig. 2 Colonoscopic intestinal findings on Day 14. a Stenosis in the hepatic flexure of the transverse colon, b ulcer in the sigmoid colon, and c 55-mm stenosis of the transverse descending colon (arrow) on contrast study\n\nAlthough the coagulation profile of the patient was normal on the day of admission (Day 1), an abnormal coagulation profile was seen on Day 25; the international normalized ratio of prothrombin time (PT-INR) was elevated (8.35) and the activated partial thromboplastin time (APTT) was prolonged (170.8 s). As a result, rivaroxaban was discontinued. Up till then, the patient had received a total of 18 units of fresh-frozen plasma (FFP) and 180 mg of vitamin K. However, the coagulation profile had not improved. Although the platelet count was 113 × 109 cells/L on admission, the count began decreasing since Day 25 till it reached 73 × 109 cells/Lon Day 31. Therefore, to further explore the cause of the coagulation abnormality and continue the treatment of CMV colitis, the patient was transferred to our hospital on Day 32.\n\nOn admission to our facility, the patient’s clinical findings were as follows: Height, 163 cm; weight, 51 kg; body temperature, 36.8 °C; pulse rate, 108 beats/min; blood pressure, 118/92 mmHg; respiratory rate, 12 breaths/min; and oxygen saturation, 90% on ambient air. Breathing sounds were heard with coarse cracks on the dorsal surface of the lungs bilaterally. The heartbeat was irregular, but no heart murmur was heard. The abdomen was flat and soft, and there was no spontaneous pain; however, there was tenderness on palpation in the right hypochondrium and iliac regions. No peritoneal irritation was observed. Bilateral to the chest, approximately 20 scattered erythematous papules (~ 1 cm in length) were found; no superficial lymph nodes were palpable. Purpuric spots and pain were present on the right fifth finger, whereas only purpuric spots were seen on the left second and third fingers (Fig. 3). A peripherally inserted central catheter that was placed in the left upper arm at the previous facility was present. Fig. 3 Purpura on the apex of the fingers at the time of admission. In the right hand, there is an enlargement of the purpura\n\nTable 1 shows the patient’s laboratory data upon his admission to our hospital (Day 35 from the day of admission at the first facility). Table 1 Laboratory data of the patient upon admission to our hospital\n\nParameter\tRecorded value\tStandard value\t\nWhite blood cell count, cells/L\t14.54 × 109\t4.5–7.5 × 109\t\n Neutrophils, %\t34.0\t42–74\t\n Eosinophil, %\t50.5\t0–7.0\t\nHemoglobin, g/L\t102\t113–152\t\nPlatelet count, cells/L\t6 × 109\t130–350 × 109\t\nProthrombin time/International normalized ratio\t4.37\t0.80–1.20\t\nActivated partial thromboplastin time, s\t154.1\t26.9–38.1\t\nD-dimer, mg/L\t2.1\t< 1.0\t\nFibrin degradation product, mg/L\t3.6\t0–5.0\t\nFibrinogen, g/L\t2.97\t2.00–4.00\t\nAntithrombin III, %\t37.2\t70–120\t\nC-reactive protein, nmol/L\t184.77\t≤5.71\t\nTotal protein, g/L\t71\t69–84\t\nAlbumin, g/L\t18\t39–51\t\nTotal bilirubin, mmol/L\t0.0308\t0.0034–0.0205\t\nAspartate aminotransferase, μkat/L\t0.32\t0.18–0.5\t\nAlanine aminotransferase, μkat/L\t0.47\t0.07–0.5\t\nLactase dehydrogenase, μkat/L\t4.55\t1.8–3.6\t\nalkaline phosphatase, μkat/L\t25.02\t1.67–5.83\t\nγ- glutamyltransferase, μkat/L\t1.62\t0.17–0.83\t\nCreatine kinase, μkat/L\t0.93\t0.67–2.5\t\nBlood urea nitrogen, mmol/L\t9.43\t2.86–7.14\t\nCreatinine, mmol/L\t0.06\t0.05–0.09\t\nSodium, mmol/L\t136\t136–148\t\nPotassium, mmol/L\t4.5\t3.6–5.0\t\nChloride, mmol/L\t107\t98–108\t\nsoluble interleukin-2 receptor, U/mL\t8540\t140–520\t\nIgG4, μmol/L\t28.62\t0.33–7.80\t\nIgE, U/mL\t20,367\t≤173\t\nP-ANCA\t–\t\t\nC-ANCA\t–\t\t\nAntinuclear antibody\t40 times\t< 80 times\t\nC7-HRP\t0\t\t\nTAT, ng/mL\t2.6\t0.0–3.9\t\nPIC, μg/mL\t< 0.2\t0.0–0.8\t\nHaptoglobin, mg/dL\t126\t71–160\t\nActivation of factor II, %\t49.1\t66–118\t\nActivation of factor V, %\t< 1.0\t73–122\t\nActivation of factor X, %\t59.7\t58–200\t\nProtein C, %\t37%\t70–140%\t\nProtein S, %\t64.1%\t63–149%\t\nCardiolipin antibody IgG, U/mL\t25\t0–9\t\nCardiolipin antibody IgM, U/mL\t3\t0–7\t\nAnti-human beta-2 glycoprotein 1 Antibody, U/mL\t< 1.3\t0.0–3.4\t\nlupus anticoagulant\tUnknown\t0.0–1.2\t\nActivation of ADAMTS13, %\t18\t≥78\t\nC-ANCA cytoplasmic anti-neutorophil antibody, C7-HRP cytomegalovirus pp65 antigen, P-ANCA perinuclear anti-neutorophil antibody, PIC plasmin-α2 plasmin inhibitor complex, TAT thrombin anti-thrombin complex\n\nThese were as follows: White blood cell count, 14.54 × 109 cells/L; C-reactive protein, 1847.62 nmol/L; platelet count, 60 × 109 cells/L; and normocytic anemia. There was no significant abnormality in the peripheral blood; however, biliary enzymes were elevated (alkaline phosphatase: 20.02 μkat/L; γ- glutamyltransferase: 1.62 μkat/L). The coagulation disorder was apparent (PT-INR, 4.37; APTT, 154.1 s) but the D-dimer level was virtually unchanged (2.1 mg/L) and the level of fibrin degradation products was normal (3.6 mg/mL). Levels of thrombin-antithrombin complex (2.6 ng/mL) and plasmin-α2 plasmin inhibitor complex (< 0.2 ng/mL) were also normal. However, soluble interleukin-2 receptor (sIL-2R) was elevated (8540 U/mL), factor II activity was marginally reduced (49.1%), factor X activity was reduced to 59.7%, factor V activity was < 1.0%, and ADAMTS13 activity had decreased to 18%. Abdominal CT showed splenomegaly with a maximum splenic length of 9.6 cm and enlargement of axillary, left superior fossa, and paraortic lymph nodes. On Day 1, the patient had a maximum splenic length of 7.6 cm, indicating that the splenomegaly had increased since then.\n\nFigure 4 shows the clinical course after admission at the first facility. The administration of 5 mg/kg GCV every 12 h was continued. The purpura on the right hand observed at the time of admission to our facility widened. A total of 16 units of FFP were transfused to the patient at our hospital for 3 days (from Day 35, Day 4 from the admission to our hospital) but the coagulation profile did not improve. Since this patient had CMV enteritis, we considered vasculitis or malignant lymphoma as the cause based on the purpura on the fingertips, truncal rash, increasing splenomegaly, high alkaline phosphatase (ALP) level, high sIL-2R level, low platelet count, and PT-INR and APTT prolongation. A biopsy of the skin rash on the right lateral surface of the abdomen and of a left axillary lymph node was performed on Day 34 and Day 36 (Day 3 and 5 from the admission to our hospital), respectively. However, there were no indications of vasculitis or malignant lymphoma. Fig. 4 Chart showing the clinical course after admission. PE: pulmonary embolism; GCV: ganciclovir; CFPM: cefepime; MEPM: meropenem; VCM: vancomycin; A/S: Ampicillin/Sulbactam\n\nOn Day 35 (Day 4 from the admission to our hospital), the patient developed bacteremia caused by Staphylococcus aureus and Fusobacterium species. He was treated with meropenem (MEPM) 2 g/day and vancomycin (VCM; trough ≥15 μg/mL). On Day 37 (Day 6 from the admission to our hospital), his abdominal pain worsened, and he went into shock. Non-contrast CT of the abdomen showed extensive free air in the abdominal cavity, which led to the diagnosis of gastrointestinal perforation that warranted an emergency surgery. During the operation, scattered necrotic changes were observed in the small intestine. A 1-cm perforation was found 10 cm to the right from the top of the transverse colon; the colon was resected from the ileum to the perforated area (Fig. 5). An additional excision was performed on the left side of the transverse colon because of stool drainage from that region. Subsequently, ileal colostomy was performed, and a stoma was placed in the right lower abdomen. The surgical specimen of the ileum showed a perforation in the transverse colon, necrosis due to ischemic changes associated with circulatory failure, and numerous thrombi, including microthrombi, in the small- and medium-sized arteriovenous ducts (Fig. 6). There was no evidence of lymphoma, vasculitis, or ulcerative colitis on pathological examination. We performed cardiac ultrasound scan multiple times, but no valve destruction was seen. In addition, a second blood culture was negative. Abnormal coagulation and multiple thrombosis were present before the onset of staphylococcal bloodstream infection. Furthermore, the pathology of the intestine showed no invasion by S. aureus. Therefore, we thought that Staphylococcal bloodstream infection had little to do with abnormal coagulation and multiple thrombosis. Because of the drug sensitivities of S. aureus and Fusobacterium species and the presence of intestinal perforation, VCM was discontinued, and only MEPM (1 g, 12 hourly) was administered from Day 39 (Day 8 from the admission to our hospital) onward. The thrombocytopenia and coagulation abnormalities observed preoperatively improved slightly and normalized postoperatively. In addition, the activities of factor II, factor X, factor V, and ADAMTS13 normalized. There was no evidence of vasculitis, lymphoma, or any other thrombotic disease; therefore, the final diagnosis was multiple microthrombi caused by CMV enteritis that mimicked thrombotic microangiopathy-like conditions. GCV administration was continued until Day 57 (Day 26 from the admission to our hospital). Fig. 5 Resected intestinal tract. A perforation was found 10 cm to the right from the top of the transverse colon\n\nFig. 6 Hematoxylin-eosin stained resected intestinal tract (× 2). An abundance of thrombi in small and medium-sized arteriovenous ducts (arrows) was found\n\nOn Day 88 (Day 57 from the admission to our hospital), the patient was transferred to the previous hospital for rehabilitation. One year has passed since he was discharged from the hospital; no recurrence has been observed since.\n\nDiscussion and conclusions\n\nWe presented a case of multiple microthrombosis triggered by CMV enterocolitis in a patient without an underlying disease that causes immunodeficiency. This is an extremely rare case that ADAMTS13 activity was reduced, resulting in multiple microthrombi and a thrombotic microangiopathy-like condition in the patient with CMV infection.\n\nArteriovenous thrombosis has been reported as a rare complication of CMV infection [4, 5]. As shown in Fig. 7, the mechanism that contributes to the formation of a thrombus due to CMV infection has been reported [1] to stimulate vascular endothelial cells, promote the production of tissue factor and von Willebrand factor (vWF) [2], produce factor VIII, and [3] activate factor X [1]. To date, approximately 100 cases have been reported [1], most of which report the presence of relatively large single thrombi in sites such as deep veins, pulmonary arteries, or visceral arteriovenous ducts [5, 6]. Multiple thrombi are extremely rare in such cases. To the best of our knowledge, there are only two similar cases that report multiple microthrombi as a consequence of CMV infection [2, 7]. One case is that of thrombotic thrombocytopenic purpura (TTP) in an immunocompromised individual [2] and the other is of hemolytic-uremic syndrome (HUS) in an immunocompetent individual [7]. In the presented case, however, no fragmented red blood cells were observed in the peripheral blood, but laboratory data showed a marked decrease in the platelet count and ADAMTS13 activity (baseline value, > 78%). The diagnosis of a TMA-like pathology was made based on the necrosis of the fingers and the presence of microthrombi in the intestinal tract in the surgical specimen. However, differing from previously reported pathogenesis of TTP, the ADAMTS13 activity was not < 10% [8]. Moreover, the condition differed from HUS because Shiga toxins were not involved and kidney failure did not occur [9, 10]. We believe that ADAMTS13 was markedly reduced in the present case as a result of the presumed mechanism of the stimulation of vascular endothelial cells and promotion of excessive tissue factor and vWF production [1]. The treatment of simple large thrombosis, such as pulmonary embolism and superior mesenteric venous embolism, associated with CMV infection is anticoagulation therapy with heparin or warfarin [5] in conjunction with antiviral medication such as GCV to treat the CMV infection [11]. Fig. 7 Coagulation cascade and interference of cytomegalovirus in this case. 1) Stimulation of endovascular cells. As a result, production of TF and vVF are decreased and activation of ADAMTS13 is decreased. 2) Production of factor VII. 3) Activation of factor X\n\nThe hyper prolongation of PT-INR and APTT in the presented case was initially suspected to be due to an exhaustive coagulopathy caused by an increased secondary hemostatic mechanism like coagulation factor activation or a disseminated intravascular coagulation-like condition. However, there was no hyper prolongation of other coagulation systems, such as thrombin-antithrombin complex, plasmin-α2 plasmin inhibitor complex, and fibrin degradation products, and D-dimer was not elevated (Fig. 7). The activity of factor V, a cofactor of the secondary hemostatic cascade, was greatly reduced, indicating that the cause was an acquired factor V deficiency due to the action of factor V inhibitors. Factor V deficiency is the second most common form of acquired hemophilia [12], with a reported incidence of 0.09 to 0.29 per million people per year [13], and has several causes, including viral infections, collagen diseases, malignancies, medicines, diabetes mellitus, and inflammatory bowel disease [14]. We theorize that an acquired factor V deficiency was triggered by the CMV infection in the present case because PT-INR, APTT, and coagulation factors normalized after the CMV infection was cured.\n\nMost adults are subclinically infected with CMV during childhood and remain latently infected throughout their lives without developing noticeable symptoms or pathology in normal immune conditions. However, immunosuppressive conditions, such as acquired immunodeficiency syndrome, post-organ transplantation, and reception of immunosuppressive medicines such as anticancer drugs/corticosteroids, may lead to CMV reactivation that may cause opportunistic infections [15, 16]. Further, the management of patients affected by autoimmune/idiopathic diseases has been revolutionized by the development of targeted therapies in recent years. However, targeted therapies are also a risk for CMV reactivation [17]. In the present case, although the patient was regularly inhaling formoterol fumarate for managing bronchial asthma, there was no preexisting disease that could cause immunosuppression. Thrombosis associated with CMV infection often occurs in immunocompromised individuals [1, 18], but in recent years, it has been reported in immunocompetent patients [4, 19] as well. In the present case, as colon cancer was initially suspected, lower gastrointestinal endoscopy was delayed until Day 14 and was not performed immediately after hospitalization. In addition, it took 2 weeks to confirm the pathological diagnosis. Therefore, GCV treatment was delayed as it commenced on Day 27 after admission.\n\nThe eosinophil percentage was 50% at admission, gradually improved, and normalized with improvement of the coagulation abnormalities after surgery. In addition to bronchial asthma as one of the underlying diseases, coagulation abnormalities associated with infection are thought to be involved in eosinopenia, but the actual cause is unknown.\n\nIn conclusion, we present an extremely rare case wherein the ADAMTS13 activity was reduced, resulting in a thrombotic microangiopathy-like condition in an immunocompetent patient with CMV enterocolitis. Our findings suggest that CMV infection may be considered as a differential diagnosis when treating immunocompetent individuals who present with thrombosis of an unspecified cause.\n\nAbbreviations\n\nALP Alkaline phosphatase\n\nAPTT Activated partial thromboplastin time\n\nCMV Cytomegalovirus\n\nCT Computed tomography\n\nFFP Fresh-frozen Plasma\n\nGCV Ganciclovir\n\nHUS Hemolytic-uremic syndrome\n\nMEPM Meropenem\n\nPT-INR International normalized ratio of prothrombin time\n\nsIL-2R Soluble interleukin-2 receptor\n\nTMA Thrombotic microangiopathy\n\nTTP Thrombotic thrombocytopenic purpura\n\nVCM Vancomycin\n\nvWF von Willebrand factor\n\nNot applicable.\n\nAuthors’ contributions\n\nKK and RS managed the case, and prepared and revised the manuscript. TK assisted with the preparation and revision of the manuscript. AKumabe and AKitao assisted with data analysis and revision of the manuscript. HA assisted with manuscript revision and prepared the figures. All co-authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. All co-authors take full responsibility for the integrity of the study and the final manuscript.\n\nFunding\n\nNot applicable.\n\nAvailability of data and materials\n\nData sharing is not applicable to this article as no datasets were generated or analyzed during the current study.\n\nDeclarations\n\nEthics approval and consent to participate\n\nEthics approval and consent for this case report were waived.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor of this journal.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Neppelenbroek SIM Rootjes PA Boxhoorn L Wagenaar JFP Simsek S Stam F Cytomegalovirus-associated thrombosis Neth J Med 2018 76 251 254 30019682\n2. Boteju M, Weeratunga P, Sivashangar A, Chang T. Cytomegalovirus induced refractory TTP in an immunocompetent individual: a case report. BMC Infect Dis 2019;19:394, 1, DOI: 10.1186/s12879-019-4037-9.\n3. Wang T Kuttikat A Pulsalkar P Nanguzgambo A Bhalara S Cytomegalovirus-associated portal vein thrombosis in an immunocompetent patient: an underestimated complication Oxf Med Case Rep 2015 2015 294 296 10.1093/omcr/omv041\n4. Atzmony L Halutz O Avidor B Finn T Zimmerman O Steinvil A Zeltser D Giladi M Justo D Incidence of cytomegalovirus-associated thrombosis and its risk factors: a case-control study Thromb Res 2010 126 e439 e443 10.1016/j.thromres.2010.09.006 20926120\n5. Justo D Finn T Atzmony L Guy N Steinvil A Thrombosis associated with acute cytomegalovirus infection: a meta-analysis Eur J Intern Med 2011 22 195 199 10.1016/j.ejim.2010.11.006 21402253\n6. Kalaitzis J, Basioukas P, Karzi E, Markakis C, Liarmakopoulos E, Hadjimarkou A, Rizos S. Small-bowel necrosis complicating a cytomegalovirus-induced superior mesenteric vein thrombosis in an immunocompetent patient: a case report. J Med Case Rep 2012;6:118, DOI: 10.1186/1752-1947-6-118.\n7. Catón B Díaz de Otazu R Aldamiz-Echebarria M Viguri A Haemolytic-uraemic syndrome with thrombotic microangiopathy of the retina following cytomegalovirus infection: postmortem findings Postgrad Med J 1993 69 653 655 10.1136/pgmj.69.814.653 8234116\n8. Rieger M Mannucci PM Kremer Hovinga JA Herzog A Gerstenbauer G Konetschny C Zimmermann K Scharrer I Peyvandi F Galbusera M Remuzzi G Böhm M Plaimauer B Lämmle B Scheiflinger F ADAMTS13 autoantibodies in patients with thrombotic microangiopathies and other immunomediated diseases Blood 2005 106 1262 1267 10.1182/blood-2004-11-4490 15890682\n9. Haemolytic uraemic syndrome (HUS) guideline making group editing HUS guideline 2014 Tokyo Tokyo-igakusha.co.jp\n10. Hirata C Kenzaka T Akita H Late onset of hemolytic uremic syndrome after the appearance of prodromal gastrointestinal tract symptoms Clin Case Rep 2020 8 1910 1913 10.1002/ccr3.3020 33088517\n11. Bertoni M Squizzato A Foretic M Zanieri S Di Natale ME Cytomegalovirus-associated splanchnic vein thrombosis in immunocompetent patients: a systematic review Thromb Res 2018 168 104 113 10.1016/j.thromres.2018.06.015 29960252\n12. Franchini M Lippi G Acquired factor V inhibitors: a systematic review J Thromb Thrombolysis 2011 31 449 457 10.1007/s11239-010-0529-6 21052780\n13. Ang AL Kuperan P Ng CH Ng HJ Acquired factor V inhibitor. A problem-based systematic review Thromb Haemost 2009 101 852 859 10.1160/TH08-11-0767 19404538\n14. Favaloro EJ Posen J Ramakrishna R Soltani S McRae S Just S Aboud M Low J Gemmell R Kershaw G Coleman R Dean M Factor V inhibitors: rare or not so uncommon? A multi-laboratory investigation Blood Coagul Fibrinolysis 2004 15 637 647 10.1097/00001721-200412000-00003 15613918\n15. Garrido E Carrera E Manzano R Lopez-Sanroman A Clinical significance of cytomegalovirus infection in patients with inflammatory bowel disease World J Gastroenterol 2013 19 17 25 10.3748/wjg.v19.i1.17 23326158\n16. Lawlor G Moss AC Cytomegalovirus in inflammatory bowel disease: pathogen or innocent bystander? Inflam Bowel Dis 2010 16 1620 1627 10.1002/ibd.21275\n17. Bavaro DF Fiordelisi D Angarano G Monno L Saracino A Targeted therapies for autoimmune/idiopathic nonmalignant diseases: risk and management of opportunistic infections Expert Opin Drug Saf 2020 19 817 842 10.1080/14740338.2020.1767585 32394759\n18. Narimatsu H Kami M Hara S Matsumura T Miyakoshi S Kusumi E Kakugawa Y Kishi Y Murashige N Yuji K Masuoka K Yoneyama A Wake A Morinaga S Kanda Y Taniguchi S Intestinal thrombotic microangiopathy following reduced-intensity umbilical cord blood transplantation Bone Marrow Transplant 2005 36 517 523 10.1038/sj.bmt.1705099 16025150\n19. Nishimura N Ueda N Kawaguchi T Shirahama T Himeji D Yamanaka A A case of multiple venous thromboses associated with acute cytomegalovirus infection Kansenshogaku Zasshi 2017 91 20 24 10.11150/kansenshogakuzasshi.91.20 30277683\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2334",
"issue": "21(1)",
"journal": "BMC infectious diseases",
"keywords": "ADAMTS13; Cytomegalovirus; Immunocompetent; Thrombotic microangiopathy; Thrombus",
"medline_ta": "BMC Infect Dis",
"mesh_terms": "D000071120:ADAMTS13 Protein; D000368:Aged; D000925:Anticoagulants; D000998:Antiviral Agents; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D004760:Enterocolitis; D015774:Ganciclovir; D006801:Humans; D007416:Intestinal Perforation; D008297:Male; D000069552:Rivaroxaban; D012698:Serologic Tests; D013927:Thrombosis",
"nlm_unique_id": "100968551",
"other_id": null,
"pages": "530",
"pmc": null,
"pmid": "34090366",
"pubdate": "2021-06-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "30277683;23326158;29960252;31068128;16025150;8234116;21052780;21402253;33088517;20232408;15890682;15613918;30019682;19404538;26069839;22531275;20926120;32394759",
"title": "Multiple thrombosis associated with Cytomegalovirus enterocolitis in an immunocompetent patient: a case report.",
"title_normalized": "multiple thrombosis associated with cytomegalovirus enterocolitis in an immunocompetent patient a case report"
} | [
{
"companynumb": "JP-CHEPLA-C20213008",
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"activesubstancename": "FORMOTEROL FUMARATE"
},
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... |
{
"abstract": "This case-report describes a massive voriconazole (VRZ) intoxication in a patient with a poor metabolizer profile, highlighted by low plasma main metabolite concentrations (N-oxide voriconazole), despite an extensive genetic profile for CYP2C19 and CYP2C9. The patient was treated with a therapeutic dose of VRZ but developed a neurotoxicity leading to hallucinations and coma while the plasma concentration of VRZ reached an exceptional level (20.0 µg/mL on day 10 of the treatment). Since neurological disorders diminished in parallel with the decrease of VRZ plasma concentrations, the coma was likely due to VRZ. The VRZ half-life, calculated to 58 h in this patient, was by far higher than the values reported in the literature. While VRZ concentrations slowly decreased, the N-oxide voriconazole concentrations slowly increased from day 15. Hypotheses for this lack of metabolization of VRZ are an inhibition of the metabolism by esomeprazole, a saturation of the metabolism or an enzymatic auto-inhibition of VRZ metabolism but none of these hypotheses have yet been explored. This case-report of unpredictable accumulation of VRZ in a patient without any genetic risk factor is an advocacy for systematic therapeutic drug monitoring of VRZ.",
"affiliations": "Department of Clinical and Biological Pharmacology and Pharmacovigilance, Pharmacoepidemiology and Drug Information Center, Rennes University Hospital.",
"authors": "Lemaitre|Florian|F|;Barbaz|Mathilde|M|;Scailteux|Lucie-Marie|LM|;Uhel|Fabrice|F|;Tadié|Jean-Marc|JM|;Verdier|Marie-Clémence|MC|;Bellissant|Eric|E|",
"chemical_list": "D011743:Pyrimidines; D014230:Triazoles; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D065819:Voriconazole",
"country": "England",
"delete": false,
"doi": "10.2133/dmpk.dmpk-13-nt-007",
"fulltext": null,
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"issn_linking": "1347-4367",
"issue": "28(5)",
"journal": "Drug metabolism and pharmacokinetics",
"keywords": null,
"medline_ta": "Drug Metab Pharmacokinet",
"mesh_terms": "D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D016903:Drug Monitoring; D006207:Half-Life; D006801:Humans; D008297:Male; D020258:Neurotoxicity Syndromes; D011743:Pyrimidines; D014230:Triazoles; D065819:Voriconazole",
"nlm_unique_id": "101164773",
"other_id": null,
"pages": "439-41",
"pmc": null,
"pmid": "23545593",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case-report of unpredictable and massive voriconazole intoxication in a patient with extensive CYP2C19 and CYP2C9 polymorphisms.",
"title_normalized": "a case report of unpredictable and massive voriconazole intoxication in a patient with extensive cyp2c19 and cyp2c9 polymorphisms"
} | [
{
"companynumb": "FR-MYLANLABS-2014M1006287",
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"patient": {
"drug": [
{
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"activesubstance": {
"activesubstancename": "CEFTRIAXONE"
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... |
{
"abstract": "Bupropion is a norepinephrine dopamine-reuptake inhibitor that has been found to be effective in the treatment of nicotine dependence. Although well tolerated, seizures and psychosis have been described to occur with bupropion as severe adverse effects. We report the precipitation of acute psychosis with bupropion prescribed for smoking cessation in an elderly patient.",
"affiliations": "Department of Psychiatry, Kasturba Medical College, Manipal, Karnataka, India.",
"authors": "Munoli|Ravindra Neelakanthappa|RN|;Kongasseri|Sreejayan|S|;Praharaj|Samir Kumar|SK|;Sharma|Podila S V N|PS|",
"chemical_list": "D018765:Dopamine Uptake Inhibitors; D016642:Bupropion",
"country": "United States",
"delete": false,
"doi": "10.1097/MJT.0b013e31823581c8",
"fulltext": null,
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"issn_linking": "1075-2765",
"issue": "21(2)",
"journal": "American journal of therapeutics",
"keywords": null,
"medline_ta": "Am J Ther",
"mesh_terms": "D000208:Acute Disease; D016642:Bupropion; D018765:Dopamine Uptake Inhibitors; D006801:Humans; D008297:Male; D008875:Middle Aged; D011605:Psychoses, Substance-Induced; D016540:Smoking Cessation",
"nlm_unique_id": "9441347",
"other_id": null,
"pages": "e45-7",
"pmc": null,
"pmid": "23698185",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bupropion precipitating acute psychosis: a case report.",
"title_normalized": "bupropion precipitating acute psychosis a case report"
} | [
{
"companynumb": "IN-WATSON-2014-27038",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"drugadditional": null... |
{
"abstract": "The increasing demand and popularity of bariatric surgery are not only due to the ever-increasing obesity epidemic but to tackle obesity-related comorbidities like diabetes and hypertension. However, bariatric surgery is not free of complications. One rare complication is intussusception, jejuno-jejunal intussusception being the most common. Intussusception has been defined both in pregnant and in non-pregnant women as well as men. We describe the case of a 40-year-old woman in the first trimester of pregnancy came to the hospital with worsening abdominal pain, was found to have intussusception of small bowel involving the jejunum, along with ischaemic perforation and necrosis of the fundus of the stomach. Postsurgery, the patient had a complete recovery and eventually, she successfully delivered an intact, viable fetus.",
"affiliations": "Internal Medicine, St. Vincent Charity Medical Center, Cleveland, Ohio, USA.;Internal Medicine, St. Vincent Charity Medical Center, Cleveland, Ohio, USA.;St. Vincent Charity Medical Center, The Center for Bariatric Surgery, Cleveland, Ohio, USA.;Internal Medicine, St. Vincent Charity Medical Center, Cleveland, Ohio, USA.",
"authors": "Bhadra|Rajarshi|R|http://orcid.org/0000-0002-5211-1285;Somasundaram|Meyappan|M|;Nowak|Michael M|MM|;Ravakhah|Keyvan|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-226094",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "11(1)",
"journal": "BMJ case reports",
"keywords": "gastrointestinal surgery; obesity (nutrition); pregnancy; small intestine; stomach and duodenum",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D015746:Abdominal Pain; D000328:Adult; D005260:Female; D015390:Gastric Bypass; D005748:Gastric Fundus; D017219:Gastric Outlet Obstruction; D006801:Humans; D007443:Intussusception; D007511:Ischemia; D007579:Jejunal Diseases; D007583:Jejunum; D010535:Laparoscopy; D000067491:Near Miss, Healthcare; D011183:Postoperative Complications; D011247:Pregnancy; D011248:Pregnancy Complications; D011261:Pregnancy Trimester, First",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30567094",
"pubdate": "2018-11-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18294922;4053880;24960726;19161938;16234497;25406213;517504;17894160;22991661;18069069;15306679;23477956;17705885;29026515;23741115",
"title": "A near-fatal case of intussusception and ischaemic perforation of stomach in first-trimester pregnancy: eight years after laparoscopic Roux-en-Y gastric bypass.",
"title_normalized": "a near fatal case of intussusception and ischaemic perforation of stomach in first trimester pregnancy eight years after laparoscopic roux en y gastric bypass"
} | [
{
"companynumb": "PHHY2019US000567",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PANTOPRAZOLE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "We present a patient with acute myeloid leukemia and prolonged, severe neutropenia who developed fulminant Clostridioides difficile infection refractory to medical therapy and was high-risk for surgical intervention. He was treated with fecal microbiota transplantation (FMT) for life-saving cure. The patient had subsequent clinical improvement, however, developed multidrug-resistant Pseudomonas aeruginosa bacteremia 2 days post-procedure. We describe subsequent investigation of this event that found this bacteremia was not related to the donor stool administered during FMT. This case adds to the literature that FMT could be considered in heavily immunocompromised patients with fulminant Clostridioides difficile infection where maximal medical therapy has been ineffective and surgery may carry an excessively high mortality risk.",
"affiliations": "Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Boston, MA, USA.;OpenBiome, Cambridge, MA, USA.;Harvard Medical School, Boston, MA, USA.;Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Boston, MA, USA.;Harvard Medical School, Boston, MA, USA.",
"authors": "Lee|Matthew S L|MSL|https://orcid.org/0000-0002-3186-2020;Ramakrishna|Bharat|B|;Moss|Alan C|AC|;Gold|Howard S|HS|;Branch-Elliman|Westyn|W|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13216",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "22(1)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "Clostridioides difficile infection; fecal microbiota transplantation; immunocompromised",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D016360:Clostridioides difficile; D003015:Clostridium Infections; D003967:Diarrhea; D000069467:Fecal Microbiota Transplantation; D006801:Humans; D016867:Immunocompromised Host; D015470:Leukemia, Myeloid, Acute; D008297:Male; D009503:Neutropenia; D011552:Pseudomonas Infections; D016896:Treatment Outcome",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13216",
"pmc": null,
"pmid": "31769569",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Successful treatment of fulminant Clostridioides difficile infection with emergent fecal microbiota transplantation in a patient with acute myeloid leukemia and prolonged, severe neutropenia.",
"title_normalized": "successful treatment of fulminant clostridioides difficile infection with emergent fecal microbiota transplantation in a patient with acute myeloid leukemia and prolonged severe neutropenia"
} | [
{
"companynumb": "US-TEVA-2020-US-1234139",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYTARABINE"
},
"drugadditional": "3",
... |
{
"abstract": "Central nervous system (CNS) involvement is a severe complication of BCR-ABL-positive leukemia after allogenic stem cell transplantation (alloSCT) associated with fatal outcome. Although second-generation tyrosine-kinase inhibitors (TKI) such as nilotinib have shown activity in systemic BCR-ABL(+) disease, little data exists on their penetration and efficacy within the CNS. Four patients (3 male, 1 female; age 15-49) with meningeal relapse after alloSCT and subsequent treatment with nilotinib were identified. A total of 17 cerebrospinal fluid (csf) and serum samples were assessed for nilotinib concentration and patient outcome was recorded. Nilotinib concentrations showed a low median csf/plasma ratio of 0.53% (range 0.23-1.5%), yet pronounced clinical efficacy was observed with long-lasting responses (>1 year) in three patients. Comparison with historical data showed a trend towards superior efficacy of nilotinib versus imatinib. Despite poor csf penetration, nilotinib showed significant clinical activity in CNS relapse of BCR-ABL(+) leukemias. As nilotinib has a high protein-binding affinity, the low-protein concentration in csf could translate into a relatively higher amount of free and therefore active nilotinib in csf as compared to blood, possibly explaining the observed efficacy. Thus, treatment with a 2nd generation TKI warrants further investigation and should be considered in cases of CNS relapse of BCR-ABL-positive leukemia after alloSCT.",
"affiliations": "Department of Hematology and Oncology, University Hospital Mannheim, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.;Department of Hematology and Oncology, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany ; Department of Internal Medicine, Klinikum Merseburg, Weiße Mauer 52, 06217 Merseburg, Germany.;Department of Hematology, Oncology and Tumor Immunology, Campus Benjamin Franklin, Charité Berlin, Hindenburgdamm 30, 12203 Berlin, Germany.;Department of Hematology, Oncology and Tumor Immunology, Campus Benjamin Franklin, Charité Berlin, Hindenburgdamm 30, 12203 Berlin, Germany.;Department of Hematology, Oncology and Tumor Immunology, Campus Benjamin Franklin, Charité Berlin, Hindenburgdamm 30, 12203 Berlin, Germany.;Department of Hematology and Oncology, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany.;Department of Hematology, Oncology and Tumor Immunology, Campus Benjamin Franklin, Charité Berlin, Hindenburgdamm 30, 12203 Berlin, Germany.;Department of Hematology, Oncology and Tumor Immunology, Campus Benjamin Franklin, Charité Berlin, Hindenburgdamm 30, 12203 Berlin, Germany.;Department of Hematology, Oncology and Tumor Immunology, Campus Benjamin Franklin, Charité Berlin, Hindenburgdamm 30, 12203 Berlin, Germany.;Department of Hematology and Oncology, University Hospital Mannheim, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.;Division of Pediatric Hematology/Oncology, Department of Pediatrics, Technische Universität München, Kölner Platz 1, 80804 München, Germany.;Division of Pediatric Hematology/Oncology, Department of Pediatrics, Technische Universität München, Kölner Platz 1, 80804 München, Germany.;Division of Pediatric Hematology/Oncology, Department of Pediatrics, Technische Universität München, Kölner Platz 1, 80804 München, Germany.",
"authors": "Reinwald|Mark|M|;Schleyer|Eberhard|E|;Kiewe|Philipp|P|;Blau|Igor Wolfgang|IW|;Burmeister|Thomas|T|;Pursche|Stefan|S|;Neumann|Martin|M|;Notter|Michael|M|;Thiel|Eckhard|E|;Hofmann|Wolf-Karsten|WK|;Kolb|Hans-Jochem|HJ|;Burdach|Stefan|S|;Bender|Hans-Ulrich|HU|",
"chemical_list": "C498826:4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl",
"country": "United States",
"delete": false,
"doi": "10.1155/2014/637059",
"fulltext": "\n==== Front\nBiomed Res IntBiomed Res IntBMRIBioMed Research International2314-61332314-6141Hindawi Publishing Corporation 10.1155/2014/637059Clinical StudyEfficacy and Pharmacologic Data of Second-Generation Tyrosine Kinase Inhibitor Nilotinib in BCR-ABL-Positive Leukemia Patients with Central Nervous System Relapse after Allogeneic Stem Cell Transplantation Reinwald Mark \n1\n*Schleyer Eberhard \n2\n\n3\nKiewe Philipp \n4\nBlau Igor Wolfgang \n4\nBurmeister Thomas \n4\nPursche Stefan \n2\nNeumann Martin \n4\nNotter Michael \n4\nThiel Eckhard \n4\nHofmann Wolf-Karsten \n1\nKolb Hans-Jochem \n5\nBurdach Stefan \n5\nBender Hans-Ulrich \n5\n1Department of Hematology and Oncology, University Hospital Mannheim, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany2Department of Hematology and Oncology, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany3Department of Internal Medicine, Klinikum Merseburg, Weiße Mauer 52, 06217 Merseburg, Germany4Department of Hematology, Oncology and Tumor Immunology, Campus Benjamin Franklin, Charité Berlin, Hindenburgdamm 30, 12203 Berlin, Germany5Division of Pediatric Hematology/Oncology, Department of Pediatrics, Technische Universität München, Kölner Platz 1, 80804 München, Germany*Mark Reinwald: mark.reinwald@medma.uni-heidelberg.deAcademic Editor: Carlo Visco\n\n2014 15 6 2014 2014 6370599 3 2014 21 5 2014 Copyright © 2014 Mark Reinwald et al.2014This 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.Central nervous system (CNS) involvement is a severe complication of BCR-ABL-positive leukemia after allogenic stem cell transplantation (alloSCT) associated with fatal outcome. Although second-generation tyrosine-kinase inhibitors (TKI) such as nilotinib have shown activity in systemic BCR-ABL+ disease, little data exists on their penetration and efficacy within the CNS. Four patients (3 male, 1 female; age 15–49) with meningeal relapse after alloSCT and subsequent treatment with nilotinib were identified. A total of 17 cerebrospinal fluid (csf) and serum samples were assessed for nilotinib concentration and patient outcome was recorded. Nilotinib concentrations showed a low median csf/plasma ratio of 0.53% (range 0.23–1.5%), yet pronounced clinical efficacy was observed with long-lasting responses (>1 year) in three patients. Comparison with historical data showed a trend towards superior efficacy of nilotinib versus imatinib. Despite poor csf penetration, nilotinib showed significant clinical activity in CNS relapse of BCR-ABL+ leukemias. As nilotinib has a high protein-binding affinity, the low-protein concentration in csf could translate into a relatively higher amount of free and therefore active nilotinib in csf as compared to blood, possibly explaining the observed efficacy. Thus, treatment with a 2nd generation TKI warrants further investigation and should be considered in cases of CNS relapse of BCR-ABL-positive leukemia after alloSCT.\n==== Body\n1. Introduction\nIn BCR-ABL-positive acute lymphoblastic leukemia (ALL) and advanced stages of chronic myeloid leukemia (CML; accelerated phase, blast crisis (BC)) central nervous system (CNS) involvement is a lethal complication, typically occurring late in the course of the disease, particularly after allogeneic stem cell transplantation (alloSCT). Imatinib was the first specific BCR-ABL tyrosine kinase inhibitor (TKI) to be approved for the treatment of BCR-ABL+ ALL and CML and has led to a major breakthrough in the treatment of these malignancies. Nonetheless, 15–20% of patients (pts) with BCR-ABL+ ALL or CML-BC develop CNS relapse during ongoing imatinib therapy [1]. This may possibly be attributed to poor CNS penetration and increased cellular resistance mechanisms against the drug such as p-glycoprotein mediated efflux. Standard treatment of CNS relapse is based on intrathecal (ith) and systemic application of cytostatic agents, and/or craniospinal irradiation [2]. Unfortunately, the majority of patients develop subsequent systemic relapse with a very poor outcome of usually less than three months [3] despite initial successful CNS clearance.\n\nSecond-generation TKIs such as dasatinib and nilotinib have been approved for the treatment of CML patients who are refractory or intolerant to imatinib. In vitro tests of these new TKIs show considerably higher activity in comparison with imatinib, with a 40-fold increased potency for nilotinib and a 325-fold for dasatinib [3].\n\nMoreover, nilotinib and dasatinib were able to overcome imatinib resistance caused by several BCR-ABL tyrosine kinase domain mutations. The potential of these second-generation TKIs in targeting BCR-ABL+ CNS disease however is not clear and warrants further investigation. Efficacy of dasatinib in BCR-ABL+ CNS leukemia has been demonstrated in an animal model and was furthermore observed in 11 patients. This study also analysed the csf/plasma ratios of dasatinib in 3 patients, showing low levels of dasatinib in csf. For nilotinib, no data on csf penetration and clinical efficacy against CNS relapse of BCR-ABL+ leukemia is available so far. Specifically, in pediatric patients very little data has been published on treatment with second generation TKIs at all.\n\nWe therefore investigated the clinical activity and csf penetration of nilotinib in four patients with CNS relapse of BCR-ABL+ aggressive leukemia after alloSCT.\n\n2. Patients and Methods\n2.1. Patients\nFour patients (3 BCR-ABL+ ALL, 1 CML-BC; 3 male, 1 female, age 15–49 years) in two centers (Berlin, Munich) treated with nilotinib for CNS relapse after alloSCT were identified. Previous therapeutic regimens include imatinib and dasatinib TKI-therapy for systemic relapse in patients 1–3 while patient 4 had received dasatinib in combination with intrathecal therapy and radiotherapy for meningeal relapse. Investigation of nilotinib csf concentration was performed within a noninterventional diagnostic study, approved by the local ethics committee of the Charite Berlin, Germany (EA4/023/08). Informed consent was obtained from all patients or their legal representatives according to Good Clinical Practice guidelines and in concordance with the Declaration of Helsinki.\n\n2.2. Treatment Schedules\nNilotinib 400 mg bid was administered to patients 1–3 while the pediatric patient 4 received an age-adjusted nilotinib dose of 150 mg bid. All patients received additional concomitant antineoplastic treatment (Table 1). Nilotinib was given until obvious disease progression (in patient 1) or detection of the T315I mutation and progression (in patients 2 and 3). Patient 4 is continuing nilotinib treatment at the time of paper submission.\n\n2.3. Evaluation of Efficacy\nWhen CNS relapse was suspected, each patient received CNS diagnostics consisting of a cerebral and a spinal magnetic resonance imaging (MRI) scan, csf analysis by lumbar puncture with analysis consisting of cytology including csf differential cell analysis, csf clinical chemistry (glucose, lactate, albumin, and total protein), csf immunophenotyping, chimerism analysis of the csf, and molecular testing for BCR-ABL using PCR for detection of minimal residual disease (MRD).\n\nFurther lumbar puncture for assessment of leukemia and nilotinib concentration in csf was performed as clinically indicated. Blood samples were drawn concurrently to calculate csf/plasma ratios for nilotinib. Response assessment was based on analysis of cell count, cytomorphology, immunophenotyping, BCR-ABL quantitative RT-PCR (qPCR) [4], and chimerism analysis [5] in csf. Nilotinib concentration was measured as described previously [6]. Additional cerebral/spinal imaging was performed as clinically indicated.\n\nA csf complete remission (CR) was defined as negative csf cytology, normal csf cell count, immunophenotyping, and cytogenetic and chimerism analysis; a csf partial remission (PR) was defined as negative cytology and csf cell count, but detection of residual disease by either csf immunophenotyping, cytogenetics, or chimerism analysis. Csf minimal residual disease (MRD) negativity was defined as a CR without detection of BCR-ABL amplicons in csf PCR.\n\n3. Results\n3.1. Clinical Data (Table 1)\nAll four patients experienced CNS relapse after alloSCT. Clinical signs and symptoms that lead to the suspicion of CNS relapse consisted of headache (patients 1–4), facial palsy (patients 1–3), vomiting (patients 1 and 4), and seizures (patient 4). In addition, MRI scans and csf analysis showed the following results for these patients, confirming the diagnosis.\n\nInitial diagnosis of CNS relapse was established by positive cytology, detection of BCR-ABL transcripts, and decrease in donor chimerism in csf with concurrent radiological findings (meningeal enhancement in MRI) in patient 1. In patient 2, a positive csf cytology and immunophenotyping showing lymphatic blasts, a decrease in donor-chimerism, and positivity for BCR-ABL qPCR in csf could be found serologically while MRI scans showed a slight enhancement and an increase in contrast agent uptake. Patient 3 initially had an unremarkable MRI; however in the csf BCR-ABL transcripts could be repeatedly and unequivocally detected, while csf cytology, cell count, chimerism analysis, and immunophenotyping were negative. Patient 4 showed positive radiomorphological results (meningeal enhancement), leukemic blasts in csf cytology, positive immunophenotyping, and BCR-ABL qPCR in csf.\n\nMedian time from alloSCT to first CNS relapse was 54 months (range 17–132 months). Median duration of nilotinib treatment was 541 days (range 99–1786 days). Nilotinib treatment was discontinued in patient 1 on day 431 because of progressive disease (intracerebral chloromas), in patient 2 on day 99 because of detection of T315I mutation and systemic disease progression. Both patients died of progressive leukemia. Patient 3, while on nilotinib monotherapy for 847 days, experienced meningeal progression and periodically received additional intrathecal chemotherapy and rituximab from thereon until systemic progression with detection of T315I and F317L mutation. Subsequently TKI treatment was switched after 1786 days of nilotinib treatment to ponatinib. The patient is alive at the time of the paper writing and continuing ponatinib treatment. Patient 4 is currently in remission and continuing nilotinib treatment.\n\n3.2. Assessment of Efficacy\nPatient 1 achieved a complete remission (CR) with resolution of neurological symptoms, normalization of cytology/immunophenotyping, and restoration of csf donor chimerism; however CNS minimal residual disease (MRD) defined by csf BCR-ABL qPCR positivity persisted. Patient 2 had stable csf cell count and stable csf BCR-ABL transcript levels with minor clinical improvement. Patient 3 showed considerable improvement in symptoms and achieved csf MRD negativity on days 191 and 224 after start of nilotinib treatment. However, minimal amounts of csf BCR-ABL transcripts intermittently reappeared, while csf cytology and chimerism remained negative. When meningeal progression with positive cytology was detected 847 days after start of nilotinib monotherapy intrathecal chemotherapy was added to nilotinib, resulting in intermittent csf MRD negativity until systemic detection of T315I and F317L mutation on day 1786 of nilotinib treatment. Patient 4 achieved a CR in bone marrow and CSF and MRD negativity after three months of treatment with nilotinib and concomitant intrathecal chemotherapy. This patient is continuing nilotinib treatment in complete remission.\n\nIn summary, long-lasting responses of more than one year were observed. Patients 1, 3, and 4 had sustained clinical improvement and csf responses while on nilotinib for 431 days (patient 1), 1786 days (patient 3), and >650 days (patient 4), respectively. Both patient 3 and patient 4 are alive; patient 4 is continuing nilotinib treatment.\n\n3.3. Comparison of Nilotinib and Imatinib for Duration of Response\nMedian time to progression (TTP) leading to discontinuation in the nilotinib-treated patients was 541 days with 1 of 4 patients still in remission. Compared with historical data published for imatinib [1] by Pfeifer et al. there was a trend towards an increased TTP for nilotinib treatment (P > 0.17, Figure 1).\n\n3.4. CSF Pharmacology (Table 2)\nIn summary 17 csf and corresponding serum samples from 4 patients were assessed for csf penetration of nilotinib. Median csf concentration of nilotinib in patient 1 was 4 ng/mL (n = 5, median csf/plasma ratio 0.26%; range 0.23–0.47%), 13 ng/mL in patient 2 (n = 3, median csf/plasma ratio 0.83%; range 0.54–1.52%), 7 ng/mL in patient 3 (n = 4, median csf/plasma ratio 0.63%; range 0.5–6.5%), and 2.7 ng/mL (n = 5, median csf/plasma ratio 0.42%; range 0.26–0.58%) in patient 4. Additionally, a ratio of csf free (unbound) nilotinib and free plasma nilotinib was calculated based on the published nilotinib protein binding of 98% (Table 2).\n\n4. Discussion\nIn CNS relapse of BCR-ABL+ leukemia treatment options are limited and survival is poor, especially after alloSCT. The influence of imatinib in treatment and prevention of CNS manifestations seems to be limited, probably due to poor CNS penetration and insufficient antileukemic activity.\n\nTo our knowledge, this is the first report on nilotinib csf pharmacology and efficacy in patients with CNS manifestations of BCR-ABL+ leukemia after alloSCT. We acknowledge that one limitation of our study is the small number of patients (n = 4) with the pediatric patient (patient 4) representing a single case. However, CNS relapse of BCR-ABL+ leukemia after allogeneic stem cell transplantation is a rare event with lethal consequences, impeding observation of larger patient cohorts. The number of patients with available pharmacological data (n = 4) is similar to that of patients for dasatinib by Porkka et al. (n = 3) [7] and the report by Pfeifer et al. for imatinib (n = 7) [1].\n\nCsf nilotinib concentrations were within the range of those reported for imatinib [8]. For dasatinib, equally low csf levels were reported by Porrka et al. [7] suggesting that these TKIs have only minimal ability to cross the blood-brain barrier. In dasatinib-treated patients with CNS relapse of BCR-ABL+ leukemia the authors found limited csf penetration with low csf/plasma ratios for all 3 patients evaluated. Complete responses were observed in 7/11 patients; the majority received concomitant antileukemic treatment (dexamethasone and intrathecal chemotherapy) but csf MRD analysis for response evaluation was not reported. Additional animal experiments showed superior survival of mice inoculated with CNS leukemia and treated with dasatinib compared to imatinib in the control group. In summary, these combined findings suggest improved efficacy of dasatinib over imatinib in targeting CNS BCR-ABL+ leukemia despite poor csf penetration.\n\nOur experience of nilotinib treatment in BCR-ABL+-CNS leukemia patients suggests similar clinical activity with sustained responses for more than 1 year (patients 1, 3, and 4) despite low csf drug levels.\n\nIn theory, the superior affinity of 2nd generation TKIs to the BCR-ABL-kinase domain could explain these supposedly contradictory findings. The profoundly protein-bound drugs nilotinib and dasatinib have been shown to be active even at subnanomolar concentrations [3]; in vitro data suggest considerably higher activity compared to imatinib and there might not be a strict dose-response relationship. As csf is a low protein compartment TKI and is more likely to exist as protein-unbound and therefore as active drug. The ratio of free (not-protein-bound) nilotinib in csf relative to free drug in plasma could therefore be increased 5–30 folds compared to the csf/plasma ratio of total nilotinib (Table 2). As meningeal intracellular concentrations could approach systemic intracellular levels, inhibitory concentrations previously published for plasma might thus not reflect those needed for inhibition of bcr-abl in csf. Using patients' csf and plasma protein concentration and an estimation of the amount of free (active) nilotinib the ratio of free to protein-bound nilotinib in the low-protein compartment csf is drastically higher (42–82 times) compared to the high-protein compartment serum. Thus, total nilotinib csf concentrations not reaching the inhibitory concentrations required for systemic activity might nevertheless provide sufficient clinical efficacy in the low-protein compartment csf. This could explain the responses we observed for nilotinib and the results Porrka et al. reported for dasatinib [7]; however as we cannot prove it, further studies should address that issue in more detail.\n\nRecent publications for the TKI erlotinib suggest a clinical benefit in several lung cancer patients with leptomeningeal metastases treated with erlotinib despite poor csf penetration [9], supporting the theory that published inhibitory concentrations for plasma might not reflect those needed in csf.\n\nThe long-lasting responses observed in patients 1, 3, and 4 during nilotinib-based therapy clearly suggest an effect of nilotinib and are in stark contrast to the responses published for conventional chemotherapy in relapsed CNS BCR-ABL+ leukemia with a poor median overall survival of 2.9 months [10]. Although the addition of 1st generation TKI imatinib does seem to have some effect [11], a direct comparison should be interpreted with care. In our study all patients had developed CNS relapse during imatinib or even dasatinib treatment, and still the majority of patients responded to nilotinib for more than one year. Moreover, the median time to progression in the Pfeifer study was shorter than that observed for nilotinib in our cohort.\n\nWhile responses of BCR-ABL+ ALL to nilotinib monotherapy are rare [12], an early systemic relapse detected only at the molecular level can be successfully managed with TKI-therapy alone [13, 14]. This might explain the observed efficacy of nilotinib as a single agent for more than 2 years even without concomitant antineoplastic treatment in patient 3, whose initial CNS relapse diagnosis was exclusively based on molecular detection of BCR-ABL in csf suggesting a rather small CNS leukemia burden. Furthermore, even open relapse of BCR-ABL+ ALL after alloSCT was successfully treated with addition of nilotinib and donor lymphocyte infusions underlining the efficacy of second-generation TKIs in addition to conventional therapy in this clinical scenario [15].\n\nEvaluating the exact influence of TKI-therapy in patients with BCR-ABL+ CNS leukemia is difficult as these patients receive a combined treatment strategy consisting of TKI plus other therapeutic measures in routine clinical practice. Moreover, response to TKI-based therapy is additionally influenced by existing or evolving BCR-ABL mutations. Patient 2, who initially responded to a combination of nilotinib and intrathecal chemotherapy, was later found to harbor the T315I mutation. Therefore the observed response was probably exclusively related to concomitant non-TKI treatment as this mutation confers resistance to nilotinib. Compared to the other three patients, however, treatment response in this patient was short lived (99 days versus 431+ days) underlining the necessity of effective BCR-ABL suppression. The pronounced influence of mutation status is also highlighted by the clinical course of the other patients. Patient 1 experienced meningeal progression during dasatinib and INNO406 treatment, both drugs supposedly penetrating into the CNS [7, 11]. Despite progression under these treatment regimens, an excellent response to nilotinib was observed. In fact, the V299L mutation was later detected in this patient and might explain this clinical course, as this mutation confers a poorer efficacy for dasatinib [16]. The outcome of patient 3, who developed a systemic relapse with T315I and F317L mutations also demonstrates the possibility of evolving resistant mutations under constant selective pressure of long-lasting TKI treatment. Based on our data, switching therapy to a different 2nd generation TKI in BCR-ABL+ CNS disease should be strongly considered if the patient fails to respond, a strategy that has been proven effective in systemic treatment [17].\n\n5. Conclusions\nIn summary, our findings suggest relevant activity of nilotinib in BCR-ABL+ CNS relapse after alloSCT despite limited csf concentrations which may be attributed to the low-protein environment of csf. As treatment options are limited for these heavily pretreated patients with poor prognosis, clinical trials should further elucidate the role of different TKIs in this clinical setting. In light of our data, the addition of a 2nd generation TKI should be considered in BCR-ABL+ meningeal relapse after allogeneic stem cell transplantation.\n\nAcknowledgments\nThe authors thank Dr. O. Blau for help in chimerism analysis, Dr. Susanne Ganepola for helpful discussion, Dr. Daniel Nowak for language proofreading, and the patients for participating in the study. Mark Reinwald received a travel grant from Novartis in 2008.\n\nConflict of Interests\nThe authors declare that they have no conflict of interests.\n\nFigure 1 Comparison of nilotinib with imatinib. Kaplan-Meier plot of patients with Ph+ CNS relapse experiencing progressive disease leading to nilotinib discontinuation while on TKI treatment. Data for imatinib was extracted from the historical Pfeifer cohort (Pfeifer et al., [1]) and compared with data from the patients treated with nilotinib in this trial. By trend, patients treated with nilotinib had a longer time to progression, although this was not statistically significant (Chi-square-test 1.9, P = 0.17).\n\nTable 1 Patient characteristics and clinical data.\n\nPatient\tAge [year]\tUnderlying disease\tTherapy prior to CNS relapse\tTime of CNS relapse [months after diagnosis]\tSymptoms at CNS relapse\tDiagnosis of CNS relapse \tConcomitant anti leukemic treatment for CNS relapse [d]¥\n\tBCR-ABL mutation detected\tDuration of nilotinib monotherapy [d]\tBest response in CSF\tDuration of nilotinib administration (mono + concomitant therapy)\tType of relapse/progression\t\n1\t38\tCML-BC\tAlloSCT, DLIs, imatinib, and dasatinib\t132\tHeadache, vertigo, and facial palsy\tClinical signs and symptoms, csf cytology, csf immunophenotyping, csf BCR-ABL qPCR, and decrease in csf donor chimerism\tIntrathecal triple therapy∗[d−100, d−98, d−95, d−91],\nINNO406 360 mg tid, [d−66 to d−53], \nDonor lymphocytes [d−28, d−23, d−14, d−7, d0, d+7, d+14, d+25], \n2000 mg/m2 Cytarabin i.v. [d−35 to d−34]\tV299L\t406\tCR with MRD positivity\t431\tSystemic (intracerebral chloromas)\t\n\n\n\t\n2\t19\tc-ALL\tGMALL-protocol, alloSCT, and dasatinib\t17\tHeadache and anisocoria\tClinical signs and symptoms, csf cytology, csf BCR-ABL qPCR, and decrease in csf donor chimerism\tIntrathecal triple therapy∗ [d+10, d+29, d+52, d+78],\n375 mg/m2 rituximab i.v. [d+30, d+38, d+53]\n2 mg vincristine i.v. [d+29, d+56, d+78]\n4 mg dexamethasone bid. [d+52 to d+83]\tT315I\tNA£\n\tSD\t99\tSystemic (bone marrow)\t\n\n\n\t\n3\t49\tc-ALL\tGMALL-protocol, alloSCT, and dasatinib\t28\tFacial palsy headache\tClinical signs and symptoms, csf BCR-ABL qPCR, and positive csf cytology on 2nd relapse\tIntrathecal triple therapy∗ [d+848, d+851, d+855, d+858, d+864, d+871, d+878, d+892, d+1310, d+1421, d+1531, d+1544, d+1547, d+1551]\nRituximab 20 mg i.th [d+1320, d+1334, d+1341, d+1356, d+1369, d+1382, d+1554, d+1560, d+1567, d+1618, d+1671, d+1740]\tT315I, F317L\t847\tMRD negativity\t1786\tSystemic (peritoneum)\t\n\n\n\t\n4\t15\tc-ALL\tALL-BFM2000, alloSCT. DLI, Ifn, GM-CSF, imatinib, and ALLRez2002\t80\tHeadache, vomiting, and seizures\tClinical signs and symptoms, csf BCR-ABL, and BM BCR-ABL\tDasatinib [d−60–182]\nRadiotherapy [d−32–45]\nIntrathecal triple therapy€ [d−60]\tNone\tNA£\n\tMRD negativity\t650+\tIn remission\t\nPR = partial response, SD = stable disease, CR = complete remission, NA = Not applicable, c-ALL = common ALL, DLI = donor lymphocyte infusion, Ifn = Interferon; GMALL-Protocol: Polychemotherapy induction, consolidation and postremision protocol of the german ALL study group for adults; BFM2000: Polychemotherapy induction, consolidation and postremision protocol of the german ALL study group for pediatric patients; i.v.: intravenous; i.th = intrathecal, \n\n\n¥relative to start of nilotinib treatment; ∗consisting of 15 mg MTX, 40 mg Cytarabin and 4 mg dexamethasone; €consisting of 12 mg MTX, 30 mg Cytarabin and 10 mg prednisone at 4-week intervals for one year and 6-week intervals after one year; £nilotinib applied with periodic concomitant anti-leukemic treatment.\n\nTable 2 Pharmacokinetic data. \n\nPatient\tNilotinib csf concentration [ng/mL], (range)\tNilotinib plasma concentration [ng/mL], (range)\tNilotinib csf/plasma ratio [%], (range)\tCsf protein concentration [g/L]\tPlasma protein concentration [g/L]\t\nFree nilotinib in plasma concentration [ng/mL]∗\t Nilotinib csf concentration/free nilotinib plasma concentration [%,]∗\t\n1\t4 (3.6–15)\t1640 (1544–1736)\t0.26 (0.23–0.84)\t0.49 (0.31–0.75)\t76 (69–77)\t32.8\t12\t\n2\t13 (4–18)\t955 (734–1176)\t0.83 (0.54–1.52)\t0.40 (0.34–0.89)\t65 (56–69)\t19.1\t68\t\n3\t7 (6–9)\t1159 (1082–1237)\t0.63 (0.5–0.79)\t0.50 (0.28–0.67)\t59 (56–67)\t23.2\t30\t\n4\t2.7 (1.5–4.8)\t682 (430–1034)\t0.42 (0.26–0.58)\t0.23 (0.19–0.31)\t71 (62–78)\t13.6\t20\t\nAll values are given as median.\n\n\n∗Unbound (=free) nilotinib concentration calculated by using published nilotinib protein binding of 98%.\n==== Refs\n1 Pfeifer H Wassmann B Hofmann W-K Risk and prognosis of central nervous system leukemia in patients with Philadelphia chromosome-positive acute leukemias treated with imatinib mesylate Clinical Cancer Research 2003 9 13 4674 4681 2-s2.0-10744223495 14581336 \n2 Sanders KE Ha CS Cortes-Franco JE Koller CA Kantarjian HM Cox JD The role of craniospinal irradiation in adults with a central nervous system recurrence of leukemia Cancer 2004 100 10 2176 2180 2-s2.0-2342501796 15139061 \n3 O’Hare T Walters DK Stoffregen EP In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants Cancer Research 2005 65 11 4500 4505 2-s2.0-21144451094 15930265 \n4 Gabert J Beillard E van der Velden VHJ Standardization and quality control studies of “real time” quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia—a Europe Against Cancer Program Leukemia 2003 17 12 2318 2357 2-s2.0-9144222001 14562125 \n5 Thiede C Bornhäuser M Oelschlägel U Sequential monitoring of chimerism and detection of minimal residual disease after allogeneic blood stem cell transplantation (BSCT) using multiplex PCR amplification of short tandem repeat-markers Leukemia 2001 15 2 293 302 2-s2.0-17744376761 11236950 \n6 Pursche S Ottmann OG Ehninger G Schleyer E High-performance liquid chromatography method with ultraviolet detection for the quantification of the BCR-ABL inhibitor nilotinib (AMN107) in plasma, urine, culture medium and cell preparations Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences 2007 852 1-2 208 216 2-s2.0-34249667739 17291840 \n7 Porkka K Koskenvesa P Lundán T Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system philadelphia chromosome positive leukemia Blood 2008 112 4 1005 1012 2-s2.0-51649111035 18477770 \n8 Takayama N Sato N O’Brien SG Ikeda Y Okamoto S-I Imatinib mesylate has limited activity against the central nervous system involvement of Philadelphia chromosome-positive acute lymphoblastic leukaemia due to poor penetration into cerebrospinal fluid British Journal of Haematology 2002 119 1 106 108 2-s2.0-0036399992 12358909 \n9 Togashi Y Masago K Masuda S Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer Cancer Chemotherapy and Pharmacology 2012 70 3 399 405 2-s2.0-84866364723 22806307 \n10 Reman O Pigneux A Huguet F Central nervous system involvement in adult acute lymphoblastic leukemia at diagnosis and/or at first relapse: results from the GET-LALA group Leukemia Research 2008 32 11 1741 1750 2-s2.0-47249115216 18508120 \n11 Yokota A Kimura S Masuda S INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph+ leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity Blood 2007 109 1 306 314 2-s2.0-33846018356 16954504 \n12 Kantarjian H Giles F Wunderle L Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL The New England Journal of Medicine 2006 354 24 2542 2551 2-s2.0-33745086350 16775235 \n13 Wassmann B Pfeifer H Stadler M Early molecular response to posttransplantation imatinib determines outcome in MRD+ Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) Blood 2005 106 2 458 463 2-s2.0-22144460555 15817679 \n14 Merante S Colombo AA Calatroni S Nilotinib restores long-term full-donor chimerism in Ph-positive acute lymphoblastic leukemia relapsed after allogeneic transplantation Bone Marrow Transplantation 2009 44 4 263 264 2-s2.0-69749124900 19204710 \n15 Tiribelli M Sperotto A Candoni A Simeone E Buttignol S Fanin R Nilotinib and donor lymphocyte infusion in the treatment of Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) relapsing after allogeneic stem cell transplantation and resistant to imatinib Leukemia Research 2009 33 1 174 177 2-s2.0-55049088837 18471874 \n16 Jabbour E Hochhaus A Cortes J La Rosée P Kantarjian HM Choosing the best treatment strategy for chronic myeloid leukemia patients resistant to imatinib: weighing the efficacy and safety of individual drugs with BCR-ABL mutations and patient history Leukemia 2010 24 1 6 12 2-s2.0-74149095067 19798095 \n17 Garg RJ Kantarjian H O’Brien S The use of nilotinib or dasatinib after failure to 2 prior tyrosine kinase inhibitors: long-term follow-up Blood 2009 114 20 4361 4368 2-s2.0-73349100015 19729517\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2014()",
"journal": "BioMed research international",
"keywords": null,
"medline_ta": "Biomed Res Int",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D001549:Benzamides; D002490:Central Nervous System; D005260:Female; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D000068877:Imatinib Mesylate; D053208:Kaplan-Meier Estimate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010879:Piperazines; D011743:Pyrimidines; D033581:Stem Cell Transplantation; D014184:Transplantation, Homologous",
"nlm_unique_id": "101600173",
"other_id": null,
"pages": "637059",
"pmc": null,
"pmid": "25025064",
"pubdate": "2014",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": "18477770;18471874;16954504;11236950;15817679;15139061;22806307;12358909;16775235;14562125;19729517;19798095;14581336;15930265;19204710;18508120;17291840",
"title": "Efficacy and pharmacologic data of second-generation tyrosine kinase inhibitor nilotinib in BCR-ABL-positive leukemia patients with central nervous system relapse after allogeneic stem cell transplantation.",
"title_normalized": "efficacy and pharmacologic data of second generation tyrosine kinase inhibitor nilotinib in bcr abl positive leukemia patients with central nervous system relapse after allogeneic stem cell transplantation"
} | [
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"companynumb": "PHHY2014DE093136",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYTARABINE"
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"drugadditional": null,
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{
"abstract": "Accurate estimation of conception is critical in the assessment of the effects of drugs used during pregnancy or to prevent pregnancy. In a novel application, we studied the effectiveness of oral contraceptives (OCs), where misclassification of conception relative to OC exposure may obscure effect estimates.\n\n\n\nWe studied OC failure, in a large claims database, among women who used antiepileptic drugs with metabolizing enzyme-inducing properties (carbamazepine or oxcarbazepine), which reduce OC's effectiveness or enzyme-neutral properties (lamotrigine or levetiracetam), with no expected impact on OC effectiveness. We compared conception rates in women 12-48 years of age concomitantly using OCs and enzyme-inducing drugs with rates in concomitant users of OCs and enzyme-neutral drugs. We measured conception with a validated algorithm that estimates gestational age based on pregnancy endpoints. We estimated relative and attributable risk using generalized estimating equation models after standardized mortality ratio weighting.\n\n\n\nWe identified 89,777 concomitant use episodes with adjusted contraceptive failure rates of 1.6 (95% confidence interval (CI) = 1.4, 1.8) per 100 person-years among users of enzyme-neutral drugs and 18,964 episodes with a rate of 2.3 (1.9, 2.8) among users of enzyme-inducing drugs. The relative risk of conception for enzyme-inducing group was 1.4 (1.1, 1.8), and the rate difference was 0.7 (0.2, 1.2).\n\n\n\nOCs in combination with antiepileptic drugs that interact with metabolic enzymes were associated with increased contraceptive failure rates. Measurement of conception in claims data had adequate accuracy to uncover a strong drug-drug interaction, offering promise for broader application in comparative effectiveness studies on hormonal contraceptives to inform clinical and regulatory decisionmaking.",
"affiliations": "From the Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, FL.;From the Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, FL.;From the Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, FL.;From the Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, FL.;From the Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, FL.;Department of Pharmaceutics, College of Pharmacy, University of Florida, FL.;From the Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, FL.;Department of Pharmaceutics, College of Pharmacy, University of Florida, FL.;From the Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, FL.",
"authors": "Sarayani|Amir|A|;Brown|Joshua D|JD|;Goodin|Amie J|AJ|;Squires|Patrick|P|;Pham|Phuong|P|;Cicali|Brian|B|;Henriksen|Carl|C|;Schmidt|Stephan|S|;Winterstein|Almut G|AG|",
"chemical_list": "D000927:Anticonvulsants; D003276:Contraceptives, Oral; D004364:Pharmaceutical Preparations",
"country": "United States",
"delete": false,
"doi": "10.1097/EDE.0000000000001302",
"fulltext": "\n==== Front\nEpidemiology\nEpidemiology\nEDE\nEpidemiology (Cambridge, Mass.)\n1044-3983 1531-5487 Lippincott Williams & Wilkins Hagerstown, MD \n\n33196560\n00014\n10.1097/EDE.0000000000001302\nOriginal Article\nA Pharmacoepidemiologic Approach to Evaluate Real-world Effectiveness of Hormonal Contraceptives in the Presence of Drug–drug Interactions\nSarayani Amir ab Brown Joshua D. ab Goodin Amie J. ab Squires Patrick ab Pham Phuong ab Cicali Brian c Henriksen Carl a Schmidt Stephan cd Winterstein Almut G. ab From the a Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, FL\nb Center for Drug Evaluation and Safety, University of Florida, FL\nc Department of Pharmaceutics, College of Pharmacy, University of Florida, FL\nd Center for Pharmacometrics and Systems Pharmacology, University of Florida, FL.\nCorrespondence: Almut G. Winterstein, Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, 1225 Center Drive, HPNP 3320 Building, Gainesville, FL 32610. E-mail: almut@cop.ufl.edu\n16 11 2020 \n3 2021 \n32 2 268 276\n05 5 2020 02 11 2020 Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.2020This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background:\nAccurate estimation of conception is critical in the assessment of the effects of drugs used during pregnancy or to prevent pregnancy. In a novel application, we studied the effectiveness of oral contraceptives (OCs), where misclassification of conception relative to OC exposure may obscure effect estimates.\n\nMethods:\nWe studied OC failure, in a large claims database, among women who used antiepileptic drugs with metabolizing enzyme-inducing properties (carbamazepine or oxcarbazepine), which reduce OC’s effectiveness or enzyme-neutral properties (lamotrigine or levetiracetam), with no expected impact on OC effectiveness. We compared conception rates in women 12–48 years of age concomitantly using OCs and enzyme-inducing drugs with rates in concomitant users of OCs and enzyme-neutral drugs. We measured conception with a validated algorithm that estimates gestational age based on pregnancy endpoints. We estimated relative and attributable risk using generalized estimating equation models after standardized mortality ratio weighting.\n\nResults:\nWe identified 89,777 concomitant use episodes with adjusted contraceptive failure rates of 1.6 (95% confidence interval (CI) = 1.4, 1.8) per 100 person–years among users of enzyme-neutral drugs and 18,964 episodes with a rate of 2.3 (1.9, 2.8) among users of enzyme-inducing drugs. The relative risk of conception for enzyme-inducing group was 1.4 (1.1, 1.8), and the rate difference was 0.7 (0.2, 1.2).\n\nConclusions:\nOCs in combination with antiepileptic drugs that interact with metabolic enzymes were associated with increased contraceptive failure rates. Measurement of conception in claims data had adequate accuracy to uncover a strong drug–drug interaction, offering promise for broader application in comparative effectiveness studies on hormonal contraceptives to inform clinical and regulatory decisionmaking.\n\nAnticonvulsantBipolar disorderComparative effectivenessContraceptionCYP3A4EpilepsyOPEN-ACCESSTRUE\n==== Body\nObservational study designs employing real-world data are commonly used to evaluate the safety and effectiveness of medications during pregnancy.1,2 To ensure accurate timing of drug exposure, pregnancy episodes are usually determined via a specific pregnancy endpoint, estimation of gestational age at the time of the endpoint, and imputation of the pregnancy start date.3–5 Although the International Classification of Disease (ICD) coding offers detail on gestational age at delivery, the codes are not consistently applied to medical encounter claims, thus leaving some uncertainty about the exact date of conception. Such inaccuracies are more pronounced for preterm deliveries and other adverse pregnancy endpoints such as stillbirths and abortions.6,7 Inappropriate timing of conception will in turn result in misclassification of drug exposure, and introduce bias. Misclassification bias will be most pronounced if the exposure window to be studied is close to conception (such as when evaluating effects of first-trimester exposure on the risk for malformation), or exposure pattern varies over time.8 It will be even more prominent in scenarios where the pregnancy was not intended or when studying drugs with safety concerns regarding use during pregnancy, and thus exposure is terminated as soon as pregnancy is discovered, leading to only a short period of fetal exposure during pregnancy.\n\nAnother research area where accurate timing of conception is critical is in the evaluation of contraceptive effectiveness. Contraceptive failure is operationalized as conception during exposure to the contraceptive agent, and if such failure occurs, the contraceptive use will be discontinued as soon as pregnancy is discovered. Delayed conception estimates may inaccurately conclude that the contraceptive was effective. On the other hand, estimates that time conception too early may conclude that the contraceptive failed even though it may have been discontinued because intentions to prevent pregnancy had changed. Thus, even small errors of conception estimation of only a few weeks, which would be expected for some live births and to a larger extent for nonlive pregnancies, may yield claims data unusable to evaluate the real-world effectiveness of contraceptives. In the previous study, we developed a pregnancy identification algorithm based on several validation studies6,7 to evaluate the effectiveness of regulatory requirements designed to prevent maternal exposure to teratogenic medications.9 We have recently expanded the algorithm to incorporate diagnosis and procedure codes from the ICD-10. In light of the above-described concerns about conception timing, we aimed to investigate whether pregnancy identification algorithm can accurately identify contraception failure. We chose a clinical scenario where a well-documented drug–drug interaction modifies the failure rate of hormonal contraceptives. In this scenario, possible misclassifications of exposure or outcome could obscure causal inferences when evaluating the drug–drug interaction. However, if shown to be sensitive to detect the drug–drug interaction, this approach would offer opportunities to study a broad range of clinical risk factors for unintended pregnancy using real-world data, including interactions involving hormonal contraceptives, and thus advance pharmacoepidemiologic methods.\n\nMETHODS\nStudy Design and Data Source\nWe conducted a cohort study using the IBM MarketScan Commercial Claims Databases (2005–2017). This database includes data on inpatient and outpatient medical encounters and pharmacy dispensing claims for a large sample of the privately insured population in the United States. The beneficiaries have encrypted identifiers in the database, which allows for longitudinal follow-up. This database is certified as de-identified data, and the present study was approved as exempt by the Institutional Review Board at the University of Florida (IRB approval number: 201801093).\n\nClinical Scenario\nCarbamazepine and oxcarbazepine are among the first-generation antiepileptic drugs with several approved and off-label indications, including epilepsy and bipolar disorder.10 Both drugs are inducers of Cytochrome P450 3A4 (CYP3A4), with well-documented evidence for reduction of estrogen/progestin plasma levels of oral contraceptives (OCs), and ovulation pattern disruption.11–13 The enzyme induction effect of carbamazepine and oxcarbazepine is comparable and may result in approximately 50% change in area under the curve (AUC) of OC products. 12,14 Therefore, and because both antiepileptic drugs are associated with neural tube defects, clinical guidelines recommend against the use of OCs when using carbamazepine or oxcarbazepine to avoid unintended pregnancy.15,16 In contrast, newer antiepileptic drugs, including lamotrigine and levetiracetam, have minimal effect on CYP3A4 and are not expected to reduce OC efficacy.17,18 In the present study, we aimed to compare the rate of OC failure in two cohorts of OC users who had concomitant use of either a CYP3A4-inducer (i.e., carbamazepine or oxcarbazepine) or a CYP3A4-neutral (i.e., lamotrigine or levetiracetam) antiepileptic drugs.\n\nStudy Cohorts\nWe identified female patients of childbearing age (12–48 years old) who had at least one pharmacy claim for a combined OC with low-dose estrogen (<50 µg) or a progestin-only OC, referred to as OCs. We identified pharmacy claims for lamotrigine or levetiracetam to create a cohort of OC users without drug–drug interaction and extracted claims for carbamazepine or oxcarbazepine to create a cohort of OC users with drug–drug interaction. These four antiepileptic drugs were selected based on their profile of CYPA34 activity and potential clinical uses to create comparable study cohorts with regard to baseline clinical characteristics and pregnancy rates. We defined the cohort entry date (i.e., index date) as the first day of concomitant use of the drugs of interest and OCs and defined a look-back period of six months before the index date with continuous insurance enrollment to ascertain drug indications and other covariates. Patients were required to have at least one medical claim for epilepsy, bipolar disorder, or personality disorder (i.e., indications for antiepileptic drugs) during the look-back period. The indications were measured using coding algorithms developed by the Center for Medicare and Medicaid Services, Chronic Conditions Data Warehouse based on the ICD, ninth, and tenth versions, clinical modification (ICD9/10-CM) codes.19 We excluded patients if they had medical diagnoses for infertility, ovary dysfunction, or hirsutism in their look back period to rule out off-label indications for OCs. The list of ICD codes is provided in eAppendix 1; http://links.lww.com/EDE/B746.\n\nConcomitancy Definition\nWe assumed drug exposure started at the prescription dispensing date and ended on the last day of the pharmacy-entered dispensed days’ supply. We defined “concomitancy” as overlapping exposure periods regardless of the order of drug dispensing for antiepileptic drugs or OCs. 20 We excluded concomitancy periods that had exposure to valproate sodium, topiramate, or phenytoin because of potential CYP3A4 activity and teratogenic effects, which may encourage patients to use a second contraceptive method (e.g., barrier methods). We also excluded concomitancy periods where we observed any other hormonal contraceptive agents, including long-acting reversible contraceptives (e.g., intrauterine devices), injectables, or high-dose estrogen OCs. For users of CYP3A4-neutral antiepileptic drugs, we excluded the concomitancy periods with CYP3A4-inducer drugs. Then we created concomitant use episodes for patients in each study group, and a gap of ≥14 days for either of the medications during an episode was allowed. If we observed a gap of more than 14 days concomitant use, the concomitancy episode ended on the last day of concomitant use. Patients were allowed to reenter the cohort if they had subsequent concomitant use episodes after their first observation period and met all inclusion criteria, including the availability of the 6-months look-back period to allow re-evaluation of baseline characteristics.\n\nOutcome Definition\nThe study outcome was contraception failure defined as conception during a concomitancy period. Conception was estimated via the pregnancy identification algorithm that uses medical encounters with ICD-9/10-CM, Current Procedural Terminology, and Healthcare Common Procedure Coding System codes to identify specific pregnancy endpoints, including live birth, ectopic pregnancies, stillbirth, terminations, and prenatal screening visits.6,7,21,22 Once pregnancy episodes were identified, the algorithm estimated gestational age to calculate the last menstrual period (LMP). The conception date was assumed to be 14 days after the estimated LMP date. We provide more details on the pregnancy identification algorithm in eAppendix 1; http://links.lww.com/EDE/B746.\n\nCovariates\nWe measured several demographic and clinical variables at baseline to assess the comparability of study cohorts, including patient age, residence region, insurance plan type, and relationship to the employee covered by the health plan (spouse, employee, children/other). Clinical variables measured during the 6-months look-back period included recent pregnancy history (based on any pregnancy endpoint), use of teratogenic drugs (with or without mandated pregnancy prevention programs), and a variety of clinical conditions that may affect OC efficacy.\n\nStudy Follow-up\nAll patients were required to have insurance enrollment for a minimum of 90 days after their concomitancy episode ended. This requirement allows the pregnancy identification algorithm to capture pregnancy-related medical encounters, which are then used to date conception. This minimum number of days was defined based on our previous work that showed approximately 90% of live deliveries in our database have prenatal visits within the first 90 days after conception. We followed each patient from the index date of each concomitancy episode until conception, infertility, ovary dysfunction, hirsutism diagnoses, initiation of a teratogenic drug, end of concomitancy, maximum of 3 years’ follow-up, or end of study (December 31, 2017).\n\nStatistical Analysis\nThe unit of analysis was a concomitancy episode. We compared baseline demographic and clinical characteristics of each study cohort using a threshold of an absolute standardized difference (ASD) higher than 10% as clinically significant.23 To account for confounding, we used a logistic regression model to create an exposure propensity score and selected covariates into the model based on a literature review on potential risk factors for the study outcome.24 We used the common support region of the score to create weights to estimate the average treatment effect among the treated, also known as the standardized mortality ratio (SMR) weighting method.23,25 In this weighted pseudo-population, the confounding effect of measured covariates is eliminated, and the effect estimates can approximate the causal effect. We used these SMR weights in a generalized estimating equation model with a Poisson distribution and offset of follow-up time to compare contraception failure rates among the study cohort. We used a robust variance estimator to account for the clustering of episodes within the same patient. We conducted all data management and analyses using SAS 9.4 and SAS/STAT 15.1 (Cary, NC).\n\nSensitivity Analysis\nWe performed several sensitivity analyses to evaluate the robustness of the study findings. For the concomitancy definition, we changed the gap allowance to 1 or 7 days instead of 14 days. We also excluded concomitancy periods that overlapped with other moderate or strong inducers or inhibitors of CYP3A4 for more than 14 days (see eAppendix-1; http://links.lww.com/EDE/B746: eTable 1; http://links.lww.com/EDE/B746 and eTable 2; http://links.lww.com/EDE/B746). For the outcome definition, we varied the estimated conception date by ±14 days, limited the analysis to episodes indexed before 2015 (confining coding to ICD-9-CM), limited the outcome definition to only live birth episodes (which allows the most accurate conception date estimation). To evaluate the impact of more homogeneous comparison groups, we restricted the maximum follow-up time to 6 months, limited the analysis to only the first episode of concomitancy for each patient, and restricted drug initiation sequence to patients who initiated OC initiation while on antiepileptic drug treatment.\n\nRESULTS\nIn the main analysis, we identified 89,777 concomitancy episodes involving CYP3A4-neutral antiepileptic drug and 18,964 episodes with the CYP3A4 inducers. Cohorts had similar age distributions with a mean age of 26.3 ± 8.5 years for the CYP3A4-neutral and 25.5 ± 9.2 for the CYP3A4-inducing drugs (Table 1). About 70% of women in each cohort had a bipolar disorder diagnosis, and 30% had an epilepsy diagnosis. We observed a high prevalence of anxiety (29% vs. 29%) and teratogenic medication use (30% vs. 28%) in the baseline period. The baseline covariates were balanced between study cohorts except for age, beneficiary status, and paralysis diagnosis (ASD < 15%). SMR weighting successfully balanced all measured characteristics (Table 1). Propensity score distributions, SMR weights, and hazard plots are available in eAppendix 1; http://links.lww.com/EDE/B746.\n\nTABLE 1. Demographic and Clinical Characteristics of the Study Cohorts\n\nCovariates\tBefore SMR Weighting\tAfter SMR Weighting\t\nConcomitant OC Plus Enzyme-neutral AED Episodesa (N = 89,777)\tConcomitant OC Plus Enzyme-inducing AED Episodesb (N = 18,964)\tASD (%)\tConcomitant OC Plus Enzyme-neutral AED Episodesa (N = 18,973)\tConcomitant OC Plus Enzyme-inducing AED Episodesb (N = 18,964)\tASD (%)\t\nAge\tn (%)\tn (%)\t\tn (%)\tn (%)\t\t\n <20\t23,297 (26)\t6337 (33)\t16\t6359 (34)\t6337 (33)\t0\t\n 20–29\t36,339 (41)\t6748 (36)\t10\t6741 (36)\t6748 (36)\t0\t\n 30–39\t21,618 (24)\t3918 (21)\t8\t3910 (21)\t3918 (21)\t0\t\n ≥40\t8523 (10)\t1961 (10)\t3\t1964 (10)\t1961 (10)\t0\t\nHypertension\t3732 (4)\t946 (5)\t4\t958 (5)\t946 (5)\t0\t\nHyperlipidemia\t4114 (5)\t1011 (5)\t3\t1021 (5)\t1011 (5)\t0\t\nObesity\t1277 (1)\t357 (2)\t4\t358 (2)\t357 (2)\t0\t\nEpilepsy\t23,309 (26)\t5816 (31)\t10\t5853 (31)\t5816 (31)\t0\t\nBipolar disorder\t65,116 (73)\t13,081 (69)\t8\t13,057 (69)\t13,081 (69)\t0\t\nSchizophrenia\t2428 (3)\t852 (5)\t10\t853 (4)\t852 (5)\t0\t\nDepression\t50,723 (57)\t10,219 (54)\t5\t10,215 (54)\t10,219 (54)\t0\t\nPersonality Disorder\t5606 (6)\t1209 (6)\t1\t1210 (6)\t1209 (6)\t0\t\nAnxiety\t26,043 (29)\t5544 (29)\t1\t5542 (29)\t5544 (29)\t0\t\nSubstance Use Disorder\t4575 (5)\t1284 (7)\t7\t1288 (7)\t1284 (7)\t0\t\nRecent pregnancy (live birth)\t2248 (3)\t309 (2)\t6\t308 (2)\t309 (2)\t0\t\nRecent pregnancy (termination)\t507 (1)\t104 (1)\t0\t103 (1)\t104 (1)\t0\t\nTeratogenic drug without REMS\t24,925 (28)\t5588 (30)\t4\t5620 (30)\t5588 (30)\t0\t\nTeratogenic drug with REMS\t414 (1)\t95 (1)\t1\t96 (0)\t95 (1)\t0\t\nCharlson Comorbidity Index (CCI)3\t\t\t\t\t\t\t\n ≤1\t87,223 (97)\t18,93 (95)\tNA\t18,127 (95)\t18,093 (95)\tNA\t\n 1<\t2554 (3)\t871 (5)\tNA\t846 (5)\t871 (5)\tNA\t\nComorbidities\t\t\t\t\t\t\t\n Myocardial infarction\t31 (0)\t< 11\t0\t<11\t< 11\t0\t\n Congestive Heart Failure\t175 (0)\t50 (0)\t1\t51 (0)\t50 (3)\t0\t\n Vascular Disorder\t187 (0)\t51 (0)\t1\t54 (0)\t51 (3)\t0\t\n Cerebrovascular Disorder\t892 (1)\t197 (1)\t1\t202 (1)\t197 (1)\t0\t\n Pulmonary Disorders\t7211 (8)\t1705 (9)\t3\t1716 (9)\t1705 (9)\t0\t\n Dementia\t86 (0)\t30 (0)\t2\t31 (2)\t30 (0)\t0\t\n Paralysis\t613 (1)\t380 (2)\t11\t388 (2)\t380 (2)\t0\t\n Diabetes w/o complications\t1945 (2)\t432 (2)\t1\t434 (2)\t432 (2)\t0\t\n Diabetes with complications\t175 (0)\t40 (0)\t0\t40 (0)\t40 (0)\t0\t\n Renal Disorders\t263 (0)\t64 (0)\t1\t67 (3)\t64 (0)\t0\t\n Mild Liver Disorders\t765 (1)\t192 (1)\t2\t194 (1)\t192 (1)\t0\t\n Severe Liver Disorders\t22 (0)\t<11\t0\t<11\t<11\t0\t\n Peptic Ulcer\t193 (0)\t58 (0)\t2\t60 (3)\t58 (0)\t0\t\n Rheumatoid Disorders\t585 (1)\t156 (1)\t2\t160 (8)\t156 (1)\t0\t\n AIDS\t22 (0)\t<11\t0\t<11\t<11\t0\t\n Malignancy\t793 (1)\t170 (1)\t0\t173 (9)\t170 (1)\t0\t\n Metastatic Malignancy\t39 (0)\t<11\t0\t<11\t<11\t0\t\nBeneficiary status\t\t\t\t\t\t\t\n Employee\t32,469 (36)\t5702 (30)\t13\t5698 (30)\t5702 (30)\t0\t\n Spouse\t14,208 (16)\t2764 (15)\t3\t2677 (15)\t2764 (15)\t0\t\n Child/other\t43,100 (48)\t10,498 (55)\t15\t10,509 (55)\t10,498 (55)\t0\t\nResidence region\t\t\t\t\t\t\t\n Northeast\t16,228 (18)\t3045 (17)\t5\t3047 (16)\t3045 (16)\t0\t\n Northcentral\t19,394 (22)\t4363 (23)\t4\t4370 (23)\t4363 (23)\t0\t\n South\t35,322 (39)\t8074 (43)\t7\t8071 (42)\t8074 (43)\t0\t\n West\t17,594 (20)\t3225 (17)\t7\t3228 (17)\t3225 (17)\t0\t\n Unknown\t1239 (1)\t257 (1)\t0\t257 (1)\t257 (1)\t0\t\nHealth plan type\t\t\t\t\t\t\t\n COM\t1525 (2)\t479 (2)\t6\t482 (3)\t479 (3)\t0\t\n HMO\t12,955 (14)\t2749 (14)\t0\t2733 (14)\t2749 (15)\t0\t\n PPO\t53,996 (60)\t11,362 (60)\t1\t11,373 (60)\t11,362 (60)\t0\t\n POS\t6853 (8)\t1594 (8)\t0\t1597 (8)\t1594 (8)\t0\t\n CDHP\t5887 (6)\t1216 (6)\t1\t1218 (6)\t1216 (6)\t0\t\n Other\t8561 (9)\t1564 (8)\t5\t1570 (8)\t1564 (8)\t0\t\nASD, absolute standardized difference; COM, comprehensive; HMO, health maintenance organization; PPO, preferred provider organization; POS, noncapitated point-of-service; CDHP, consumer-driven health plan; Other: includes capitated/partially capitated point-of-service, exclusive provider organization, high deductible health plan; REMS, risk evaluation and mitigation strategy.\n\naCohort A: concomitant use of oral contraceptives and CYP3A4-neutral drugs (lamotrigine or levetiracetam). After SMR weighting, the size of the pseudo-population in cohort A becomes comparable to cohort B.\n\nbCohort B: concomitant use of oral contraceptives and CYP3A4-inducer drugs (carbamazepine or oxcarbazepine).\n\nEpisodes involving concomitant use of enzyme-neutral antiepileptic drugs had a slightly larger mean follow-up time of 96 days (vs. 79 days among women who used enzyme-inducers). Concomitancy periods ended with 400 conceptions among women who used enzyme-neutral antiepileptic drugs, resulting in a crude contraception failure rate of 1.7 events per 100 person–years. Women with concomitant use of OCs and enzyme-inducing antiepileptic drug had 94 conceptions with a crude contraception failure rate of 2.3 per 100 person–years (Table 2). Figure 1 shows unadjusted survival plots for contraception failure outcome. Approximately two-thirds of all conceptions were identified based on liveborn deliveries (both groups 63%), whereas abortions were the second prevalent pregnancy endpoint (28% in the enzyme-neutral group vs. 27% in the enzyme-inducing group) (Table 3).\n\nTABLE 2. Relative and Absolute Risk of Oral Contraceptive Failure in the Presence or Absence of Drug–drug Interaction\n\nStudy Cohort\tEvents\tTotal Follow-up Time (Person-years)\tIncidence Rate (per 100 Person-years)\tRelative Risk\tRisk Difference\t\nUnadjusted analysis\t\nConcomitant OC plus enzyme-neutral AED episodesa\t400\t23,647\t1.7 (1.5, 1.9)\tREF\tREF\t\nConcomitant OC plus enzyme-inducing AED episodesb\t94\t4102\t2.3 (1.9, 2.8)\t1.4 (1.1, 1.7)\t0.6 (0.1, 1.1)\t\nAdjusted Analysis\t\nConcomitant OC plus enzyme-neutral AED episodesa\t400\t23,647\t1.6 (1.4, 1.8)\tREF\tREF\t\nConcomitant OC plus enzyme-inducing AED episodesb\t94\t4102\t2.3 (1.9, 2.8)\t1.4 (1.1, 1.8)\t0.7 (0.2, 1.2)\t\nASD, absolute standardized difference; OC, oral contraceptive.\n\naCohort A: concomitant use of oral contraceptives and CYP3A4-neutral drugs (lamotrigine or levetiracetam)—Reference cohort.\n\nbCohort B: concomitant use of oral contraceptives and CYP3A4-inducer drugs (carbamazepine or oxcarbazepine).\n\nTABLE 3. Pattern of Pregnancy Episodes that Contributed to Measurement of Contraception Failure\n\nStudy Cohort\tFull-term \nn (%)\tPreterm \nn (%)\tPost-term \nn (%)\tEctopic \nn (%)\tStillbirth \nn (%)\tSpontaneous abortion \nn (%)\tInduced abortion \nn (%)\tUnknown outcome \nn (%)\tTotal \nn\t\nConcomitant OC plus enzyme-neutral AED episodesa\t233 (58)\t16 (4)\t3 (1)\t4 (1)\t3 (1)\t65 (16)\t46 (12)\t30 (8)\t400\t\nConcomitant OC plus enzyme-inducing AED episodesb\t54 (57)\t4 (4)\t1 (1)\t1 (1)\t0 (0)\t14 (15)\t11 (12)\t9 (10)\t94\t\nASD, absolute standardized difference; OC, oral contraceptive.\n\naCohort A: concomitant use of oral contraceptives and CYP3A4-neutral drugs (lamotrigine or levetiracetam)—Reference cohort.\n\nbCohort B: concomitant use of oral contraceptives and CYP3A4-inducer drugs (carbamazepine or oxcarbazepine).\n\nThe adjusted contraceptive failure rates were 1.6 (95% CI = 1.4, 1.8) per 100 person–years among users of enzyme-neutral drugs and 2.3 (1.9, 2.8) among users of enzyme-inducing drugs. The marginal models with SMR weights increased the unadjusted relative risk for contraception failure slightly from 1.4 (1.1, 1.7) to 1.4 (1.1, 1.8), comparing women who used enzyme-inducing antiepileptic drugs to those who used enzyme-neutral antiepileptic drug. Concomitant use of enzyme-inducing antiepileptic drug and OCs resulting in an additional 0.7 conceptions (0.2, 1.2) per 100 person–years of concomitant use.\n\nAll sensitivity analyses corroborated our findings (Table 4). Analyses with conceivably superior measurement of confounding (analysis number 6, 7, 9 in Table 4) showed as expected slightly larger relative risk estimates with 1.6 (1.2, 2.2) when restricting to the first concomitancy episode per patient, 1.5 (1.1, 2.1) with a fixed sequence of drug initiation, and 1.5 (1.2, 1.9) after eliminating concomitant use of all other potential CYP3A4 inducers/inhibitors.\n\nTABLE 4. Sensitivity Analyses on the Definitions of Concomitancy, Outcome Measurement, and Study Design Features\n\nRow\tSensitivity Analysis\tIncidence Rate (per 100 Person-year)\tAdjusted Rate Ratio\tAdjusted Rate Difference\t\nConcomitant OC Plus Enzyme-neutral AED Episodesa\tConcomitant OC Plus Enzyme-inducing AED Episodesb\t\n1\tConception date altered by +14 days\t1.5 (1.3, 1.7)\t1.9 (1.5, 2.4)\t1.3 (1.0, 1.6)\t0.4 (0.0, 0.9)\t\n2\tConception date altered by −14 days\t1.9 (1.7, 2.1)\t2.5 (2.1, 3.0)\t1.3 (1.1, 1.7)\t0.6 (0.1, 1.1)\t\n3\tRestriction to episodes with index date before 2015 (ICD-9 era)\t1.6 (1.4, 1.8)\t2.3 (1.9, 2.9)\t1.6 (1.1, 1.8)\t0.7 (0.2, 1.3)\t\n4\tConception ascertained based on live birth only\t1.0 (0.9, 1.2)\t1.4 (1.1, 1.8)\t1.4 (1.1, 1.9)\t0.4 (0.2, 8.0)\t\n5\tMaximum follow-up time restricted to 6 months\t1.7 (1.5, 1.9)\t2.3 (1.9, 2.9)\t1.4 (1.1, 1.8)\t0.6 (0.1, 1.2)\t\n6\tEpisodes restricted to first episode per patient\t1.6 (1.4, 1.8)\t2.5 (1.9, 3.3)\t1.6 (1.2, 2.2)\t0.9 (0.2, 1.6)\t\n7\tEpisodes restricted to those where OC initiation follows AED use\t1.5 (1.3, 1.8)\t2.3 (1.8, 3.1)\t1.5 (1.1, 2.1)\t0.8 (0.1, 1.5)\t\n8\tPermissable gap in concomitancy 7 days\t1.6 (1.5, 1.8)\t2.2 (1.8, 2.7)\t1.4 (1.1, 1.7)\t0.6 (0.1, 1.0)\t\n9\tPermissable gap in concomitancy 1 day\t1.6 (1.5, 1.8)\t2.1 (1.7, 2.6)\t1.3 (1.0, 1.6)\t0.5 (0.0, 0.9)\t\n10\tExclusion of all follow-up time with other CYP3A4 inducers or inhibitors\t1.6 (1.4, 1.8)\t2.4 (1.9, 2.9)\t1.5 (1.2, 1.9)\t0.7 (0.2, 1.3)\t\nASD, absolute standardized difference; ICD, International Classification of Disease; OC, oral contraceptive.\n\naCohort A: concomitant use of oral contraceptives and CYP3A4-neutral drugs (lamotrigine or levetiracetam)—Reference cohort.\n\nbCohort B: concomitant use of oral contraceptives and CYP3A4-inducer drugs (carbamazepine or oxcarbazepine).\n\nDISCUSSION\nOur study found that women who concomitantly used OCs and CYP3A4-inducing antiepileptic drugs were 40% more likely to experience contraceptive failure compared to CYP3A4-neutral antiepileptic users. Our findings suggest that conception estimation was sufficiently accurate to identify this well-documented strong drug–drug interaction, and thus, our approach may be useful to generate real-world evidence on mechanisms of contraceptive failure, including the examination of interactions.\n\nBecause respective drug approval requirements are largely confined to pharmacokinetic studies, limited information exists on the clinical significance of drug–drug interaction involving OCs. A meta-analysis published in 2010 identified only pharmacokinetic studies that examined the potential for contraceptive failure among patients who use antiepileptic drugs.26 We identified one small cohort study published in 1979 that followed 41 epilepsy patients with concomitant use of antiepileptic drugs and OCs and reported ~2.9 failures per 100 person–years, which is slightly higher than in our cohorts.27 In our study, we observed a failure rate of 1.6 or 2.3 per 100-person years, depending on the type of antiepileptic drugs in terms of enzyme-inducing properties. The observed magnitude of the drug–drug interaction impact on failure rates in our study is biologically plausible based on evidence from pharmacokinetic evaluations, which recommend higher OC doses when used concomitantly with carbamazepine (e.g., 80–100 mcg of ethinyl estradiol that far exceeds the observed doses of 20–35 mcg observed in our data). 11,12 A clinical trial on healthy volunteers showed a 46.1% reduction in the AUC for levonorgestrel, and 44.5% for ethinyl estradiol when the OC was administrated with carbamazepine (600 mg). The study also reported more ovulations (5/10 cycles vs. 1/10 cycles) among carbamazepine users versus OC use alone.12 The diminishing effects of CYP3A4 inducers, including carbamazepine and oxcarbazepine, on the efficacy of OC is also emphasized in the guidance document for labeling of combined hormonal contraceptives.28\n\nBecause clinical trials on contraceptive failure are typically infeasible, observational studies, especially prospective cohorts, have a pivotal role.29–31 Broader availability of real-world data and advancements in pharmacoepidemiologic methods can facilitate comparative effectiveness studies and help to translate mechanistic findings into clinically significant outcomes. To the best of our knowledge, the present study is the first attempt to investigate contraceptive failure in claims data. To evaluate the performance of this approach, we designed our study based on a clinical scenario of decreased OC efficacy in the presence of a known drug–drug interaction with a well-studied potent enzyme inducer. We successfully replicated mechanistic findings regarding a significant interaction between OC use and the perpetrator drug (a CYP3A4-inducer), resulting in contraceptive failure. Therefore, we envision that this approach could serve as a novel platform to evaluate the comparative effectiveness of hormonal contraceptives, considering different routes of administration and differences in pharmacokinetic profiles, among diverse patient populations with comorbidities or other concomitant medications. However, researchers should be vigilant about potential misclassification biases in exposure (contraceptive use) or outcome (conception) measurements and their consequences on the ability to make causal inferences, especially, for quantifying the magnitude of risk, and the possibility of inadequate sensitivity of our approach to detect weaker drug–drug interaction effects.\n\nWe operationalized exposure in our claims data by using “days of supply” recorded on the pharmacy claims. Although this measurement approach is more reliable than patient self-report, it may not be fully reflective of the actual medication consumption.32 For instance, women might discontinue OC treatment before their supply is exhausted to plan for pregnancy. This decision would possibly result in misclassification of exposure and overestimation of the contraception failure rate. The use of active comparator groups that exhibit similar demographics and comorbidities, such as demonstrated in our cohort, may mitigate some of these concerns, but even nondifferential exposure misclassification could bias relative risk estimates either away or toward the null hypothesis (eAppendix 2; http://links.lww.com/EDE/B747).\n\nRegarding outcome measurement, we relied on an algorithm to infer pregnancy episodes from medical encounters with the healthcare system that use validated coding to specify pregnancy endpoints, but without an actual recording of LMP. Based on previous literature, estimation of conception will have varying degrees of accuracy for each type of pregnancy endpoint.6,22 In our pregnancy identification algorithm, we assigned gestational age for live-birth episodes based on an algorithm of ICD codes indicating gestational age or preterm status, and the overall agreement against birth certificates is reported to be >93% in the Medicaid database.22 For ectopic pregnancy, induced/spontaneous abortion, and stillbirth, we used fixed values for gestational age (8, 10, and 28 weeks, respectively) similar to previous literature.6,7 This approach has shown a moderate agreement both against medical charts (70% for ectopic pregnancy and 67% for spontaneous abortions within four weeks)7, and a cohort of in-vitro fertilization patients (77% agreement for ectopic pregnancy, 47% for stillbirth, and 36% for abortions cases).6 Validation studies on pregnancy identification algorithms typically report the agreement between the estimated LMP and the gold standard (e.g., the clinical estimate of gestational age on the birth certificate) within a prespecified number of weeks (e.g., 2 weeks) as the margin of error.4,6,22 It should be noted; however, that such a margin might need to be varied according to the pregnancy endpoint that was used to estimate LMP. For example, previous studies have shown that the capture of preterm status among deliveries improves with decreasing gestational age.33 Thus, considering the relationship between measurement sensitivity and gestational age as well as the pronounced left-skewed distribution of gestational age among preterm infants, error margins of 2–4 weeks used in sensitivity analyses may be appropriate. In contrast, stillbirth with a flat gestational age frequency distribution ranging from 20 to 42 weeks may require broader margins that should be tested.34 We should also note that available conception algorithms typically estimate LMP, following long-established conventions in timing gestational age, and thus, conception must be imputed as LMP + 14 days to operationalize contraceptive failure.35 In our study, we conducted sensitivity analyses by varying the estimated conception date, limiting the analysis to the ICD-9-CM era with previously validated pregnancy endpoint definitions, and restricting the events to pregnancies with the liveborn outcome. The two latter analyses aimed to increase the specificity of the outcome measure.\n\nOur adjustment for potential confounding was based on a literature review on risk factors for contraceptive failure, but we acknowledge that several predictive factors were not or were only partially measurable in claims data. For example, sexual activity may be an important factor for contraceptive failure but is not available in claims data. However, we believe that our use of an active comparator group successfully balanced for the majority of risk factors, as exemplified by fairly well-balanced comparison groups before SMR weighting. We should also acknowledge that race and socioeconomic status were unmeasured in our dataset and could act as confounding factors. However, the study drugs are available on the market as generic products, yielding channeling for economic reasons unlikely. Finally, we should note that our adjustment for confounding further increased the observed relative risk estimates, thus suggesting that enzyme inducers were slightly more prevalent among patients with fewer risk factors for contraceptive failure. Thus, to explain our findings, any unmeasured covariate would need to be distributed in the opposite direction than the measured risk factors. Researchers could apply probabilistic bias analysis methods to evaluate the impact of exposure, outcome, and confounder misclassifications, simultaneously.36,37\n\nIn conclusion, women who use OCs in combination with carbamazepine or oxcarbazepine should be aware of increased contraceptive failure rates. Our study showed that measurement of conception in claims data has adequate accuracy to reveal the effect of a known drug–drug interaction with hormonal contraceptives. Our pharmacoepidemiologic approach is promising for comparative effectiveness studies on hormonal contraceptives to generate real-world evidence and inform clinical and regulatory decision-making.\n\nFIGURE 1. Survival curves for contraception failure during follow-up in each study cohort.\n\nACKNOWLEDGMENTS\nNone.\n\nSupplementary Material\n A.S., J.B., S.S., and A.W. participated in study conceptualization and design. A.S., J.B., A.G., B.C., C.H., P.P., P.S., and A.W. involved in data acquisition, analysis, and interpretation. A.S. participated in drafting the article. A.S., J.B., A.G., B.C., C.H., P.P., P.S., and A.W. participated in the critical revision and final approval of the manuscript.\n\nThe results reported herein correspond to specific aims of grant #OPP1185454 to Stephan Schmidt and Joshua Brown from the Bill & Melinda Gates Foundation.\n\nA.G.W. has active research support from Merck & Co, which is unrelated to this project. The other authors have no conflicts to report.\n\nThe IBM MarketScan database is available via a data use agreement with the company.\n==== Refs\nREFERENCES\n1. Hernandez-Diaz S Huybrechts KF Desai RJ \nTopiramate use early in pregnancy and the risk of oral clefts: a pregnancy cohort study.\n\nNeurology . 2018 ;90 :e342 –e351\n.29282333 \n2. Huybrechts KF Hernández-Díaz S Straub L \nAssociation of maternal first-trimester ondansetron use with cardiac malformations and oral clefts in offspring.\n\nJAMA . 2018 ;320 :2429 –2437\n.30561479 \n3. MacDonald SC Cohen JM Panchaud A McElrath TF Huybrechts KF Hernández-Díaz S \nIdentifying pregnancies in insurance claims data: methods and application to retinoid teratogenic surveillance.\n\nPharmacoepidemiol Drug Saf . 2019 ;28 :1211 –1221\n.31328328 \n4. Margulis AV Setoguchi S Mittleman MA Glynn RJ Dormuth CR Hernández-Díaz S \nAlgorithms to estimate the beginning of pregnancy in administrative databases.\n\nPharmacoepidemiol Drug Saf . 2013 ;22 :16 –24\n.22550030 \n5. Toh S Mitchell AA Werler MM Hernández-Díaz S \nSensitivity and specificity of computerized algorithms to classify gestational periods in the absence of information on date of conception.\n\nAm J Epidemiol . 2008 ;167 :633 –640\n.18194999 \n6. Matcho A Ryan P Fife D Gifkins D Knoll C Friedman A \nInferring pregnancy episodes and outcomes within a network of observational databases.\n\nPLoS One . 2018 ;13 :e0192033 .29389968 \n7. Hornbrook MC Whitlock EP Berg CJ \nDevelopment of an algorithm to identify pregnancy episodes in an integrated health care delivery system.\n\nHealth Serv Res . 2007 ;42 :908 –927\n.17362224 \n8. Hertz-Picciotto I Pastore LM Beaumont JJ \nTiming and patterns of exposures during pregnancy and their implications for study methods.\n\nAm J Epidemiol . 1996 ;143 :597 –607\n.8610677 \n9. Sarayani A Albogami Y Elkhider M Hincapie-Castillo JM Brumback BA Winterstein AG \nComparative effectiveness of risk mitigation strategies to prevent fetal exposure to mycophenolate.\n\nBMJ Qual Saf . 2020 ;29 :636 –644\n.\n10. Carbamazepine Clinical Pharmacology [database online] . Gold Standard, Inc .\n11. Crawford P Chadwick DJ Martin C Tjia J Back DJ Orme M \nThe interaction of phenytoin and carbamazepine with combined oral contraceptive steroids.\n\nBr J Clin Pharmacol . 1990 ;30 :892 –896\n.2126946 \n12. Davis AR Westhoff CL Stanczyk FZ \nCarbamazepine coadministration with an oral contraceptive: effects on steroid pharmacokinetics, ovulation, and bleeding.\n\nEpilepsia . 2011 ;52 :243 –247\n.21204827 \n13. Lazorwitz A Davis A Swartz M Guiahi M \nThe effect of carbamazepine on etonogestrel concentrations in contraceptive implant users.\n\nContraception . 2017 ;95 :571 –577\n.28288788 \n14. Fattore C Cipolla G Gatti G \nInduction of ethinylestradiol and levonorgestrel metabolism by oxcarbazepine in healthy women.\n\nEpilepsia . 1999 ;40 :783 –787\n.10368079 \n15. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 206: Use of hormonal contraception in women with coexisting medical conditions.\n\nObstet Gynecol . 2019 ;133 :e128 –e150\n.30681544 \n16. Curtis KM Jatlaoui TC Tepper NK \nU.S. selected practice recommendations for contraceptive use, 2016.\n\nMMWR Recomm Rep . 2016 ;65 :1 –66\n.\n17. Patsalos PN \nDrug interactions with the newer antiepileptic drugs (AEDs)—part 2: pharmacokinetic and pharmacodynamic interactions between AEDs and drugs used to treat non-epilepsy disorders.\n\nClin Pharmacokinet . 2013 ;52 :1045 –1061\n.23794036 \n18. Patsalos PN \nDrug interactions with the newer antiepileptic drugs (AEDs)—part 1: pharmacokinetic and pharmacodynamic interactions between AEDs.\n\nClin Pharmacokinet . 2013 ;52 :927 –966\n.23784470 \n19. Chronic Conditions Data Warehouse; Centers for Medicare and Medicaid Services (CMS) CCW Condition Algorithms.\n\nAvailable at: https://www2.ccwdata.org/web/guest/condition-categories. Accessed 15 June 2019 .\n20. Hennessy S Leonard CE Gagne JJ \nPharmacoepidemiologic methods for studying the health effects of drug-drug interactions.\n\nClin Pharmacol Ther . 2016 ;99 :92 –100\n.26479278 \n21. Sarayani A Wang X Thai TN Albogami Y Jeon N Winterstein AG \nImpact of the transition from ICD-9-CM to ICD-10-CM on the identification of pregnancy episodes in US health insurance claims data.\n\nClin Epidemiol . 2020 ;12 :1129 –1138\n.33116906 \n22. Zhu Y Hampp C Wang X \nValidation of algorithms to estimate gestational age at birth in the Medicaid Analytic eXtract—Quantifying the misclassification of maternal drug exposure during pregnancy.\n\nPharmacoepidemiol Drug Saf . 2020 :1 –9\n. doi: 10.1002/pds.5126 .\n23. Austin PC Stuart EA \nMoving towards best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies.\n\nStat Med . 2015 ;34 :3661 –3679\n.26238958 \n24. Sauer BC Brookhart MA Roy J VanderWeele T \nA review of covariate selection for non-experimental comparative effectiveness research.\n\nPharmacoepidemiol Drug Saf . 2013 ;22 :1139 –1145\n.24006330 \n25. Sato T Matsuyama Y \nMarginal structural models as a tool for standardization.\n\nEpidemiology . 2003 ;14 :680 –686\n.14569183 \n26. Gaffield ME Culwell KR Lee CR \nThe use of hormonal contraception among women taking anticonvulsant therapy.\n\nContraception . 2011 ;83 :16 –29\n.21134499 \n27. Coulam CB Annegers JF \nDo anticonvulsants reduce the efficacy of oral contraceptives?\n\nEpilepsia . 1979 ;20 :519 –525\n.477641 \n28. U.S. Food and Drug Administration; Center for Drug Evaluation and Research (CDER) Labeling for Combined Hormonal Contraceptives . 2017 Guidance for Industry ;\n29. Barnett C Dinger J Minh TD Heinemann K \nUnintended pregnancy rates differ according to combined oral contraceptive—results from the INAS-SCORE study.\n\nEur J Contracept Reprod Health Care . 2019 ;24 :247 –250\n.31204884 \n30. Reeves MF Zhao Q Secura GM Peipert JF \nRisk of unintended pregnancy based on intended compared to actual contraceptive use.\n\nAm J Obstet Gynecol . 2016 ;215 :71.e1 –71.e6\n.26805610 \n31. Dinger J Minh TD Buttmann N Bardenheuer K \nEffectiveness of oral contraceptive pills in a large U.S. cohort comparing progestogen and regimen.\n\nObstet Gynecol . 2011 ;117 :33 –40\n.21213475 \n32. Funk MJ Landi SN \nMisclassification in administrative claims data: quantifying the impact on treatment effect estimates.\n\nCurr Epidemiol Rep . 2014 ;1 :175 –185\n.26085977 \n33. Eworuke E Hampp C Saidi A Winterstein AG \nAn algorithm to identify preterm infants in administrative claims data.\n\nPharmacoepidemiol Drug Saf . 2012 ;21 :640 –650\n.22504840 \n34. MacDorman MF Reddy UM Silver RM \nTrends in stillbirth by gestational age in the United States, 2006-2012.\n\nObstet Gynecol . 2015 ;126 :1146 –1150\n.26551188 \n35. Bird ST Toh S Sahin L \nMisclassification in assessment of first trimester in-utero exposure to drugs used proximally to conception: the example of letrozole utilization for infertility treatment.\n\nAm J Epidemiol . 2019 ;188 :418 –425\n.30321259 \n36. Lash TL Fox MP MacLehose RF Maldonado G McCandless LC Greenland S \nGood practices for quantitative bias analysis.\n\nInt J Epidemiol . 2014 ;43 :1969 –1985\n.25080530 \n37. Lash TL Fox MP Fink AK \nApplying Quantitative Bias Analysis to Epidemiologic Data. Statistics for Biology and Health . 2011 New York Springer ;\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1044-3983",
"issue": "32(2)",
"journal": "Epidemiology (Cambridge, Mass.)",
"keywords": null,
"medline_ta": "Epidemiology",
"mesh_terms": "D000927:Anticonvulsants; D003276:Contraceptives, Oral; D004347:Drug Interactions; D005260:Female; D006801:Humans; D004364:Pharmaceutical Preparations; D011247:Pregnancy; D012307:Risk Factors",
"nlm_unique_id": "9009644",
"other_id": null,
"pages": "268-276",
"pmc": null,
"pmid": "33196560",
"pubdate": "2021-03-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A Pharmacoepidemiologic Approach to Evaluate Real-world Effectiveness of Hormonal Contraceptives in the Presence of Drug-drug Interactions.",
"title_normalized": "a pharmacoepidemiologic approach to evaluate real world effectiveness of hormonal contraceptives in the presence of drug drug interactions"
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"activesubstancename": "LEVETIRACETAM"
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{
"abstract": "Catheter-directed thrombolysis (CDT) is one of the methods in the treatment of patients with acute lower limb ischemia. It is based on intrathrombus infusion of one of the thrombolytic agents. The most common complication of CDT is bleeding. We present a patient with left lower limb ischemia, treated by CDT, in which symptoms of stroke, proved to have ischemic etiology, started during continuous intra-arterial infusion of rt-PA. As the patient presented with the history of atrial fibrillation, the most probable mechanism of stroke was related to detachment of possible intra-atrial thrombus. Ischemic stroke which happened during intra-arterial thrombolysis with rt-PA has never been mentioned in literature yet and the case stands for the statement that very effective causative treatment of ischemic stroke with rt-PA is not sufficient to \"prevent\" ischemic stroke if used in very small doses.",
"affiliations": "Barlicki Memorial Hospital, 22 Kopcinskiego Street, 90-153 Lodz, Poland.;Department of Surgery, Medical University of Lodz, 22 Kopcinskiego Street, 90-153 Lodz, Poland.;Department of Neurology, Stroke and Neurorehabilitation, Medical University of Lodz, 22 Kopcinskiego Street, 90-153 Lodz, Poland. Electronic address: jjrozniecki@afazja.am.lodz.pl.",
"authors": "Zurawska|Anna|A|;Czeczotka|Jaroslaw|J|;Rozniecki|Jacek J|JJ|",
"chemical_list": "D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator",
"country": "Poland",
"delete": false,
"doi": "10.1016/j.pjnns.2017.03.001",
"fulltext": null,
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"issn_linking": "0028-3843",
"issue": "51(3)",
"journal": "Neurologia i neurochirurgia polska",
"keywords": "Atrial fibrillation; Limb ischemia; Recombinant tissue plasminogen activator; Stroke; Thrombolysis",
"medline_ta": "Neurol Neurochir Pol",
"mesh_terms": "D000368:Aged; D001281:Atrial Fibrillation; D002318:Cardiovascular Diseases; D002544:Cerebral Infarction; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007261:Infusions, Intra-Arterial; D007511:Ischemia; D007866:Leg; D011994:Recombinant Proteins; D012307:Risk Factors; D013923:Thromboembolism; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator",
"nlm_unique_id": "0101265",
"other_id": null,
"pages": "263-265",
"pmc": null,
"pmid": "28400063",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "First case of ischemic stroke which happened during continuous intravenous infusion of rt-PA.",
"title_normalized": "first case of ischemic stroke which happened during continuous intravenous infusion of rt pa"
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{
"companynumb": "PL-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2017-BI-023187",
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"activesubstancename": "ALBUTEROL SULFATE\\IPRATROPIUM BROMI... |
{
"abstract": "Epstein-Barr virus-associated post-transplant lymphoproliferative disorder (EBV-PTLD) is increasingly recognized as a life-threatening complication after transplantation. Most areas affected by EBV-PTLD are lymph nodes, with occasional reports of extranodal lesions such as the gastrointestinal tract and central nervous system; however, orbital regions are extremely rare. We report a case of EBV-PTLD in a cord blood transplant recipient with a tumor in the upper right eyelid. Ultimately, eye symptoms were the first signs of PTLD. Transplant physicians should consider the possibility of PTLD when encountering an orbital lesion.",
"affiliations": "Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan.;Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Pathology, Shinshu University School of Medicine, Matsumoto, Japan.",
"authors": "Shigemura|Tomonari|T|https://orcid.org/0000-0001-8077-2526;Maruyama|Yuta|Y|;Shigeto|Shohei|S|;Nakazawa|Yozo|Y|https://orcid.org/0000-0003-0793-815X;Kanno|Hiroyuki|H|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13536",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "23(3)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "Epstein-Barr virus; cord blood transplantation; orbital PTLD; post-transplant lymphoproliferative disorder",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000293:Adolescent; D036101:Cord Blood Stem Cell Transplantation; D020031:Epstein-Barr Virus Infections; D005260:Female; D004854:Herpesvirus 4, Human; D006801:Humans; D008232:Lymphoproliferative Disorders; D066027:Transplant Recipients",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13536",
"pmc": null,
"pmid": "33264446",
"pubdate": "2021-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Orbital Epstein-Barr virus-related post-transplant lymphoproliferative disorder in a 13-year-old girl with cord blood transplantation.",
"title_normalized": "orbital epstein barr virus related post transplant lymphoproliferative disorder in a 13 year old girl with cord blood transplantation"
} | [
{
"companynumb": "JP-TEVA-2022-JP-1997418",
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"activesubstancename": "PREDNISOLONE"
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... |
{
"abstract": "A 45-year-old woman was admitted to the Department of Rheumatology and Immunology, Peking Union Medical College Hospital, due to weakness of the upper limbs, fever, and blurred vision. She was clinically diagnosed as systemic lupus erythematosus overlapped primary biliary cirrhosis, with renal, retinal, hematological and musculoskeletal involvement, combined with severe pulmonary infection and respiratory failure. Treated with glucocorticoids, ursodeoxycholic acid, antibiotics and respiratory support, the patient got better. A couple of days later, her fever recurred and platelets count dropped to 30×10(9)/L, hemoglobin to 78 g/L, fibrinogen to<1.5 g/L, ferritin to 1 640 ng/ml, natural killer (NK) cell count to 8/μl, the activity of NK cells 2% (reference value 9.5%-23.5%), considering the occurrence of hemophagocytic lymphohistiocytosis (HLH). Cytomegalovirus pp65 antigenemia test: 13 positive cells/2×10(5) WBC. Considered the possibility of HLH caused by cytomegalovirus infection and treated by 250 mg ganciclovir intravenous drip twice a day for a full course. The temperature of the patient was gradually reduced to 36.5 ℃, the count of platelets were increased to 229 ×10(9)/L, the hemoglobin was increased to 94 g/L, and the fibrinogen was increased to 3.26 g/L. When there were unexplained critical signs of the primary disease during systemic lupus erythematosus treatment, severe complications such as infection, HLH, thrombotic thrombocytopenic purpura should be taken into account.",
"affiliations": "Department of Rheumatology and Immunology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China.;Department of Rheumatology and Immunology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China.",
"authors": "Jing|G C|GC|;Chen|Y|Y|;Wang|L|L|;Xu|D|D|;Zheng|W J|WJ|;Li|M T|MT|;Zeng|X F|XF|;Zhang|F C|FC|",
"chemical_list": "D000900:Anti-Bacterial Agents; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D013256:Steroids",
"country": "China",
"delete": false,
"doi": "10.3760/cma.j.issn.0578-1426.2018.12.015",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0578-1426",
"issue": "57(12)",
"journal": "Zhonghua nei ke za zhi",
"keywords": "Cytomegalovirus; Lupus erythematosus, systemic; Lymphohistiocytosis, hemophagocytic",
"medline_ta": "Zhonghua Nei Ke Za Zhi",
"mesh_terms": "D000900:Anti-Bacterial Agents; D003586:Cytomegalovirus Infections; D005260:Female; D005334:Fever; D005938:Glucocorticoids; D006801:Humans; D007166:Immunosuppressive Agents; D008180:Lupus Erythematosus, Systemic; D051359:Lymphohistiocytosis, Hemophagocytic; D008875:Middle Aged; D010198:Pancytopenia; D011697:Purpura, Thrombotic Thrombocytopenic; D013256:Steroids",
"nlm_unique_id": "16210490R",
"other_id": null,
"pages": "942-944",
"pmc": null,
"pmid": "30486568",
"pubdate": "2018-12-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The 466th case:myasthenia,fever,blurred vision and pancytopenia.",
"title_normalized": "the 466th case myasthenia fever blurred vision and pancytopenia"
} | [
{
"companynumb": "CN-FRESENIUS KABI-FK201901756",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": ... |
{
"abstract": "Belatacept provides effective immunosuppression while avoiding the nephrotoxicities associated with calcineurin inhibitors (CNIs). However, existing belatacept-based regimens still have high rates of acute rejection. We hypothesized that therapy with belatacept, mycophenolic acid (MMA), steroids and induction therapy with rabbit anti-thymocyte globulin Fresenius (ATGF), rejection rate could be reduced. Prospective, single center, proof-of-concept study including males and females aged ≥18years, Epstein-Barr virus (EBV)-seropositive recipients of a first, HLA non-identical, live or deceased donor kidney allograft. Only patients with a calculated panel reactive antibody score of 0% were included. Three donors were positive for Chagas disease. Six of twelve patients had at least one infection and five were readmitted to the hospital for treatment. One patient had a Trypanosoma cruzi infection via the graft treated successfully. Median cold ischemia time for the transplant patients with a deceased donor was 21.5h. Mean serum creatinine levels at 1, 3 and 6months were 1.76±0.59, 1.55±0.60 and 1.49±0.60mg/dl, respectively. Two of twelve patients experienced clinical, biopsy-proven rejection, successfully treated with methylprednisolone. No patient developed post-transplant lymphoproliferative disorder (PTLD) or any other malignancy and no patient lost their graft or died during follow-up. The potential of this approach makes it worthy of further investigation.",
"affiliations": "Renal Transplantation, Hospital Alemán, Buenos Aires, Argentina; Foundation for Research and Assistance of Kidney Disease (FINAER), Buenos Aires, Argentina.;Renal Transplantation, Hospital Alemán, Buenos Aires, Argentina.;Renal Transplantation, Hospital Alemán, Buenos Aires, Argentina.;Renal Transplantation, Hospital Alemán, Buenos Aires, Argentina.;Renal Transplantation, Hospital Alemán, Buenos Aires, Argentina.;Foundation for Research and Assistance of Kidney Disease (FINAER), Buenos Aires, Argentina. Electronic address: javierroberti@gmail.com.",
"authors": "Cicora|Federico|F|;Mos|Fernando|F|;Petroni|Jorgelina|J|;Casanova|Matías|M|;Reniero|Liliana|L|;Roberti|Javier|J|",
"chemical_list": "D000961:Antilymphocyte Serum; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D000069594:Abatacept",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0966-3274",
"issue": "32(1)",
"journal": "Transplant immunology",
"keywords": "Antithymocyte globulin-Fresenius; Belatacept; Induction; Mycophenolate; Renal transplantation; Steroid",
"medline_ta": "Transpl Immunol",
"mesh_terms": "D000069594:Abatacept; D000328:Adult; D000368:Aged; D064591:Allografts; D000818:Animals; D000961:Antilymphocyte Serum; D005260:Female; D006084:Graft Rejection; D006801:Humans; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011817:Rabbits",
"nlm_unique_id": "9309923",
"other_id": null,
"pages": "35-9",
"pmc": null,
"pmid": "25448417",
"pubdate": "2015-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Belatacept-based, ATG-Fresenius-induction regimen for kidney transplant recipients: a proof-of-concept study.",
"title_normalized": "belatacept based atg fresenius induction regimen for kidney transplant recipients a proof of concept study"
} | [
{
"companynumb": "AR-PFIZER INC-2020419123",
"fulfillexpeditecriteria": "1",
"occurcountry": "AR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "THYMOCYTE IMMUNE GLOBULIN NOS"
},
"drugadditio... |
{
"abstract": "Loperamide is an over-the-counter, peripherally acting, μ-opioid receptor agonist used for the treatment of diarrhea. In recent times users have found that at higher doses, loperamide crosses the blood-brain barrier and reaches central μ-receptors in the brain, leading to central opiate effects including euphoria and respiratory depression. We report a case of a 37-year-old female who attempted suicide with over 200 loperamide tablets. During her overdose, her QTc was significantly prolonged at >600 ms. Our case aims to add to the growing body of literature describing life-threatening ventricular arrhythmias associated with loperamide toxicity and further suggests that a metabolite of loperamide, desmethylloperamide, may play a role in the pathogenesis.",
"affiliations": "a Department of Medicine , State University of New York , Syracuse , NY , USA.;a Department of Medicine , State University of New York , Syracuse , NY , USA.;a Department of Medicine , State University of New York , Syracuse , NY , USA.",
"authors": "Bhatti|Zabeer|Z|http://orcid.org/0000-0002-7161-4750;Norsworthy|Jessica|J|;Szombathy|Tamas|T|",
"chemical_list": "D000930:Antidiarrheals; C419149:N-demethylloperamide; D008139:Loperamide",
"country": "England",
"delete": false,
"doi": "10.1080/15563650.2017.1304555",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": "55(7)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": "Loperamide toxicity; complications of poisoning; desmethylloperamide",
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D000328:Adult; D000930:Antidiarrheals; D001711:Biotransformation; D009202:Cardiomyopathies; D062787:Drug Overdose; D004562:Electrocardiography; D005260:Female; D006801:Humans; D008133:Long QT Syndrome; D008139:Loperamide; D011237:Predictive Value of Tests; D013406:Suicide, Attempted",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "659-661",
"pmc": null,
"pmid": "28349724",
"pubdate": "2017-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Loperamide metabolite-induced cardiomyopathy and QTc prolongation.",
"title_normalized": "loperamide metabolite induced cardiomyopathy and qtc prolongation"
} | [
{
"companynumb": "PHHY2017US050781",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LOPERAMIDE"
},
"drugadditional": "3",
"druga... |
{
"abstract": "OBJECTIVE\nIncidental paradoxical antiepileptic effect of levetiracetam has been described. The aim of the present study was to identify the epilepsy patients at risk.\n\n\nMETHODS\nWe performed a retrospective analysis in 207 patients treated with levetiracetam. This entailed evaluation of patient notes and patient interviews. A paradoxical effect was defined as an increased seizure frequency or the experience of more severe seizures including generalized tonic-clonic seizures (GTCS) within 1 month after starting levetiracetam (LEV).\n\n\nRESULTS\nThirty patients (14%) experienced a paradoxical effect. Eight of them (4%) developed de novo GTCS. We could not demonstrate any association between the paradoxical effect of levetiracetam and type of epilepsy or the antiepileptic comedication used. However we found that the paradoxical effect developed preferentially (p < 0.001) in mentally retarded patients.\n\n\nCONCLUSIONS\nBecause there is an increased risk of worsening epilepsy when starting levetiracetam treatment of mentally retarded epileptic patients, there is a need for caution and close observation during the first weeks of therapy.",
"affiliations": "Epilepsy Center, National Institute of Neurosurgery, Budapest, Hungary. szucsan@gmail.com",
"authors": "Szucs|Anna|A|;Clemens|Zsófia|Z|;Jakus|Rita|R|;Rásonyi|György|G|;Fabó|Daniel|D|;Holló|András|A|;Barcs|Gábor|G|;Kelemen|Anna|A|;Janszky|József|J|",
"chemical_list": "D000927:Anticonvulsants; D000077287:Levetiracetam; D010889:Piracetam",
"country": "United States",
"delete": false,
"doi": "10.1111/j.1528-1167.2008.01585.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0013-9580",
"issue": "49(7)",
"journal": "Epilepsia",
"keywords": null,
"medline_ta": "Epilepsia",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000927:Anticonvulsants; D002648:Child; D006970:Disorders of Excessive Somnolence; D004244:Dizziness; D004347:Drug Interactions; D004827:Epilepsy; D005260:Female; D006801:Humans; D008607:Intellectual Disability; D007508:Irritable Mood; D000077287:Levetiracetam; D008297:Male; D008875:Middle Aged; D010889:Piracetam; D012189:Retrospective Studies; D012307:Risk Factors",
"nlm_unique_id": "2983306R",
"other_id": null,
"pages": "1174-9",
"pmc": null,
"pmid": "18479387",
"pubdate": "2008-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "The risk of paradoxical levetiracetam effect is increased in mentally retarded patients.",
"title_normalized": "the risk of paradoxical levetiracetam effect is increased in mentally retarded patients"
} | [
{
"companynumb": "HU-MYLANLABS-2021M1066729",
"fulfillexpeditecriteria": "1",
"occurcountry": "HU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "1",
... |
{
"abstract": "Developments in the drugs industry are leading to more rare drug side effects being encountered in clinical practice. Of these side effects, allergic reactions and hypersensitivity are seen in the usage of a large group of drugs such as antibiotics, analgesics, antineoplastics, contrast agents, corticosteroids, intravenous anesthetics, nonsteroidal anti-inflammatory drugs, and proton pump inhibitors. One important result of these reactions is acute coronary syndrome, which may have serious life-threatening results. This syndrome was first described in 1991 by Kounis as an 'allergic angina syndrome progressing to acute myocardial infarction', and thereafter called 'allergic myocardial infarction'. This case report presents a 70-year-old male who had angina and dyspnea after administration of midazolam at the beginning of a transurethral prostatectomy operation.",
"affiliations": "Department of Cardiology, Samsun Training and Research Hospital, Samsun, Turkey. ahmethakanates@yahoo.com.;Department of Cardiology, Kanuni Training and Research Hospital, Trabzon, Turkey.",
"authors": "Ateş|Ahmet Hakan|AH|;Kul|Selim|S|",
"chemical_list": "D000759:Adjuvants, Anesthesia; D008874:Midazolam",
"country": "Turkey",
"delete": false,
"doi": "10.5543/tkda.2015.44567",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1016-5169",
"issue": "43(6)",
"journal": "Turk Kardiyoloji Dernegi arsivi : Turk Kardiyoloji Derneginin yayin organidir",
"keywords": null,
"medline_ta": "Turk Kardiyol Dern Ars",
"mesh_terms": "D000759:Adjuvants, Anesthesia; D000368:Aged; D000787:Angina Pectoris; D017023:Coronary Angiography; D003329:Coronary Vasospasm; D003937:Diagnosis, Differential; D004417:Dyspnea; D004562:Electrocardiography; D006801:Humans; D006967:Hypersensitivity; D008297:Male; D008874:Midazolam; D011468:Prostatectomy",
"nlm_unique_id": "9426239",
"other_id": null,
"pages": "558-61",
"pmc": null,
"pmid": "26363750",
"pubdate": "2015-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute coronary syndrome due to midazolam use: Kounis syndrome during a transurethral prostatectomy.",
"title_normalized": "acute coronary syndrome due to midazolam use kounis syndrome during a transurethral prostatectomy"
} | [
{
"companynumb": "TR-FRESENIUS KABI-FK201506180",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MIDAZOLAM\\MIDAZOLAM HYDROCHLORIDE"
},
"d... |
{
"abstract": "Oral multifocal epithelial hyperplasia (MEH), or Heck's disease, is a rare benign proliferation of the oral mucosa associated with human papillomavirus (HPV). It clinically presents as multiple asymptomatic papules and nodules that mostly affect the lips, buccal mucosa, and tongue. MEH is predominantly found in children and young adults while relatively few cases have been reported in the elderly population. Here, we report a case of oral MEH in a 65-year-old man with history of lung transplantation. This case highlights the potential susceptibility of organ transplant recipients to the development of MEH. Since MEH that does not require treatment unless the lesion bothers the patient, clinicians should promptly establish a definitive diagnosis to rule out other HPV-related precancerous lesions.",
"affiliations": "Department of Oral Medicine, University of Pennsylvania School of Dental Medicine, Philadelphia, PA, USA.;Department of Basic and Translational Sciences, University of Pennsylvania School of Dental Medicine, Philadelphia, PA, USA.;Department of Oral Medicine, University of Pennsylvania School of Dental Medicine, Philadelphia, PA, USA.",
"authors": "Chompunud Na Ayudhya|Chalatip|C|;Alawi|Faizan|F|;Akintoye|Sunday O|SO|https://orcid.org/0000-0002-3090-1374",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13497",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "23(2)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "Heck's disease; focal epithelial hyperplasia; human papilloma virus; immunosuppression; multifocal epithelial hyperplasia; organ transplant",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D001741:African Americans; D000368:Aged; D017573:Focal Epithelial Hyperplasia; D006801:Humans; D006965:Hyperplasia; D016040:Lung Transplantation; D008297:Male; D027383:Papillomaviridae",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13497",
"pmc": null,
"pmid": "33095955",
"pubdate": "2021-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Unusual oral multifocal epithelial hyperplasia in an adult African-American lung transplant patient.",
"title_normalized": "unusual oral multifocal epithelial hyperplasia in an adult african american lung transplant patient"
} | [
{
"companynumb": null,
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "3",
"drugadmi... |
{
"abstract": "Tirofiban is widely used in patients with acute ST elevation myocardial infarction (STEMI) underwent percutaneous coronary intervention (PCI). This drug can efficiently improve myocardial perfusion and cardiac function, but its dose still remains controversial. We here investigated the effects of different dose of tirofiban on myocardial reperfusion and heart function in patients with STEMI. A total of 312 STEMI patients who underwent PCI in our hospital from March 2017 to March 2018 were enrolled and randomly divided into control group (75 cases, 0 μg/kg), low-dose group (79 cases, 5 μg/kg), medium-dose group (81 cases, 10 μg/kg) and high-dose group (77 cases, 20 μg/kg). The infarction-targeted artery flow grade evaluated by thrombolysis in myocardial infarction (TIMI), corrected TIMI frame count (CTFC) and sum-ST-segment resolution were recorded. At Day 7 and Day 30 after PCI, the left ventricular ejection fraction (LVEF), left ventricular end diastolic diameter, left ventricular end systolic diameter, major adverse cardiovascular events and the hemorrhage and thrombocytopenia were also evaluated. After PCI, the rate of TIMI grade 3, CTFC and incidence of sum-ST-segment resolution > 50% of high-dose group were significantly higher than those of control group, low-dose group and medium-dose group (P < .05), and the CTFC of medium -dose group were significantly higher than that of control group, low-dose group (P < .05). Moreover, the LVEF, left ventricular end diastolic diameter and left ventricular end systolic diameter of high-dose group were significantly improved than those of other groups, and the LVEF of medium-dose group was significantly superior to that of low-dose group (P < .05). However, the incidence of major adverse cardiac events in high-dose group was significantly decreased, while the hemorrhage and incidence of thrombocytopenia of high-dose group were significantly higher than those of other 3 groups (P < .05). The tirofiban can effectively alleviate the myocardial ischemia-reperfusion injury and promote the recovery of cardiac function in STEMI patients underwent PCI. Although the high-dose can enhance the clinical effects, it also increased the hemorrhagic risk. Therefore, the rational dosage application of tirofiban become much indispensable in view of patient's conditions and hemorrhagic risk, and a medium dose of 10 μg/kg may be appropriate for patients without high hemorrhagic risk.",
"affiliations": "Department Pharmacy, the Second Clinical Hospital of Shanxi Medical University, Taiyuan, Shanxi.;AstraZeneca (Wuxi) trading co. LTD, Wuxi, Jiangsu, China.",
"authors": "Wang|Haixia|H|;Feng|Meiqin|M|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D000077466:Tirofiban",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000020402",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974 1536-5964 Wolters Kluwer Health \n\n32501985\nMD-D-20-00967\n10.1097/MD.0000000000020402\n20402\n3400\nResearch Article\nObservational Study\nInfluences of different dose of tirofiban for acute ST elevation myocardial infarction patients underwent percutaneous coronary intervention\nWang Haixia BDa∗ Feng Meiqin MDb Sun. YX a Department Pharmacy, the Second Clinical Hospital of Shanxi Medical University, Taiyuan, Shanxi\nb AstraZeneca (Wuxi) trading co. LTD, Wuxi, Jiangsu, China.\n∗ Correspondence: Haixia Wang, Department Pharmacy, the Second Clinical Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, China (e-mail: hxwang@email.com).\n05 6 2020 \n05 6 2020 \n99 23 e204023 2 2020 22 4 2020 23 4 2020 Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.2020This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc/4.0Abstract\nTirofiban is widely used in patients with acute ST elevation myocardial infarction (STEMI) underwent percutaneous coronary intervention (PCI). This drug can efficiently improve myocardial perfusion and cardiac function, but its dose still remains controversial. We here investigated the effects of different dose of tirofiban on myocardial reperfusion and heart function in patients with STEMI. A total of 312 STEMI patients who underwent PCI in our hospital from March 2017 to March 2018 were enrolled and randomly divided into control group (75 cases, 0 μg/kg), low-dose group (79 cases, 5 μg/kg), medium-dose group (81 cases, 10 μg/kg) and high-dose group (77 cases, 20 μg/kg). The infarction-targeted artery flow grade evaluated by thrombolysis in myocardial infarction (TIMI), corrected TIMI frame count (CTFC) and sum-ST-segment resolution were recorded. At Day 7 and Day 30 after PCI, the left ventricular ejection fraction (LVEF), left ventricular end diastolic diameter, left ventricular end systolic diameter, major adverse cardiovascular events and the hemorrhage and thrombocytopenia were also evaluated. After PCI, the rate of TIMI grade 3, CTFC and incidence of sum-ST-segment resolution > 50% of high-dose group were significantly higher than those of control group, low-dose group and medium-dose group (P < .05), and the CTFC of medium -dose group were significantly higher than that of control group, low-dose group (P < .05). Moreover, the LVEF, left ventricular end diastolic diameter and left ventricular end systolic diameter of high-dose group were significantly improved than those of other groups, and the LVEF of medium-dose group was significantly superior to that of low-dose group (P < .05). However, the incidence of major adverse cardiac events in high-dose group was significantly decreased, while the hemorrhage and incidence of thrombocytopenia of high-dose group were significantly higher than those of other 3 groups (P < .05). The tirofiban can effectively alleviate the myocardial ischemia-reperfusion injury and promote the recovery of cardiac function in STEMI patients underwent PCI. Although the high-dose can enhance the clinical effects, it also increased the hemorrhagic risk. Therefore, the rational dosage application of tirofiban become much indispensable in view of patient's conditions and hemorrhagic risk, and a medium dose of 10 μg/kg may be appropriate for patients without high hemorrhagic risk.\n\nKeywords\ndifferent dosemyocardial infarctionpercutaneous coronary interventionST segment elevationtirofibanOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nAcute ST elevation myocardial infarction (STEMI) is usually caused by the coronary plaque rupture and acute thrombosis, which will result in coronary artery occlusion and myocardial necrosis, thus causing series of clinical symptoms.[1] At present, percutaneous coronary intervention (PCI) is widely accepted as a main therapy for STEMI in clinic. However, patency of epicardial vessels can not completely recover myocardial perfusion. Previous reports showed that ischemia-reperfusion injury and microembolization predominately contributed to the repurfusion of ischemic myocardium, which influenced the patients’ cardiac function and long-term prognosis severely.[2–5] A large body of evidence suggests that serious cardiovascular adverse events such as angina pectoris, heart failure, and even sudden cardiac death may occur after PCI, owing to the lack of effective blood perfusion and oxygen supply in the myocardium.[6,7] Tirofiban is a kind of antiplatelet drug belonging to glycoprotein IIb/IIIa inhibitors. This glycoprotein IIb/IIIa inhibitor can inhibit the activation, adherence and aggregation of platelets; alleviate the myocardial perfusion injury; improve cardiac function and reduce the incidence of death. All of them are needed for anchoring vessel revascularization after PCI.[8] However, the dose of tirofiban is still controversial, and its necessity and security also remain in uncertainty.[9–11] In this regard, totally 312 STEMI patients underwent PCI with different dose of tirofiban were included for case-control analysis, with aim at investigating the differences of clinical outcome, cardiac function and safety profiles between different dose of tirofiban.\n\n2 Methods\n2.1 Patients\nA total of 312 acute STEMI patients who underwent PCI in our hospital from March 2017 to March 2018 were enrolled, referring to the Guidelines for the Diagnosis and Treatment of ST Elevation Acute Myocardial Infarction.[12] Inclusion criteria were listed below: patients age ranging from 50 years to 79 years; clinical manifestations with chest pain, nausea, vomiting and so on; the electrocardiography (ECG) showing ST-segment elevation of > 0.1 mV in at least 2 leads, or new left bundle branch block; the level of creatine kinase-MB (CK-MB) and troponin-I (Tn-I) higher than normal level; residual thrombus from infarction-related culprit vessels verified by angiography. Exclusion criteria were set as below: cardiogenic shock or hemodynamic instability; severe hemorrhage inclination, high risk of bleeding (CRUSADE bleeding risk score > 40 points); severe dysfunction of hepatic and kidney; persistent severe hypertension or cerebral hemorrhage within a year; allergic to tirofiban. The study protocols were approved by ethics committee of our hospital (SXR1600013), and written informed consent was obtained from all patients or their authorised relatives.\n\n2.2 Treatment protocols\nAccording to random number table, these patients were randomly divided into control group (75 cases, 0 μg/kg), low-dose group (79 cases, 5 μg/kg), medium-dose group (81 cases, 10 μg/kg) and high-dose group (77 cases, 20 μg/kg). All patients received 100∼300 mg aspirin tablets (Xinhua Pharmaceutical Co., Ltd, Shandong, China) and 300∼600 mg clopidogrel (Sanofi Minsheng Pharmaceutical Co., Ltd, Hangzhou, China). On this basis, the control group was treated with no tirofiban. In the low-dose group, a bolus of 5 μg/kg tirofiban (Huadong pharmaceutical Co., Ltd, Hangzhou, China) was injected intravenously within 5 minutes, followed by continuous intravenous injection at 0.05 μg·kg−1·min−1 for 36 h. In the medium-dose group, a bolus of 10 μg/kg tirofiban was injected intravenously within 5 minutes, followed by continuous intravenous injection at 0.10 μg·kg−1·min−1 for 36 hour. In the high-dose group, a bolus of 20 μg/kg tirofiban was injected intravenously within 5 minutes, followed by continuous intravenous injection at 0.225 μg·kg−1·min−1 for 36 hour. The maintenance dosage of tirofiban can be adjusted according to bleeding risk among groups mentioned above. After PCI, all patients were treated with oral aspirin (100 mg/d), and clopidogrel (75 mg/d) for at least 12 months. Simultaneously, other routine treatments, including the treatment of diuretics, statin drugs, angiotensin converting enzyme inhibitor, angiotensin receptor antagonist, β-adrenergic receptor blocker and calcium channel blockers, and so on, were performed according to patients’ conditions. With the use of puncture through the right radial artery, perform coronary angiography was performed following catheter being put in to visualize infarction vessels. Based on the target lesions, patients were treated with balloon dilation, and then stents were implanted routinely, with the ratio of stent diameter and vessel diameter at (1∼1.1):1. Only the infarction related artery was intervened during operation. After that, these patients were subject to coronary arteriography examination. The operation was successful when the results showed that the presence of reperfusion of infarction related artery, residual stenosis of culprit lesion less than 30%, and no coronary arterial dissection and perforation. During the operation, for those patients who have bradycardia should be implanted with temporary pacemakers, and for those who appeared hemodynamic instability or cardiogenic shock, the intra-aortic balloon pump can be performed with alternative therapy.\n\n2.3 Observational parameters\nFor the indicators of myocardial reperfusion:[13] the myocardial reperfusion was assessed after PCI therapy. The thrombolysis in myocardial infarction (TIMI) grade 3 flow, corrected TIMI frame count and the 90-minutes sum-ST-segment resolution (sumSTR) were recorded. The cardiac function indexes:[14] the color Doppler imaging (CDI) was used to measure the left ventricular ejection fraction (LVEF), left ventricular end diastolic diameter (LVEDD) and left ventricular end systolic diameter (LVESD). For the primary clinical end point of the study: major adverse cardiac events (MACE) after 30 days after the PCI were recorded, which included angina pectoris, myocardial infarction, acute heart failure, cardiac death, and target vessel revascularization (TVR), and so on. For the hemorrhage and thrombocytopenia: after PCI, hemorrhage mainly included bleeding at puncture place, hemorrhage of skin and tunica mucosa, gastrointestinal hemorrhage, hematuria and intracranial hemorrhage, and so on. In addition, the thrombocytopenia was recorded.\n\n2.4 Statistical analysis\nAll statistical analysis was conducted by SPSS 25.0. The measurement data were expressed as mean ± standard deviation , and analysis of variance were used for comparison among 4 groups. The enumeration data were expressed as percentages (%) and were compared using the Chi-Square (χ2) test. The rank sum test was adopted to compare the ranked data. P < .05 was considered statistically significant.\n\n3 Results\n3.1 General characteristics of patients\nFrom March 2017 to March 2018, a total of 312 acute STEMI patients who underwent PCI in our hospital were enrolled and randomly assigned to control group (75 cases, 0 μg/kg), low-dose group (79 cases, 5 μg/kg), medium-dose group (81 cases, 10 μg/kg) and high-dose group (77 cases, 20 μg/kg). The general data of the 4 groups were analyzed. The 4 groups showed no significant differences in general data (P > .05) (Table 1).\n\nTable 1 Comparisons of general data of Patients.\n\n3.2 Comparisons of postoperative myocardial reperfusion indexes among the 4 groups\nTIMI grade 3 flow, CTFC, and sumSTR >50% of high-dose group were significantly higher than those of control group, low-dose group and medium-dose group (P = .010, < .001, <.001), and the CTFC of medium-dose group were significantly higher than that of control group, low-dose group (P < .05). However, there was no statistical differences in the comparison of TIMI grade 3 flow and sumSTR >50% among control group, low-dose group and medium-dose group (P > .05). (Table 2)\n\nTable 2 Comparisons of postoperative myocardial reperfusion indexes.\n\n3.3 Comparisons of cardiac function index among the 4 groups\nBefore the PCI, no the differences were observed in the comparisons of LVEF, LVEDD and LVESD among the 4 groups (P > .05). At 7 days, 30 days after the PCI, the LVEF, LVEDD and LVESD of high-dose group were all superior to those of control group, low-dose group and medium-dose group (P < .001). At 30 days after the PCI, the LVEF, LVEDD and LVESD of medium-dose group were superior to those of control group, and the LVEF of medium-dose group was superior to that of low-dose group, the differences mentioned above showed statistical significant (P < .05).\n\nTable 3 Comparisons of indexes for cardiac function.\n\n3.4 Comparisons of incidence of MACE among the 4 groups\nThe incidence of MACE in control group, low-dose group, medium-dose group and high-dose group within 30 days were 34.67%, 26.58%, 16.05%, and 7.79%, respectively. The incidence of MACE in high-dose group were significantly lower than that in control group, low-dose group and medium-dose group, and the medium-dose group were significantly lower than that in control group, these differences showed statistical significant (P < .05). No significant differences were observed at the incidence of MACE in control group and low-dose group (P > .05).\n\nTable 4 Comparisons of the incidence of MACE.\n\n3.5 Comparisons of the incidence of the hemorrhage and thrombocytopenia among the 4 groups\nThe incidence of the hemorrhag in control group, low-dose group, medium-dose group and high-dose group were 10.67%, 6.33%, 11.11%, and 29.87%, respectively, and their individual incidence of thrombocytopenia were 4.00%, 6.36%, 12.35%, and 23.38%. The incidence of the hemorrhage and thrombocytopenia in high-dose group were significantly higher than those in control group, low-dose group, medium-dose group (P < .001). However, no significant difference was observed for the incidence of the hemorrhage and thrombocytopenia among control group, low-dose group, medium-dose group (P > .05).\n\nTable 5 Comparisons of the incidence of the hemorrhage and thrombocytopenia.\n\n4 Discussion\nAcute STEMI is a common cardiovascular emergency which is induced by severe coronary artery stenosis or occlusion, leading to myocardial ischemia, anoxia, and necrosis in the relevant blood supply area, and is also 1 of the reasons that cause the death of patients with cardiovascular diseases.[15] Previous studies showed that the efficacy of PCI on patients with STEMI was remarkable, which can increase the patency of infarction-related coronary artery, recover the myocardial ischemia-reperfusion injury, and improve the prognosis of patients.[16,17] Some studies confirmed that the combined application of IIb/IIIa receptor antagonists for patients with acute myocardial infarction (AMI) undergoing PCI can significantly increase the postoperative coronary TIMI flow grading of infarction-related coronary artery, prompt the myocardial perfusion, reduce the incidence of MACE.[18–20] Tirofiban is a non-peptide reversible antagonist of glycoprotein IIb/IIIa receptor, which can block fibrinogen receptor binding to glycoprotein IIb/IIIa complex and effectively inhibit the platelet aggregation after specifically binding to surface receptors of platelet.[21] Furthermore, tirofiban can inhibit inflammatory factors and vasocontrictive substances, improve the microcirculation at the early stage, and reduce the incidence of MACE. The efficacy of tirofiban in the treatment of STEMI has drawn global attention. Unfortunately, some studies have suggested that it can also increase the risk of hemorrhage, and the clinical dose has not yet reached a wide consensus. The common recommended clinical dose is 10 μg/kg, followed by continuous intravenous injection at 0.15 μg·kg−1·min−1, which is usually accompanied with a high recurrence rate of MACE.[22] Hence, the appropriate dosage of tirofiban is still under dispute.\n\nIn this study, the LVEF, LVEDD and LVESD of the high-dose group were all superior to those of control group, low-dose group and medium-dose group at 7, 30 days (P < .001). Furthermore, the LVEF, LVEDD and LVESD of medium-dose group were all superior to those of control group, and the LVEF of medium-dose group was superior to that of low-dose group at 30 days after PCI, (P < .05). These data suggesting that the increase of tirofiban dose may have certain correlations to the improvement of efficacy, which is consistent with other's study.[23] The safety concern of tirofiban mainly refers to the risk of hemorrhage. The application of tirofiban can cause thrombocytopenia and increase the risk of hemorrhage-related complications, especially severe hemorrhage such as intracranial hemorrhage, which can lead to death in some patients.[24,25] Recently, a study showed that, the incidence and mortality of hemorrhage in AMI patients were positively correlated with the dose of antiplatelet drugs.[26]\n\nIn order to investigate the clinical effect and safety of tirofiban, the different dose of tirofiban was used for patients with STEMI undergoing PCI. The results demonstrated that the improvements of myocardial ischemia- reperfusion injury and cardiac function in high-dose group was significantly better than that in control group, medium-dose group and low-dose group, and the incidence of MACE in high-dose group was significantly lower than that in control group, medium-dose group and low-dose group (P < .001), indicating that high-dose of tirofiban can improve the cardiac function, and reduce the incidence of MACE. The mechanism underpinning this effect might be due to the strong inhibitory effect of high-dose of tirofiban on platelets, which can improve the coronary artery flow, increase blood supply of myocardial cell. More importantly, it can obviously reduce the area of myocardial infarction, and promote the ST segment down-regulation.[27] Nevertheless, the incidence of the hemorrhage in the high-dose group was significantly higher than that in control group, low-dose group and medium-dose group (P < .001), suggesting the incidence of hemorrhage occurred in a dose-dependent relationship and high-dose of tirofiban increased the incidence of hemorrhage.[28]\n\nSeveral lines of evidence demonstrated that the glycoprotein IIb/IIIa inhibitors had great effect on reducing the incidence of MACE. Fabris E, et al[29] argued that tirofiban prehospital treatment can reduce the incidence of MACE and mortality at 30 days, 1-year. Velibey Y, et al[30] pointed out that tirofiban was associated with a lower short- and long-term mortality, although the higher incidence of complications in hospital stay. Consistent with this argument, the incidence of MACE in high-dose group was also obviously higher than those in other 3 groups at 30 days (7.79% vs 34.67%, 26.58%, 16.05%), along with higher complications of hemorrhage (29.87% vs 10.67%, 6.33%, 11.11%). Hence, these data suggested that appropriate dosage of tirofiban should be cautiously applied according to patient's hemorrhagic risk.\n\nThe results of this study displayed that the application of tirofiban in STEMI patients underwent PCI can alleviate the myocardial ischemia-reperfusion injury and promote early recovery of cardiac function, along with better clinical efficacy. In other studies, Zhang Y, et al[32] drew a conclusion that the 10 μg/kg tirofiban can effectively prevent stent thrombosis, alleviate the inflammatory reaction in PCI patients, improve the quality of life with safe control of hemorrhagic risk. However, a meta-analysis pointed out that moderate tirofiban was a safe treatment, but the protocol of intra-arterial administration required further research.[31] As we know, the assessments and managements of hemorrhagic risk was an important concern for the PCI patients. The CRUSADE bleeding risk score was widely used in assessments of hemorrhagic risk, and CRUSADE bleeding risk score >40 points were considered as high risk of hemorrhage.[33] In this study, only patients without hemorrhagic risk were included into study and this study design was not suitable for hemorrhagic risk patients. In addition, the sample size of this study was a little small, which may lead to some statistical bias. The application of tirofiban in treatment for STEMI need to be investigated in randomized study with larger sample from multicenter.\n\nIn conclusion, the efficacy of tirofiban for acute STEMI patients underwent PCI was positively correlated with its dose. The high dose can enhance the clinical effects, but also increase the risk of hemorrhage. Therefore, the appropriate dose could be adopted by reference to the specific conditions of patients under assessment of hemorrhagic risk, and a medium dose of 10 μg/kg may be appropriate for patients without high hemorrhagic risk.\n\nAuthor contributions\nHW and MF designed and conducted the study, and drafted the manuscript. HW and MF help conducting the study and analyzing the data.\n\nAbbreviations: CTFC = corrected TIMI frame count, LVEDD = left ventricular end diastolic diameter, LVEF = left ventricular ejection fraction, LVESD = left ventricular end systolic diameter, MACE = major adverse cardiac events, PCI = percutaneous coronary intervention, STEMI = ST elevation myocardial infarction, sumSTR = sum-ST-segment resolution, TIMI = thrombolysis in myocardial infarction.\n\nHow to cite this article: Wang H, Feng M. Influences of different dose of tirofiban for acute ST elevation myocardial infarction patients underwent percutaneous coronary intervention. Medicine. 2020;99:23(e20402).\n\nThe authors declare that there are no sources of funding to be acknowledged.\n\nThe authors have no conflicts of interest to disclose.\n\nThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\n==== Refs\nReferences\n[1] Ugalde H Yubini MC Rozas S \nPrediction of hospital mortality of ST elevation myocardial infarction using TIMI score\n. Rev Med Chil \n2017 ;145 :572 –8\n.28898332 \n[2] Ismail S Wong C Rajan P \nST-elevation acute myocardial infarction in pregnancy: 2016 update\n. Clin Cardiol \n2017 ;40 :399 –406\n.28191905 \n[3] Heusch G Skyschally A Kleinbongard P \nCoronary microembolization and microvascular dysfunction\n. Int J Cardiol \n2018 ;258 :17 –23\n.29429637 \n[4] Cao B Zhang C Wang H \nRenoprotective effect of remote ischemic postconditioning in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention\n. Ther Clin Risk Manag \n2018 ;22 :369 –75\n.\n[5] Sigan Hu Hongju Wang Jian Zhu \nEffect of intra-coronary administration of tirofiban through aspiration catheter on patients over 60 years with ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention\n. Medicine \n2018 ;97 :e10850 .29794782 \n[6] Wickramatilake CM Mohideen MR Pathirana C \nAssociation of testosterone, inflammation with the severity of first acute ST-elevation myocardial infarction\n. Indian Heart J \n2017 ;69 :291 –1291\n.28460787 \n[7] Lee SY Shin DH Kim JS \nIntravascular ultrasound predictors of major adverse cardiovascular events after implantation of everolimus-eluting stents for long coronary lesions\n. Rev Esp Cardiol \n2017 ;70 :88 –95\n.27789170 \n[8] Kaymaz C Keleş N Özdemir N \nThe effects of tirofiban infusion on clinical and angiographic outcomes of patients with STEMI undergoing primary PCI\n. Anatol J Cardiol \n2015 ;15 :899 –906\n.25868037 \n[9] Niu J Ding Y Zhai T \nThe efficacy and safety of tirofiban for patients with acute ischemic stroke: a protocol for systematic review and a meta-analysis\n. Medicine \n2019 ;98 :e14673 .30817594 \n[10] Anderson GL Osborn JL Nei SD \nComparison of in-hospital bleeding and cardiovascular events with high-dose bolus tirofiban and shortened infusion to short-duration eptifibatide as adjunctive therapy for percutaneous coronary intervention\n. Am J Cardiol \n2019 ;123 :44 –9\n.30539747 \n[11] Yu T Lin Y Jin A \nSafety and efficiency of low dose intra-arterial tirofiban in mechanical thrombectomy during acute ischemic stroke\n. Curr Neurovasc Res \n2018 ;15 :145 –50\n.29875001 \n[12] Bainey KR Armstrong PW \nTransatlantic comparison of ST-segment elevation myocardial infarction guidelines: insights from the United States and Europe\n. J Am Coll Cardiol \n2016 ;67 :216 –29\n.26724199 \n[13] Yukio Ozaki Yuki Katagiri Yoshinobu Onuma \nCVIT expert consensus document on primary percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI) in 2018\n. Cardiovasc Interv Ther \n2018 ;33 :178 –203\n.29594964 \n[14] Storve S Grue JF Samstad S \nRealtime automatic assessment of cardiac function in echocardiography\n. IEEE Trans Ultrason Ferroelectr Freq Control \n2016 ;63 :358 –68\n.26780792 \n[15] Ahmed N Carberry J Teng V \nRisk assessment in patients with an acute ST-elevation myocardial infarction\n. J Comp Eff Res \n2016 ;5 :581 –93\n.27580675 \n[16] Agarwal SK Agarwal S \nRole of intracoronary fibrinolytic therapy in contemporary PCI practice\n. Cardiovasc Revasc Med \n2019 ;20 :1165 –71\n.30685340 \n[17] Gao R Wang J Zhang S \nThe value of combining plasma D-dimer and endothelin-1levels to predict no-reflow after percutaneous coronary intervention of ST-segment elevation in acute myocardial infarction patients with a type 2 diabetes mellitus history\n. Med Sci Monit \n2018 ;24 :3549 –56\n.29806659 \n[18] De Winter RJ \nAnticoagulation and antiplatelet therapy in acute coronary syndromes: choosing between the Scylla of bleeding and the Charybdis of ischaemic events\n. Neth Heart J \n2018 ;26 :287 –8\n.29797236 \n[19] Karathanos A Lin Y Dannenberg L \nRoutine glycoprotein IIb/IIIa inhibitor therapy in ST-segment elevation myocardial infarction: a meta-analysis\n. Can J Cardiol \n2019 ;35 :1576 –88\n.31542257 \n[20] Liu Y Liu H Hao Z \nEfficacy and safety of different doses of tirofiban combined with ticagrelor on diabetic patients withAMI receiving in emergency percutaneous coronary intervention (PCI)\n. Int J Clin Exp Med \n2015 ;8 :11360 –9\n.26379951 \n[21] Wojtukiewicz MZ Hempel D Sierko E \nAntiplatelet agents for cancer treatment: a real perspective or just an echo from the past?\n\nCancer Metastasis Rev \n2017 ;36 :305 –29\n.28752248 \n[22] Wang J Wang DZ \nEvaluation on the safety and efficacy of high-dose tirofiban in the primary percutaneous coronary intervention on patients with acute ST-elevation myocardial infarction\n. Chin Gen Prac \n2015 ;18 :3276 –82\n.\n[23] Zhao C Cheng G He R \nEffects of different routes of tirofiban injection on the left ventricular function and prognosis of patients with myocardial infarction treated with percutaneous coronary intervention\n. Exp Ther Med \n2015 ;9 :2401 –5\n.26136995 \n[24] Hermanides RS Kilic S van’t Hof AWJ \nOptimal pharmacological therapy in ST-elevation myocardial infarction-a review: a review of antithrombotic therapies in STEMI\n. Neth Heart J \n2018 ;26 :296 –310\n.29687412 \n[25] Niu XW Zhang JJ Bai M \nCombined thrombectomy and intracoronary administration of glycoprotein IIb/IIIa inhibitors improves myocardial reperfusion in patients undergoing primary percutaneous coronary intervention: a meta-analysis\n. J Geriatr Cardiol \n2017 ;14 :614 –23\n.29238362 \n[26] Wilmer CI \nIntracoronary high-dose bolus tirofiban administration during complex coronary interventions: a United States-based case series\n. Cardiovasc Revasc Med \n2018 ;19 :112 –6\n.28684062 \n[27] Ulus T Şenol U Tahmazov S \nHigh-dose bolus tirofiban versus low-dose bolus in patients with acute coronary syndrome undergoing percutaneous coronary intervention\n. Turk Kardiyol Dern Ars \n2017 ;45 :126 –33\n.28424434 \n[28] Tu Y Hu L Yang C \nOptimal antithrombotic therapy for patients with STEMI undergoing PCI at high risk of bleeding\n. Curr Atheroscler Rep \n2019 ;21 :22 –30\n.30997584 \n[29] Fabris E Kilic S Schellings DAAM \nLong-term mortality and prehospital tirofiban treatment in patients with ST elevation myocardial infarction\n. Heart \n2017 ;103 :1515 –20\n.28679686 \n[30] Velibey Y Guvenc TS Demir K \nEffects of bailout Tirofiban on in-hospital outcomes and long-term mortality in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous intervention\n. Angiology \n2019 ;70 :431 –9\n.30370779 \n[31] Gong J Shang J Yu H \nTirofiban for acute ischemic stroke: systematic review and meta-analysis\n. Eur J Clin Pharmacol \n2020 ;76 :475 –81\n.31900544 \n[32] Zhang Y Shao T Yao L \nEffects of tirofiban on stent thrombosis, Hs-CRP, IL-6 and sICAM-1 after PCI of acute myocardial infarction\n. Exp Ther Med \n2018 ;16 :3383 –8\n.30233685 \n[33] Choi SY Kim MH Serebruany V \nComparison of ACUITY, CRUSADE, and GRACE risk scales for predicting clinical outcomes in patients treated with dual-antiplatelet therapy\n. TH Open \n2018 ;2 :e399 –406\n.31249967\n\n",
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"issn_linking": "0025-7974",
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"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000368:Aged; D016009:Chi-Square Distribution; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D062645:Percutaneous Coronary Intervention; D010975:Platelet Aggregation Inhibitors; D000072657:ST Elevation Myocardial Infarction; D013318:Stroke Volume; D000077466:Tirofiban; D016896:Treatment Outcome",
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"title": "Influences of different dose of tirofiban for acute ST elevation myocardial infarction patients underwent percutaneous coronary intervention.",
"title_normalized": "influences of different dose of tirofiban for acute st elevation myocardial infarction patients underwent percutaneous coronary intervention"
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"abstract": "OBJECTIVE\nTo detail a case of Aspergillus terreus brain abscess in a patient undergoing treatment for malignant glioma. Central nervous system aspergillosis usually occurs in patients with hematopoietic neoplasms or post transplantation, not in those with solid tumors. Most systemic invasive mold infections are attributable to Aspergillus fumigatus or Aspergillus flavus.\n\n\nMETHODS\nThe patient had received external beam radiation, temozolomide chemotherapy, and high-dose steroids, and had lymphopenia, but not sustained neutropenia. She developed a brain mass that mimicked tumor progression by neuroimaging criteria; infection was not a consideration.\n\n\nRESULTS\nBrain biopsy showed fungal cerebritis and cultures grew A. terreus, a variant being reported with greater frequency as a pathogen in patients with risk factors for aspergillosis.\n\n\nCONCLUSIONS\nBrain tumor patients who receive steroids to control their peritumoral edema may be particularly susceptible to cerebral A. terreus infection, especially when they additionally develop the lymphopenia commonly associated with temozolomide.",
"affiliations": "Departments of Neurology, University of Colorado, Health Sciences Center, Aurora, CO 80045, USA.",
"authors": "Damek|D M|DM|;Lillehei|K O|KO|;Kleinschmidt-DeMasters|B K|BK|",
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"medline_ta": "Clin Neuropathol",
"mesh_terms": "D001230:Aspergillus; D001922:Brain Abscess; D001932:Brain Neoplasms; D003937:Diagnosis, Differential; D005260:Female; D005909:Glioblastoma; D006801:Humans; D008875:Middle Aged; D020953:Neuroaspergillosis",
"nlm_unique_id": "8214420",
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"pubdate": "2008",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Aspergillus terreus brain abscess mimicking tumor progression in a patient with treated glioblastoma multiforme.",
"title_normalized": "aspergillus terreus brain abscess mimicking tumor progression in a patient with treated glioblastoma multiforme"
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"abstract": "Few centers worldwide have trialed cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in pediatric rhabdomyosarcoma. This case involves a 5-year-old boy with gross hematuria who was found to have an 8 cm pelvic mass, likely arising from the prostate and extending along the bladder wall. Excisional biopsy revealed undifferentiated fusion negative sarcoma. The mass demonstrated reduction in size with chemotherapy and photon radiation therapy. He presented to our institution for delayed primary excision, and underwent cytoreductive surgery with hyperthermic intraperitoneal chemotherapy using cisplatin. Follow-up imaging 15 months postoperatively demonstrates no evidence of disease.",
"affiliations": "Mayo Clinic, Department of Urology, Rochester, MN. Electronic address: Findlay.bridget@mayo.edu.;Mayo Clinic, Department of Urology, Rochester, MN.;Mayo Clinic, Department of Urology, Rochester, MN.",
"authors": "Findlay|Bridget L|BL|;Gargollo|Patricio C|PC|;Granberg|Candace F|CF|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1016/j.urology.2020.04.032",
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"other_id": null,
"pages": "139-142",
"pmc": null,
"pmid": "32333983",
"pubdate": "2020-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Use of Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Pediatric Sarcoma for Maximal Oncologic Control.",
"title_normalized": "use of hyperthermic intraperitoneal chemotherapy hipec in pediatric sarcoma for maximal oncologic control"
} | [
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"companynumb": "US-ACCORD-183280",
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"activesubstancename": "CISPLATIN"
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{
"abstract": "A 70-year-old man was admitted to our hospital for a penile circumcision due to phimosis using continuous dose spinal anaesthesia. On postoperative day 10 he came to the emergency department with a superficial abscess localised at the injection site of the spinal catheter. He was treated with intravenous antibiotics for 10 days, and the superficial abscess was incised and drained. Ten days later, the patient was readmitted to the emergency department with complaints of back pain and fever. A repeat MRI scan of his lumbar sacral area was done and showed epidural abscesses without any compression of the medulla or the myelum. The patient did not have any signs of spinal cord or nerve root compression at that time. He was treated with intravenous antibiotics with resolution of symptoms.",
"affiliations": "Department of Surgery, Franciscus Vlietland, Schiedam.;Department of Anesthesiology, Franciscus Gasthuis, Rotterdam.;Department of Surgery, Franciscus Vlietland, Schiedam.",
"authors": "Pouwels|Sjaak|S|;Coll|Darryl M|DM|;van Marle|Alexander G J|AGJ|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-223136",
"fulltext": null,
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"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "anaesthesia; circumcision; pain; sedation",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D000775:Anesthesia, Spinal; D000900:Anti-Bacterial Agents; D002944:Circumcision, Male; D004322:Drainage; D020802:Epidural Abscess; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D010688:Phimosis; D011183:Postoperative Complications",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "1617071;291417;1978763;1152860;8148298;3589332",
"title": "Postoperative epidural abscess after spinal anaesthesia for a circumcision necessitated by phimosis.",
"title_normalized": "postoperative epidural abscess after spinal anaesthesia for a circumcision necessitated by phimosis"
} | [
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"companynumb": "NL-MYLANLABS-2018M1024397",
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{
"abstract": "BACKGROUND\nDiffuse alveolar bleeding is a potentially life-threatening condition that can be induced by several drugs. Whereas fatal cases have been reported in patients treated for other indications, no report have so far been published in a patient with multiple sclerosis treated with alemtuzumab.\n\n\nMETHODS\nWe report a case of alemtuzumab-induced diffuse alveolar bleeding in a 29 year old woman with relapsing remitting multiple sclerosis. The patient developed acute shortness of breath, chest pain on inspiration and haemoptysis following the second infusion of alemtuzumab during the first treatment cycle. Computed tomography showed bilateral alveolar opacities. Bronchoscopy and broncho-alveolar lavage showed persistently bloody return with no evidence of infection. The symptoms resolved completely without treatment and control computed tomography performed one week later showed total resolution of pulmonary infiltrates.\n\n\nCONCLUSIONS\nThis is the first published report of diffuse alveolar bleeding in a patient with multiple sclerosis treated with alemtuzumab. Four similar cases in patients treated for multiple sclerosis and several fatal cases in patients treated for other conditions are registered at the World Health Organization database of suspected adverse events (VIgiBase©), underscoring that this is a serious and possibly under-recognized complication of alemtuzumab which can also occur in the treatment of multiple sclerosis. The clinician should consider the possibility of diffuse pulmonary haemorrhage in patients with sudden onset of respiratory distress and haemoptysis following administration of alemtuzumab for multiple sclerosis.",
"affiliations": "Department of Neurology, Akershus University Hospital, Postboks 1000, 1478, Lørenskog, Norway. Aija.Zuleron.Myro@ahus.no.;Department of Pulmonary Medicine, Akershus University Hospital, Lørenskog, Norway.;Department of Radiology, Akershus University Hospital, Lørenskog, Norway.;Department of Neurology, Akershus University Hospital, Postboks 1000, 1478, Lørenskog, Norway.",
"authors": "Myro|Aija Zuleron|AZ|0000-0001-7396-6197;Bjerke|Gisle|G|;Zarnovicky|Svetozar|S|;Holmøy|Trygve|T|",
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"fulltext": "\n==== Front\nBMC Pharmacol ToxicolBMC Pharmacol ToxicolBMC Pharmacology & Toxicology2050-6511BioMed Central London 26710.1186/s40360-018-0267-5Case ReportDiffuse alveolar hemorrhage during alemtuzumab infusion in a patient with multiple sclerosis: a case report http://orcid.org/0000-0001-7396-6197Myro Aija Zuleron Aija.Zuleron.Myro@ahus.no 1Bjerke Gisle Gisle.Bjerke@ahus.no 2Zarnovicky Svetozar Svetozar.Zarnovicky@ahus.no 3Holmøy Trygve trygve.holmoy@medisin.uio.no 141 0000 0000 9637 455Xgrid.411279.8Department of Neurology, Akershus University Hospital, Postboks 1000, 1478 Lørenskog, Norway 2 0000 0000 9637 455Xgrid.411279.8Department of Pulmonary Medicine, Akershus University Hospital, Lørenskog, Norway 3 0000 0000 9637 455Xgrid.411279.8Department of Radiology, Akershus University Hospital, Lørenskog, Norway 4 0000 0004 1936 8921grid.5510.1Institute of Clinical Medicine, University of Oslo, Oslo, Norway 19 11 2018 19 11 2018 2018 19 7526 11 2017 2 11 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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\nDiffuse alveolar bleeding is a potentially life-threatening condition that can be induced by several drugs. Whereas fatal cases have been reported in patients treated for other indications, no report have so far been published in a patient with multiple sclerosis treated with alemtuzumab.\n\nCase presentation\nWe report a case of alemtuzumab-induced diffuse alveolar bleeding in a 29 year old woman with relapsing remitting multiple sclerosis. The patient developed acute shortness of breath, chest pain on inspiration and haemoptysis following the second infusion of alemtuzumab during the first treatment cycle. Computed tomography showed bilateral alveolar opacities. Bronchoscopy and broncho-alveolar lavage showed persistently bloody return with no evidence of infection. The symptoms resolved completely without treatment and control computed tomography performed one week later showed total resolution of pulmonary infiltrates.\n\nConclusion\nThis is the first published report of diffuse alveolar bleeding in a patient with multiple sclerosis treated with alemtuzumab. Four similar cases in patients treated for multiple sclerosis and several fatal cases in patients treated for other conditions are registered at the World Health Organization database of suspected adverse events (VIgiBase©), underscoring that this is a serious and possibly under-recognized complication of alemtuzumab which can also occur in the treatment of multiple sclerosis. The clinician should consider the possibility of diffuse pulmonary haemorrhage in patients with sudden onset of respiratory distress and haemoptysis following administration of alemtuzumab for multiple sclerosis.\n\nKeywords\nMultiple sclerosis- alemtuzumab-adverse events-diffuse alveolar hemorrhage-case reportissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nAlemtuzumab is a monoclonal antibody used in the treatment of relapsing remitting multiple sclerosis (MS), targeting CD-52 which is expressed on mature lymphocytes and to a lesser extent on myeloid cells [1]. Infusion reactions occur in > 90% of patients receiving alemtuzumab, and are serious in 3% [2]. We report a patient who developed diffuse alveolar bleeding, a potentially life-threatening condition not previously published in an MS patient treated with alemtuzumab.\n\nCase presentation\nA 29 year old woman with a previous history of migraine, mild asthma, congenital asymptomatic bicuspid aorta valve accidentally discovered during routine examination, missed abortion and anembryonic pregnancy was diagnosed with relapsing-remitting MS. She was treated with interferon beta1-b for five years, until it was decided to escalate the treatment due to new gadolinium enhancing MRI lesions and a sensory attack. The Expanded Disability Status Scale score was 2,0. Tests for tuberculosis, HIV, hepatitis B and C, routine blood and urine analyses, as well as respiratory examination and chest X-ray were negative. She had stopped smoking four years previously, and stopped using interferon beta 1b four months prior to the first alemtuzumab infusion because she wished to get pregnant.\n\nThe patient received standard premedication with 1000 mg methylprednisolone, 10 mg cetirizine, 1000 mg paracetamol and 400 mg acyclovir per day before each alemtuzumab infusion (12 mg per day). Prior to administration of alemtuzumab hypotension (70/35 mmHg) and bradycardia (45 beats per minute) was noticed and patient reported mild dizziness that improved after administration of Ringer’s acetate. A vasovagal reaction was suspected. For this reason, the alemtuzumab infusion was started at a low rate (12 ml/hour). Except mild headache that was treated with paracetamol and ibuprofen no infusion-associated reactions were observed the first day. Blood pressure and heart rate were normal during the alemtuzumab infusion.\n\nAt the end of the second alemtuzumab infusion, 24 h after the start of the first infusion, the patient developed chest pain on inspiration, shortness of breath, and cough. Four hours later she started coughing up bright red blood tinged sputum without clots. Body temperature, blood pressure, heart sounds and oxygen saturation were normal. Electrocardiogram showed sinus bradycardia at 48 beats/min. Auscultation revealed crepitations over the right lung, and chest x-ray showed corresponding shadowing. Platelet and leukocyte counts two hours after symptom onset were normal, and c-reactive protein was 26 mg/l (ref. < 5). Arterial blood gas analysis four hours after onset of haemoptysis was normal except for pO2 at the lower reference limit (11,0 kPa; ref. 11,0–14,4) and elevated lactate 1,3 mmol/l (ref.0,4-0,8). Haemoglobin fell from 12,0 g/dl (ref. 3, 7–15 g/dl) before the first infusion to 10,5 g/dl the day after onset of haemoptysis. Urinary analysis and serum creatinine remained normal.\n\nComputed tomography (CT) pulmonary angiography performed shortly after onset of haemoptysis showed extensive bilateral upper and lower lobe opacities with centrilobular distribution and minimal (up to 5 mm) bilateral pleural effusions without evidence of pulmonary embolism (Fig. 1). Interlobular septal thickening and dependent gradient were not present. The heart size was normal. At bronchoscopy performed 60 h after onset of haemoptysis the bronchoalveolar lavage (BAL) fluid was persistently macroscopically markedly bloody, without dilution on successive aliquots. There were no evidence of pathogenic bacteria, viruses, or atypical cells. Differential cell count of the BAL revealed 6% macrophages without hemosiderin inclusions on iron staining and 94% neutrophils indicating acute lung injury. Microscopy of BAL fluid showed many erythrocytes but counting in successive aliquots was not performed.Fig. 1 Computed tomography of the chest taken 11 h after onset of hemoptysis showing bilateral alveolar opacities\n\n\n\nThe patient remained stable from a respiratory point of view with normal vital parameters. No treatment for lung haemorrhage was given. Chest pain and haemoptysis resolved in two days. At discharge from hospital one week after onset of haemoptysis CT showed total resolution of pulmonary opacities and pleural effusions on the right side, and unchanged minimal amounts of pleural effusion on the left side. Her cough resolved after four weeks, and she has thereafter not experienced respiratory symptoms.\n\nAlemtuzumab was discontinued after the second infusion. Her MS has remained clinically and radiologically stable, and new treatment has not been initiated because of prolonged lymphopenia (0,33 10*9/l 13 months after alemtuzumab infusions).\n\nDiscussion and conclusions\nDiffuse alveolar haemorrhage (DAH) is a clinical-pathological syndrome with accumulation of red blood cells in the alveolar spaces due to injury of the pulmonary microcirculation, that can be caused by immune and coagulation disorders, heart disease, infections and drugs [3]. The mechanism of drug-induced DAH is heterogeneous and involves pulmonary capillaritis, direct toxic damage of the alveolar epithelium and basement membrane and coagulation defects [4]. The typical symptoms are acute or subacute haemoptysis, cough and dyspnea. Haemoptysis can be absent in 30% of patients [3].\n\nMacroscopically haemorrhagic BAL fluid is considered diagnostic of acute alveolar haemorrhage [3]. CT typically shows ground-glass opacities and consolidation reflecting alveolar filling, which may also be seen in pulmonary oedema [3]. Since our patient had normal heart size, centrilobular distribution of opacities, there was no evidence of interlobular septal thickening and dependent gradient usually seen in lung oedema and only minimal pleural effusion, we find DAH due to pulmonary oedema less likely.\n\nPleural effusion is uncommon in DAH [3] but can be seen in pleuritis that has been reported as a serious infusion reaction in an MS patient treated with alemtuzumab [5]. Pericardial effusion along with pneumonitis was also described in another MS patient after the second alemtuzumab infusion [6]. As our patient also had pain on inspiration, we consider pleuritis caused by alemtuzumab as the most likely cause of the minimal pleural effusions.\n\nHaemosiderin-laden macrophages are typically present in the BAL fluid 36–72 h after diffuse alveolar bleeding [3], but were not seen in our patient 60 h after symptom onset. It should be noted that the target antigen of alemtuzumab (CD52) is also expressed on myeloid cells including macrophages [7], and that the function of such cells is severely impaired in the early phase after alemtuzumab infusion [8]. It is therefore conceivable that the uptake of haemosiderin by macrophages could be perturbed shortly after alemtuzumab infusion. The two previously published case reports of alemtuzumab-associated alveolar haemorrhage do not mention whether this finding was present [9, 10].\n\nAlveolar haemorrhage can be induced by several drugs including monoclonal antibodies [4, 11]. Two reports on patients with Alport’s syndrome who received alemtuzumab as a part of immunosuppressive induction protocols during kidney transplantation have been published [9, 10]. Like our patient both these patients received premedication with steroids before administration of alemtuzumab, and in one BAL fluid was also positive for polymorphs [10]. In contrast to our patient who received 12 mg alemtuzumab on two consecutive days, both these patients received 30 mg alemtuzumab as one single subcutaneous or intravenous injection at the transplantation day, and both developed acute respiratory failure and haemoptysis the second day after alemtuzumab administration. Unlike our patient who recovered without any treatment after cessation of alemtuzumab, both developed severe respiratory failure and required mechanical ventilation, and were treated with steroids, plasma exchange and dialysis due to acute tubular necrosis. One of these patients died due to worsening respiratory function and failing graft function [10].\n\nAlport’s syndrome possibly predisposes to alveolar haemorrhage due to altered collagen structure [10]. Our patient has an asymptomatic bicuspid aortic valve which can be associated with connective tissue disorders [12]. High throughput sequencing of 44 genes associated with connective tissue disorders did however not reveal relevant pathology.\n\nIn total, 22 cases of alveolar haemorrhage associated with alemtuzumab have been reported to VigiBase©, the World Health Organization’s international database for suspected adverse drug reactions [13]. Including our patient, five of these received alemtuzumab for MS. Like our patient all other patients treated for MS received two infusions, and all recovered. Unfortunately, no further details about treatment are available at VigiBase©. The remaining 17 patients received alemtuzumab as part of immunosuppression for transplantation or for haematological malignancies, and 14 of these died [13].\n\nThe mechanism underlying alveolar bleeding induced by alemtuzumab is unknown. Alemtuzumab is associated with secondary autoimmune diseases, including nephritis with antibodies against basal membranes that could induce alveolar haemorrhage [2]. Anti-glomerulus basement membrane antibodies and anti-neutrophil cytoplasmic antibodies were however negative, and the short interval from treatment to symptoms also excludes this possibility. Cytokine-release syndrome is the most common cause of infusion reactions associated with alemtuzumab, and may cause a number of symptoms including headache, rash, pyrexia, nausea, dyspnea, chest discomfort and hypotension [2, 14]. Cytokine-release syndrome associated with monoclonal antibodies is however usually a first dose phenomenon with decreasing severity during subsequent administrations [14, 15]. Our patient had only mild headache and no other evidence of cytokine-release syndrome during the first alemtuzumab infusion. Sinus bradycardia is a common side effect of alemtuzumab [16], and was not likely associated with the alveolar bleeding.\n\nNotably, alemtuzumab activates both cellular and complement dependent cytotoxicity and induces profound and immediate effects on the innate immune system [8]. It can be speculated that effector mechanisms induce acute inflammation that in some cases may damage membranes and cells not expressing the CD52 target molecule.\n\nThe treatment of DAH associated with drugs is cessation of the suspected medication, and in more severe cases high dose steroids [4]. Plasma exchange is used in selected autoimmune disorders [3] and can be considered in severe cases of drug-induced DAH but its effectiveness is questionable [4].\n\nThis case along with those previously reported to VigiBase© [13], as well as published cases treated for other diseases [9, 10], underscore that diffuse pulmonary haemorrhage is a potentially fatal complication of alemtuzumab, usually occurring after few infusions. Clinicians should consider this diagnosis in patients who develop sudden onset of respiratory distress and haemoptysis during or shortly after administration of alemtuzumab.\n\nAbbreviations\nBALBronchoalveolar lavage\n\nCTComputed tomography\n\nDAHDiffuse alveolar haemorrhage\n\nMSMultiple sclerosis\n\nAcknowledgements\nThe authors express their gratitude to Ane Simensen at The Norwegian Medicines Agency for collecting data from VigiBase©.\n\nData obtained from VigiBase© does not represent the opinion of the World Health Organisation. Information reported to VigiBase© comes from a variety of sources, and the likelihood that the suspected adverse reaction is drug-related is not the same in all cases.\n\nFunding\nNo funding was obtained for the preparation of this case report.\n\nAvailability of data and materials\nAll data are contained within the manuscript.\n\nAuthors’ contributions\nAM and TH wrote the manuscript. AM, GB, SZ and TH collected data and reviewed the manuscript for intellectual content. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nAccording to Norwegian regulations no ethics approval was required for this case report.\n\nConsent for publication\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\nT Holmøy has received speakers honoraria and research grants from Merck, Biogen, Genzyme, Novartis and Teva, and has served on advisory board for Genzyme, Merck and Biogen. The other authors declared no potential conflicts of interest.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Gross Catharina C. Ahmetspahic Diana Ruck Tobias Schulte-Mecklenbeck Andreas Schwarte Kathrin Jörgens Silke Scheu Stefanie Windhagen Susanne Graefe Bettina Melzer Nico Klotz Luisa Arolt Volker Wiendl Heinz Meuth Sven G. Alferink Judith Alemtuzumab treatment alters circulating innate immune cells in multiple sclerosis Neurology - Neuroimmunology Neuroinflammation 2016 3 6 e289 10.1212/NXI.0000000000000289 27766281 \n2. Hardova E Horakova D Kovarova I Alemtuzumab in the treatment of multiple sclerosis: key clinical trials results and considerations for use Ther Adv Neurol Disord 2015 8 1 31 45 10.1177/1756285614563522 25584072 \n3. Lara AR Schwarz MI Diffuse alveolar hemorrhage CHEST 2010 137 5 1164 1171 10.1378/chest.08-2084 20442117 \n4. Schwarz MI Fontenot AP Drug-induced diffuse alveolar hemorrhage syndromes and vasculitis Clin Chest Med 2004 25 133 140 10.1016/S0272-5231(03)00139-4 15062605 \n5. Cohen JA Coles AJ Arnold DL Confavreux C Fox EJ Hartung HP Hardova E Selmaj KW Weiner HL Fisher E Brinar VV Giovannoni G Stojanovic M Ertic BI Lake SL Margolin DH Panzara MA Compston DAS Alemtuzumab versus interferon beta 1a as a first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial Lancet 2012 380 1819 1828 10.1016/S0140-6736(12)61769-3 23122652 \n6. Blasco MR Ramos A Malo CG Garcia-Merino A Acute pneumonitis and pericarditis related to alemtuzumab therapy in relapsing-remitting sclerosis J Neurol 2017 264 168 169 10.1007/s00415-016-8306-x 27888417 \n7. Zhao Y Su H Shen X Du J Zhang X Zhao Y The immunological function of CD52 and its targeting in organ transplantation Inflamm Res 2017 66 7 571 578 10.1007/s00011-017-1032-8 28283679 \n8. Thomas K Eisele J Rodriguez-Leal FA Hainke U Ziemssen T Acute effects of alemtuzumab infusion in patients with active relapsing-remitting MS Neurol Neuroimmunol Neuroinflamm 2016 3 e228 10.1212/NXI.0000000000000228 27213173 \n9. Sachdeva A Matuschak G Diffuse alveolar hemorrhage following alemtuzumab Chest 2008 133 1476 1478 10.1378/chest.07-2354 18574290 \n10. Tachir W Hakeem A Baker R Diffuse alveolar hemorrhage: a fatal complication after Alemtuzumab induction therapy in renal transplantation Transplant Proc 2015 47 151 154 10.1016/j.transproceed.2014.10.037 25645795 \n11. Barber NA Ganti AK Pulmonary toxicities from targeted therapies: a review Target Oncol 2011 6 235 243 10.1007/s11523-011-0199-0 22076388 \n12. Freeze SL Landis BJ Ware SM Bicuspid aortic valve: a review with recommendation for genetic counseling J Genet Couns 2016 25 6 1171 1178 10.1007/s10897-016-0002-6 27550231 \n13. Uppsala Monitoring Centre. VigiBase, the World Health Organization international database of suspected adverse drug reactions. https://www.who-umc.org/vigibase/vigibase/. (accessed 13 June 2017).\n14. Bugelski PJ Achuthanandam R Capocasale RJ Monoclonal antibody-induced cytokine-release syndrome Expert Rev Clin Immunol 2009 5 499 521 10.1586/eci.09.31 20477639 \n15. Maggi E Vultaggio A Matucci A Acute infusion reactions induced by monoclonal antibody therapy Expert Rev Clin Immunol 2011 7 55 63 10.1586/eci.10.90 21162650 \n16. Genzyme Therapeutics. Summary of Product Characteristics for Lemtrada©. Updated Dec 20 2017. https://www.medicines.org.uk/emc/product/5409/smpc. Accessed June 15 2018.\n\n",
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"abstract": "Leiomyosarcomas (LMS) are rare tumors with poor prognosis owing to the high rate of recurrent and metastatic disease. The combination of doxorubicin (Adriamycin) plus ifosfamide and mesna (AIM) results in moderate response rates of 10%-30%. The aim of this study was to assess the efficacy of the AIM regimen along with multimodality treatment including surgery and radiotherapy in patients with LMS. The clinicopathologic characteristics and outcomes of 51 patients with recurrent or metastatic LMS diagnosed between 2000 and 2014 who received the AIM regimen were analyzed retrospectively. Treatment consisted of ifosfamide 2500mg/m² on days 1-3 (with mesna 2500mg/m² days 1-3, 4-hour i.v. infusion), and doxorubicin 60mg/m² on day 1 (2-hour i.v. infusion), which was repeated every 21 days. The mean age of the patients at diagnosis was 48.9 ± 11.2 years. A total of 42 patients were females (82.4%). The primary tumor site was the uterus in 30 (58.8%) patients. The most common metastatic sites were lung and liver. The median follow-up was 27.9 months (min: 4.3 max: 164.8). The median progression-free survival was 6.7 months (95% CI: 4.1-9.2). The median overall survival (OS) was 24.6 months (95% CI: 16.2-33.0). The overall response rate was 12% (6/51 pts). Response rates were higher in patients with uterine LMS (17%) compared with those with nonuterine LMS (5%); however, the OS times were similar. Surgical intervention for local or distant recurrence was associated with improved median OS (41 vs 16.6 months, P < 0.001). Myelosuppression was the major toxicity of this combination. In our study, the AIM regimen was effective in patients with LMS. Resection of local or distant recurrence was found to improve survival in our study.",
"affiliations": "Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey. Electronic address: drserkanakin@gmail.com.;Department of Preventive Oncology, Hacettepe University Cancer Institute, Ankara, Turkey.;Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey.;Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey.;Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey.",
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"abstract": "This retrospective study reports 81% long-term (> 3 years) adherence to and 77% persistence with zoledronic acid (ZA) treatment in osteoporosis patients, with ZA being costfree for patients. Eight percent of patients discontinued treatment because of adverse events (AEs), with a tendency of higher discontinuation rate in older patients.\n\n\n\nThis study investigated (1) long-term adherence to and persistence with ZA treatment in a real-world setting, (2) extent to which an adverse reaction to ZA impacted on adherence and persistence, and (3) whether there were sex or age differences in patients that had early treatment termination (ETT) due to AEs and those who adhered to the regimen.\n\n\n\nAll patients treated with ZA at the Endocrinology Department at Linköping University Hospital, Linköping, Sweden between 2012 and 2017 were included. ETT was defined as < 3 ZA infusions, which was confirmed from patients' medical records.\n\n\n\nA total of 414 patients were treated with ZA, with 81% receiving > 3 ZA infusions. Three-year persistence was 77% for a treatment window of 365 days ± 90 days (75% with 365 days ± 60 days window). The most common reason for ETT was AEs (8%), followed by medical conditions (5%), biological aging (3%), and other (e.g., lost to follow-up [3%]). Most patients who discontinued treatment because of AEs reported symptoms of acute-phase reaction, and tended to be older than those who adhered to treatment (74 ± 9 vs 70 ± 13 years, p = 0.064). There was no difference in sex ratio between the 2 groups (85% vs 90% females, p = 0.367).\n\n\n\nRates of long-term adherence to and persistence with ZA treatment were high with a pre-scheduled 3-year treatment regimen in the tax-financed Swedish healthcare system. AEs-mainly acute-phase reaction-were the most common reason for ETT, occurring in nearly 1 out of 10 patients.",
"affiliations": "Department of Acute Internal Medicine and Geriatrics, Linköping University Hospital, Linköping, Sweden. anna.spangeus@liu.se.;Division of Diagnostics and Specialist Medicine, Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden.;Division of Diagnostics and Specialist Medicine, Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden.",
"authors": "Spångeus|Anna|A|https://orcid.org/0000-0002-7130-9158;Johansson|Simon|S|;Woisetschläger|Mischa|M|https://orcid.org/0000-0003-0066-4985",
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"fulltext": "\n==== Front\nArch Osteoporos\nArch Osteoporos\nArchives of Osteoporosis\n1862-3522 1862-3514 Springer London London \n\n733\n10.1007/s11657-020-00733-4\nOriginal Article\nAdherence to and persistence with zoledronic acid treatment for osteoporosis—reasons for early discontinuation\nhttps://orcid.org/0000-0002-7130-9158Spångeus Anna anna.spangeus@liu.se 12 Johansson Simon 2 https://orcid.org/0000-0003-0066-4985Woisetschläger Mischa 23 1 grid.411384.b0000 0000 9309 6304Department of Acute Internal Medicine and Geriatrics, Linköping University Hospital, Linköping, Sweden \n2 grid.5640.70000 0001 2162 9922Division of Diagnostics and Specialist Medicine, Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden \n3 grid.411384.b0000 0000 9309 6304Department of Radiology, Linköping University Hospital, Linköping, Sweden \n17 4 2020 \n17 4 2020 \n2020 \n15 1 5824 2 2020 7 4 2020 © The Author(s) 2020Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons 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/.Summary\nThis retrospective study reports 81% long-term (> 3 years) adherence to and 77% persistence with zoledronic acid (ZA) treatment in osteoporosis patients, with ZA being costfree for patients. Eight percent of patients discontinued treatment because of adverse events (AEs), with a tendency of higher discontinuation rate in older patients.\n\nPurpose\nThis study investigated (1) long-term adherence to and persistence with ZA treatment in a real-world setting, (2) extent to which an adverse reaction to ZA impacted on adherence and persistence, and (3) whether there were sex or age differences in patients that had early treatment termination (ETT) due to AEs and those who adhered to the regimen.\n\nMethods\nAll patients treated with ZA at the Endocrinology Department at Linköping University Hospital, Linköping, Sweden between 2012 and 2017 were included. ETT was defined as < 3 ZA infusions, which was confirmed from patients’ medical records.\n\nResults\nA total of 414 patients were treated with ZA, with 81% receiving > 3 ZA infusions. Three-year persistence was 77% for a treatment window of 365 days ± 90 days (75% with 365 days ± 60 days window). The most common reason for ETT was AEs (8%), followed by medical conditions (5%), biological aging (3%), and other (e.g., lost to follow-up [3%]). Most patients who discontinued treatment because of AEs reported symptoms of acute-phase reaction, and tended to be older than those who adhered to treatment (74 ± 9 vs 70 ± 13 years, p = 0.064). There was no difference in sex ratio between the 2 groups (85% vs 90% females, p = 0.367).\n\nConclusion\nRates of long-term adherence to and persistence with ZA treatment were high with a pre-scheduled 3-year treatment regimen in the tax-financed Swedish healthcare system. AEs—mainly acute-phase reaction—were the most common reason for ETT, occurring in nearly 1 out of 10 patients.\n\nKeywords\nOsteoporosisBisphosphonateZoledronic acidAdherenceDiscontinuationAdverse eventLinköping UniversityOpen access funding provided by Linköping University.\n\nissue-copyright-statement© International Osteoporosis Foundation and National Osteoporosis Foundation 2020\n==== Body\nIntroduction\nFragility fractures secondary to osteoporosis are highly prevalent, with about 9 million cases yearly worldwide [1]. Despite being associated with substantial morbidity and mortality and representing a significant economic burden for society [2–5], osteoporosis remains highly underdiagnosed and undertreated [6]. Additionally, previous studies have reported poor persistence with osteoporosis treatment [7–12].\n\nVarious cost-effective treatment options are available for osteoporosis including antiresorptive and anabolic treatments [13, 14]. Antiresorptive bisphosphonate, either oral or parenteral, is a first-line treatment in many guidelines including the Swedish [15]. Several studies have reported low persistence to and adherence with both oral and parenteral antiosteoporotic therapies, but most studies had short observation times (i.e., 12–24 months) [7–12, 14] whereas guidelines recommend a longer treatment (minimum of 3 years) consisting of yearly administration of parenteral bisphosphonate zoledronic acid (ZA) [14].\n\nA common adverse event (AE) of ZA is acute phase reaction (APR), which occurs in about 40% of patients [16] and causes influenza-like symptoms such as fatigue, arthralgia, nausea, headache, and fever [14]. This reaction is linked to the pharmacodynamics of ZA and typically begins within 24 h after administration, and usually resolves a few days post-infusion [14, 16]. Symptoms are often mild and can be alleviated with nonsteroidal anti-inflammatory drugs (NSAIDs) or paracetamol [14], but in some patients symptoms are prolonged and less tolerable. The extent to which these symptoms interfere with patients’ willingness to continue ZA treatment is unclear.\n\nGiven the importance of compliance in maximizing the effects of therapeutic interventions, the present study investigated (1) long-term (3 years) adherence to and persistence with ZA treatment in a real-world setting, (2) the extent to which these are impacted by APR, and (3) whether patients with early treatment termination (ETT) because of adverse events (AEs) differ from those who adhered to ZA treatment with respect to sex ratio and age.\n\nMaterial and methods\nStudy context\nThe study was carried out at the osteoporosis unit at Linköping University Hospital, Sweden. Patients were either receiving ZA treatment for severe osteoporosis or were being followed at the unit, or patients with a milder form of the disease who were being routinely followed at a primary healthcare unit but were referred to the osteoporosis unit for assistance with ZA infusion—most primary health care units in the catchment area did not handle infusions during the study period. Other specialized clinics (e.g., rheumatology clinic) administered infusions. Patients receiving bisphosphonates for cancer were not treated at the osteoporosis unit.\n\nThe healthcare system in Sweden is tax-financed and patients do not pay for ZA treatment. Three yearly infusions are routinely scheduled unless otherwise indicated. Nurses contact the patients before each treatment for blood tests and schedule an appointment for the infusion. Patients received a standardized information letter prior to ZA infusion, including recommendations of being well hydrated and using paracetamol peri-infusion (starting 1 day before and ending 2 days after).\n\nStudy design\nTo identify all patients treated with ZA at the osteoporosis unit, we used the local database connected to the Cosmic intelligence software case record system (Cambio, Linköping, Sweden). The search included all patients who visited a clinic from 2012 to 2017 and who met the following three criteria: (1) coded with procedure code DT016 (“intravenous drug administration”), (2) assigned to the osteoporosis unit of the endocrinology clinic, and (3) coded for ZA in the planning system. Exclusion criteria were patients receiving ZA for reasons other than osteoporosis (e.g., Paget disease) and patients that had received < 2 ZA treatments and deceased the same or following year after the last ZA infusion (n = 27).\n\nThe output file included dates of ZA infusions as well as year of birth and sex. Treatments were confirmed through medical records, and patients were categorized as either ETT or fully treated (non-ETT; i.e., > 3 ZA infusions). Some patients were wrongly categorized with too few infusions in the output file, which was corrected by referring to case records. Major reasons for this were that 1 or more infusions had been performed by other clinics, or the procedure code was missing in the documentation for the treatment visit. Patients who received their first or second ZA infusion in 2017 were followed until the third ZA infusion or ETT. Adherence was defined as > 3 ZA treatments. Persistence was assigned a permissive time of 90 days in a planned 1-year interval. Fewer patients were included in the persistence analysis (n = 390) than in the adherence analysis (n = 414) due to missing dates of ZA infusion (when performed in other clinics or before 2012).\n\nETT\nReasons for ETT were categorized as follows: (1) AEs (ETT-Adverse) such as acute phase reaction, but also other symptoms debuting in adjunction to the treatment and making patients unwilling to take additional ZA; (2) medical reasons (ETT-Medical) such as reduced glomerular filtration rate (GFR), termination of cortisone treatment, and lack of response to treatment; (3) biological aging (ETT-BiologicalAge)—i.e., the patient refused further treatment because of advancing age or terminal illness; and (4) other reasons (ETT-Other), e.g., failure of the healthcare unit to follow up with the patient. AEs were further subclassified into APR (ETT-APR) or other AE.\n\nStatistical analysis\nIBM SPSS v25.0 for Windows software (IBM Inc., Armonk, NY, USA) was used for statistical analyses. ANOVA and the χ2 test were used to compare continuous and categorical variables, respectively, between groups. Kaplan-Meyer curves were used for persistence analysis, and intergroup comparisons were performed with the log-rank (Mantel-Cox) test. All statistical tests were performed at the 5% significance level.\n\nEthics\nThe Regional Research Ethics Committee of the Faculty of Health Sciences, Linköping University approved this study (2017/507–31).\n\nResults\nPatients\nA total of 414 patients initiated ZA infusion for osteoporosis between 2012 and 2017. The number of females who received ZA treatment was 6 times higher than the number of males (86% vs 14%); mean age at first ZA infusion was 71 ± 13 years (Table 1).Table 1 Patient characteristics and comparative data for patients receiving full ZA treatment vs those discontinuing treatment because of adverse events\n\n\t\tFull treatment vs early treatment termination because of adverse event\t\n\t\tFull treatment\tETT-Adverse†\tp value\t\nNumber of patients\t414\t338\t33\t\t\nAge at first ZA infusion, years*\t71 ± 13\t70 ± 13\t75 ± 9\t0.064\t\nAge > 80 years at first ZA, years\t26%\t23%\t30%\t0.388\t\nSex (% female)\t86%\t85%\t90%\t0.367\t\n*Age is shown as mean ± standard deviation\n\n†Early treatment discontinuation because of adverse events\n\n\n\nAdherence and ETT\nIn total, 81% of patients received > 3 ZA infusions; the remaining 19% had ETT (Fig. 1), with AEs being the most common reason (8% of all treated patients), followed by ETT-Medical (e.g., progressive kidney failure; 5%).Fig. 1 Patient treatment profile. Of the patients receiving ZA infusions between 2012 and 2017, 81% received full treatment (> 3 infusions); ETT was recorded in 19% of patients, with reasons including AEs (ETT-Adverse), medical reasons, biological aging, and other. ETT early treatment termination, AE adverse event\n\n\n\nMost patients in the ETT-Adverse group reported symptoms of APR including fever, muscle pain, weakness, and low energy. Other patients reported heart symptoms (atrial fibrillation and pericardial effusion) with association with ZA treatment initiation, which made patients unwilling to continue treatment. Most ETT-Adverse patients (82%) terminated ZA treatment after the first infusion and the remaining 18% after the second infusion. There was no difference in sex ratio between the non-ETT and ETT-Adverse groups (85% vs 90% females, p = 0.367) but patients in the latter group tended to be older (70 ± 13 vs 75 ± 9; p = 0.064) (Table 1).\n\nPersistence\nOverall persistence rates were 85% at 2 years (i.e., with a second ZA infusion given) and 77% at 3 years (i.e., with a third ZA infusion) (Fig. 2a). With a shorter permissive time of 60 days instead of 90 days, 2- and 3-year persistence was 85% and 75%, respectively, and with a longer permissive time of 150 days, corresponding figures were 86% and 79%, respectively.Fig. 2 Persistence with ZA treatment. a All patients. b Patients separated into 2 age groups. c Patients separated into 2 age groups, and including only patients with AEs as the reason for ETT\n\n\n\nWhen patients were analyzed as 2 separate age categories (≤ 80 and > 80 years), persistence was lower in patients > 80 years compared to those ≤ 80 years (3-year persistence: 65% vs 81%; p = 0.002) (Fig. 2b). However, when the analysis was limited to the ETT-Adverse group (i.e., excluding patients with ETT because of medical reasons, aging, and other reasons), the difference between the 2 age groups in terms of 3-year persistence was smaller (82% vs 88%, p = 0.130) (Fig. 2c).\n\nDiscussion\nIn the present study, we show that long-term adherence and persistence to ZA is high (81% and 77%, respectively) in a real-world setting organized with a tax-financed system with yearly follow-up by sending an appointment for treatment. AEs (mainly APR) were the most common reason for ETT (8%), followed by medical reasons (5%), and biologically aging (3%). ETT-Adverse was equally common in males and females but tended to be more common with increasing age.\n\nSeveral studies have found low compliance with ZA; the 2-year persistence rate (i.e., with a second ZA infusion) was shown to be 25–41%, with a permissive gap of 60–90 days [8–10]. Other investigators have reported a higher rate (75% after 2 years, with a permissive gap of 112 days) [12], which is closer to our 2-year persistence data (85% with a 60- or 90-day permissive gap). There is little information on longer persistence with ZA treatment. An 80% discontinuation rate after 2 years has been observed [9]—that is, only 20% of patients received the third ZA infusion. Higher figures were reported by Tremblay et al. (54% of patients receiving ≥ 3 ZA infusions) [12]. We recorded a 3-year adherence rate of 81% and persistence rates of 77% and 75% (with 90- and 60-day grace periods, respectively), which are higher than previous findings. There are several possible reasons for the difference in the persistence rates of our cohort and rates reported in earlier studies. One is the tax-financed healthcare system in Sweden, in contrast to insurance-based systems in which treatment costs could influence patient compliance. Furthermore, logistics can vary across systems; a 3-year treatment was pre-planned for our patients, who were included on clinics’ waiting list. Because of a reminder function in this system, patients do not need to actively remember their appointment time or arrange a visit for their next ZA infusion. Furthermore, the clinic provides the ZA; thus, patients do not need to visit a pharmacy beforehand. The healthcare system in Sweden also assists with travel arrangements for patients with disabilities, thereby increasing the accessibility of the treatment program. At the visit for ZA infusion, patients are in the care of experienced osteoporosis nurses who may encourage adherence through informal education and by offering a feedback service where patients can phone with questions regarding their ZA infusion or any side effects that they experience.\n\nIn a previous study conducted in Sweden, oral bisphosphonate treatment had a low persistence rate, with just 25% of patients continuing for 3 years [7]. Thus, persistence rate varies significantly even within the same tax-financed system. In general, less frequent drug administration via the intravenous route is preferred [14] and could promote adherence.\n\nWe categorized ETT into 4 groups—namely, AE, medical reasons, biological aging, and other—so that underlying problems could be recognized and handled accordingly. Many patients who receive ZA treatment are in an age were comorbidities are common. Thus, treatment discontinuation because of biological aging and medical reasons such as reduced GFR is expected when treating this patient group. As the mean age of our patients was similar to that in other studies, our findings may also apply to those cohorts [9, 11, 12]. Patients over 80 years, sometimes referred to as the oldest old, have a high fracture burden, are often undertreated, and show a slightly different fracture risk profile compared to younger patients [6, 17]. In the present study, we show that the oldest old have a lower persistence to ZA treatment.\n\nAPR is a well-known side effect of ZA that is observed in about 40% of patients at the first infusion [16]. While it is usually mild, APR can in some cases cause more prolonged and severe symptoms. In our study, 1 in 20 ZA-treated patients (5%) terminated their treatment because of APR symptoms. These patients tended to be older than those who adhered to the treatment (mean age 75 years vs 70 years, p = 0.064). This finding is in disagreement with a previous report indicating that younger age is a risk factor for experiencing APR following ZA infusion [16]. However, that study examined a different outcome, i.e., the prevalence of APR post-infusion, whereas we analyzed the APRs effect on willingness for continued ZA treatment. It is possible that APRs are more severe or less tolerated in older fragile patients where APR symptoms may cause a more severe impact on daily life activity. Thus, older patients may be less willing to endure side effects compared to younger, healthier individuals, rendering a poorer adherence. Adequate hydration and NSAIDs/paracetamol are recommended for reducing APR and is routine clinical practice at our hospital. It has also been suggested that peri-infusion cortisone might prevent APR but this requires validation by additional studies.\n\nConclusion\nLong-term adherence to and persistence with ZA treatment was high among osteoporosis patients in Sweden, where a pre-planned therapeutic regimen is available within a tax-financed healthcare system. AEs (mainly APR) were the most common cause of ETT, occurring in about 1 of 10 patients. Further analysis of risk profiles in these patients and strategies that mitigate APR might further increase patient compliance.\n\nLimitations\nThe present retrospective study had some limitations. Firstly, reasons for ETT were obtained from medical records, which may not have included all of the reasons for patients’ decision to discontinue treatment. Secondly, the number of observations was small compared to some earlier studies. One reason for this is that, unlike most other drugs, large scale data from the national prescription registry cannot be used in the case of ZA studies in Sweden. This is because most hospitals arrange ZA infusions by having it directly delivered to the clinic, i.e., not through a pharmacy prescription on patient level. Without this prescription, patients will not be registered in the national prescription database, and thus unlike other drugs, e.g., alendronate, these patients cannot be studied using national registry data. Finally, we used local county-specific patient registers combined with clinics’ booking systems to search for patients who received ZA treatment. As stated above, these patients included most osteoporosis patients on ZA in the catchment area while excluding those who were followed at other specialized clinics (e.g., rheumatology patients). A strength of our study is that unlike in larger-scale studies, all data were confirmed by referring to case records, which included the reasons for ETT.\n\nPublisher’s note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAvailability of data and material (data transparency)\nData and materials described in this article are available from the corresponding author upon reasonable request.\n\nFunding Information\nOpen access funding provided by Linköping University. This work was supported by the County council of Östergötland, Sweden (ALF).\n\nCompliance with ethical standards\nConflict of interest\nAnna Spångeus has received lecture fees from Amgen Inc., Renapharma, and Mylan. Simon Johansson and Mischa Woisetschläger declare that they have no conflict of interest.\n\nEthics approval\nThe Regional Research Ethics Committee of the Faculty of Health Sciences, Linköping University, approved the study (2017/507-31).\n\nConsent to participate\nThis was a retrospective registry study and no consent was needed according to Ethics Committee.\n==== Refs\nReferences\n1. Johnell O Kanis JA An estimate of the worldwide prevalence and disability associated with osteoporotic fractures Osteoporos Int 2006 17 1726 1733 10.1007/s00198-006-0172-4 16983459 \n2. Bliuc D Nguyen ND Milch VE Mortality risk associated with low-trauma fracture in men and women JAMA 2010 301 513 521 10.1001/jama.2009.50 \n3. Hallberg I Bachrach-Lindström M Hammerby S Toss G Ek AC Health-related quality of life after vertebral or hip fracture: a seven-year follow-up study BMC Musculoskelet Disord 2009 10 1 13 10.1186/1471-2474-10-135 19118498 \n4. National Board of Health and Welfare (2012). Nationella riktlinjer för rörelseorganens sjukdomar 2012 Systematisk riskvärdering, utredning och behandling vid fragilitetsfraktur National Board of Health and Welfare web-site: https://wwwsocialstyrelsense/globalassets/sharepoint-dokument/artikelkatalog/nationella-riktlinjer/2012-5-1-uppdateringpdf Accessed 20 February 2020\n5. Hernlund E Svedbom A Ivergård M Compston J Cooper C Stenmark J McCloskey EV Jönsson B Kanis JA Osteoporosis in the European Union: medical management, epidemiology and economic burden. A report prepared in collaboration with the International Osteoporosis Foundation (IOF) and the European Federation of Pharmaceutical Industry Associations (EFPIA) Arch Osteoporos 2013 8 36 10.1007/s11657-013-0136-1 \n6. Toth E, Banefelt J, Åkesson K, Spångeus A, Ortsäter G, Libanati C (2020) History of previous fracture and imminent fracture risk in Swedish women aged 55–90 years presenting with a fragility fracture. J Bone Miner Res 8. 10.1002/jbmr.3953\n7. Landfeldt E Ström O Robbins S Borgström F Adherence to treatment of primary osteoporosis and its association to fractures–the Swedish adherence register analysis (SARA) Osteoporos Int 2012 23 433 443 10.1007/s00198-011-1549-6 21286686 \n8. Hadji P Kyvernitakis I Kann PH Niedhart C Hofbauer LC Schwarz H Kurth AA Thomasius F Schulte M Intorcia M Psachoulia E Schmid T GRAND-4: the German retrospective analysis of long-term persistence in women with osteoporosis treated with bisphosphonates or denosumab Osteoporos Int 2016 27 2967 2978 10.1007/s00198-016-3623-6 27172934 \n9. Modi A Sajjan S Insinga R Weaver J Lewiecki EM Harris ST Frequency of discontinuation of injectable osteoporosis therapies in US patients over 2 years Osteoporos Int 2017 28 1355 1363 10.1007/s00198-016-3886-y 28058444 \n10. Durden E Pinto L Lopez-Gonzalez L Juneau P Barron R Two-year persistence and compliance with osteoporosis therapies among postmenopausal women in a commercially insured population in the United States Arch Osteoporos 2017 12 1 9 10.1007/s11657-017-0316-5 28004295 \n11. Tasci I Cintosun U Safer U Naharci MI Bozoglu E Aydogdu A Doruk H Assessment of geriatric predictors of adherence to Zoledronic acid treatment for osteoporosis: a prospective follow-up study Acta Clin Belgica Int J Clin Lab Med 2018 73 237 243 10.1080/17843286.2017.1412863 \n12. Tremblay É Perreault S Dorais M Persistence with denosumab and zoledronic acid among older women: a population-based cohort study Arch Osteoporos 2016 11 30 10.1007/s11657-016-0282-3 27679503 \n13. Jonsson E Hansson-Hedblom A Ljunggren Ö Åkesson K Spångeus A Kanis JA Borgström F A health economic simulation model for the clinical management of osteoporosis Osteoporos Int 2018 29 545 555 10.1007/s00198-017-4325-4 29196775 \n14. Eastell R Rosen CJ Black DM Cheung AM Murad MH Shoback D Pharmacological management of osteoporosis in postmenopausal women: an endocrine society clinical practice guideline J Clin Endocrinol Metab 2019 104 1595 1622 10.1210/jc.2019-00221 30907953 \n15. Swedish Osteoporosis Society (2015). National Guidelines. http://www.svos.se/site/wp-content/uploads/2015/12/SVOS-vårdprogram-osteoporos-2015-1.pdf. Published\n16. Reid IR Gamble GD Mesenbrink P Lakatos P Black DM Characterization of and risk factors for the acute-phase response after zoledronic acid J Clin Endocrinol Metab 2010 95 4380 4387 10.1210/jc.2010-0597 20554708 \n17. Lauppe R Åkesson KE Ljunggren Ö Spångéus A Ortsäter G Feudjo-Tepie M Ström O Differing impact of clinical factors on the risk of fracture in younger and older women in the general population and an osteoporosis clinic population Arch Osteoporos 2019 14 1 45 10.1007/s11657-019-0592-3 30963310\n\n",
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"journal": "Archives of osteoporosis",
"keywords": "Adherence; Adverse event; Bisphosphonate; Discontinuation; Osteoporosis; Zoledronic acid",
"medline_ta": "Arch Osteoporos",
"mesh_terms": "D000368:Aged; D050071:Bone Density Conservation Agents; D005260:Female; D006801:Humans; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D010024:Osteoporosis; D012189:Retrospective Studies; D013548:Sweden; D013997:Time Factors; D028761:Withholding Treatment; D000077211:Zoledronic Acid",
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"title": "Adherence to and persistence with zoledronic acid treatment for osteoporosis-reasons for early discontinuation.",
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"abstract": "OBJECTIVE\nUnilateral analgesia often occurs with epidural analgesia. Traditional methods of troubleshooting this problem can be insufficient in obtaining adequate pain relief in a timely manner for terminal cancer patients. This case report demonstrates a safe and effective solution which can be utilized in these circumstances.\n\n\nMETHODS\nA 55-year-old female with stage IV pancreatic cancer and life expectancy of a few weeks presented to the interventional pain clinic with intractable sacral pain. The decision to place an epidural catheter and external pump for analgesia was made. An epidural catheter placed at the L5-S1 level showed contrast spread only along the right nerve roots and a test dose produced only right-sided analgesia. Suspecting compartmentalization of the epidural space, a second left-sided epidural catheter was placed and bilateral analgesia was achieved by using both catheters. This dual catheter technique gave the patient effective bilateral analgesia until she passed away several weeks later.\n\n\nCONCLUSIONS\nThe bilateral epidural catheter technique is safe and effective in patients who present with persistent unilateral epidural analgesia despite exhausting traditional solutions.",
"affiliations": "Pain Medicine, University of South Florida, Tampa, FL, USA.;Physical Medicine and Rehabilitation, University of South Florida, Tampa, FL, USA.;Pain Medicine, University of South Florida, Tampa, FL, USA.;Edward Via College of Osteopathic Medicine, Blacksburg, VA, USA.;Interventional Pain, Moffitt Cancer Center, University of South Florida, Tampa, FL, USA.",
"authors": "Padalia|Raj B|RB|;Reeves|Corey J|CJ|;Shah|Neal|N|;Patel|Ankur A|AA|;Padalia|Devang M|DM|",
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"fulltext": "\n==== Front\nLocal Reg AnesthLocal Reg AnesthLocal and Regional AnesthesiaLocal and Regional Anesthesia1178-7112Dove Medical Press 10.2147/LRA.S135809lra-10-079Case ReportCase report: bilateral tunneled epidural catheters to prevent unilateral analgesia for cancer-related pain Padalia Raj B 1Reeves Corey J 2Shah Neal 1Patel Ankur A 3Padalia Devang M 4\n1 Pain Medicine, University of South Florida, Tampa, FL, USA\n2 Physical Medicine and Rehabilitation, University of South Florida, Tampa, FL, USA\n3 Edward Via College of Osteopathic Medicine, Blacksburg, VA, USA\n4 Interventional Pain, Moffitt Cancer Center, University of South Florida, Tampa, FL, USACorrespondence: Raj B Padalia, James A. Haley Veterans’ Hospital, 13000 Bruce B. Downs Boulevard, Tampa, FL 33612, USA, Tel +1 813 972 2000 ext 7085, Fax +1 813 949 0116, Email rajpadalia@gmail.com2017 20 7 2017 10 79 82 © 2017 Padalia et al. This work is published and licensed by Dove Medical Press Limited2017The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Objective\nUnilateral analgesia often occurs with epidural analgesia. Traditional methods of troubleshooting this problem can be insufficient in obtaining adequate pain relief in a timely manner for terminal cancer patients. This case report demonstrates a safe and effective solution which can be utilized in these circumstances.\n\nCase report\nA 55-year-old female with stage IV pancreatic cancer and life expectancy of a few weeks presented to the interventional pain clinic with intractable sacral pain. The decision to place an epidural catheter and external pump for analgesia was made. An epidural catheter placed at the L5-S1 level showed contrast spread only along the right nerve roots and a test dose produced only right-sided analgesia. Suspecting compartmentalization of the epidural space, a second left-sided epidural catheter was placed and bilateral analgesia was achieved by using both catheters. This dual catheter technique gave the patient effective bilateral analgesia until she passed away several weeks later.\n\nConclusion\nThe bilateral epidural catheter technique is safe and effective in patients who present with persistent unilateral epidural analgesia despite exhausting traditional solutions.\n\nKeywords\npain managementpalliative carecancerregional techniques\n==== Body\nIntroduction\nPain is one of the most feared aspects for patients diagnosed with cancer. In the majority of cases, oral opioids and adjuvant therapy are sufficient in treating this pain. Unfortunately, a small percentage of patients do not respond to conservative management and must undergo interventional procedures to maximize their pain relief. Some techniques used in the management of cancer-related pain include neurolytic blocks as well as spinal and epidural analgesia. Spinal analgesia is the delivery of agents such as opioids and local anesthetics to the cerebrospinal fluid (CSF) usually via an implanted catheter and pump system. This is a very effective method for pain control but can be difficult to manage and titrate in an outpatient setting. Epidural analgesia via a catheter is also an effective system and more likely to be used when the life expectancy of the patient is less than 3 months, secondary to cost considerations. One particular problem is unilateral epidural analgesia from the uneven distribution of local anesthetic in the epidural space which has been described in the literature. The combination of a misplaced catheter with contributing secondary causes such as small volumes of injectate, a dorsomedian septum (plica mediana dorsalis [PMD]), or even disruption of the PMD through high pressure injection or the epidural needle may affect the restriction of epidural spread and change the likelihood of a unilateral spread of local anesthetic.1–4 Many non-uniform distributions of contrast have been shown to produce bilateral analgesia. 2,3 What is certain is that the epidural space is not uniform throughout and it can often have significant variability which can create a signifi-cant challenge in obtaining effective epidural analgesia.2–5 Here we present a case requiring the use of bilateral epidural catheters in order to achieve bilateral analgesia.\n\nCase report\nA 55-year-old Caucasian female with stage IV pancreatic cancer and without other significant medical history presented to the interventional pain clinic with increasing sacral, lower extremity, and pelvic pain. The patient was unable to ambulate secondary to pain and deconditioning. Magnetic resonance imaging without contrast and computed tomography (CT) with contrast just prior to her clinic visit showed a large pancreatic mass with liver infiltration, multiple pelvic and sacral metastatic lesions, and a significant collection of intra-abdominal fluid. Of note, the lumbar and sacral epidural space showed no abnormalities or lesions. Her oncology team determined she was no longer a candidate for any further treatment and recommended palliative measures only. Her prognosis was poor with a life expectancy of a few weeks. Her pain control regimen included fentanyl patch 200 mcg every 72 hours, hydrocodone/acetaminophen 10/325 mg every 6 hours as needed, duloxetine 60 mg daily, and gabapentin 300 mg three times a day; however, she continued to have uncontrolled pain with significant decrease in her quality of life.\n\nDue to the patient’s poor prognosis and short life expectancy, an implantable intrathecal pain pump was not pursued. It was decided that a tunneled multiorifice epidural catheter with an external infusion pump would be the best treatment option for her pain. The epidural catheter was placed at the L5-S1 level using standard fluoroscopic technique. A paramedian approach with the Tuohy bevel directed cephalad was used to advance the catheter to the L3–4 vertebral level. Then 2 mL of injected contrast showed spread along the right L5 and S1 nerve roots. There was no contralateral spread seen (Figure 1) and therefore the decision was made to inject a test dose of 6 mL of bupivacaine 0.25%. After waiting for 10 minutes, the patient was assessed and she had marked anesthesia and decreased pain on her right side, but normal pain on the left. To get full relief of her symptoms, it was decided to place a second tunneled epidural catheter using the same technique as the previous catheter placement along the left side of the epidural space at the same L5-S1 level in order to achieve bilateral analgesia. Then 2 mL of contrast was again injected through this catheter after placement, and it showed spread only along the left L5 and S1 nerve roots (Figure 2). To achieve contrast spread bilaterally, injection through both epidural catheters was required. The placement of two epidural catheters was therefore performed in order to avoid the anticipated poor bilateral spread of infused local anesthetic and subsequent inadequate pain relief. The patient tolerated the procedure well and was placed on dual patient controlled epidural analgesia (PCEA) pumps with each pump delivering a basal dose of 3 mL of bupivacaine 0.2% per hour with a demand dose of 3 mL every 30 minutes. She received excellent pain control and her reported numeric pain score for her lower extremity and sacral pain went from a 10 to a 3. She was discharged to hospice and placed under the care of the palliative physician. On phone call follow-up, it was reported that she had no adverse effects associated with the epidural infusion and continued to have numeric pain scores in the 3 to 6 range. While in hospice she was continued on the same basal epidural infusion and with approximately five demand doses per day. The patient remained on the same topical and oral pain medication regimen, which included transdermal fentanyl and oral hydrocodone/acetaminophen. Unfortunately after 4 weeks, the patient passed away in her sleep with her husband at her bedside. Written informed consent was obtained from the patient’s next of kin (husband) to publish this case report and any accompanying images.\n\nDiscussion\nAlthough unilateral epidural analgesia is relatively rare, we must be aware of its possibility and adapt our decision making appropriately. This is an especially important consideration to achieve the best outcomes for patients with cancer-related pain. There have been many proposed mechanisms for the uneven distribution of local anesthetic causing unilateral analgesia including slow injection of small volumes of local anesthetic, acquired adhesions in the epidural space, misplacement of the catheter in the epidural space, and a dorsomedian septum in the lumbar epidural space.1,6–9 A substantial amount of disagreement still surrounds the hypothesis that a PMD often exists in the epidural space and that it clinically affects local anesthetic spread. Previous case reports have described unilateral analgesia associated with partitioning within the epidural space confirmed through imaging.7,10,11 The existence of PMD and its prevention of bilateral spread of contrast in the lumbar epidural space have been demonstrated using CT with contrast and epidurography.1,5,12,13 However, CT scans without contrast and histologic examinations have often failed to determine the composition of the PMD as no fibrous fold or septum was found in the epidural space.1–4,14 Alternatively, it has been proposed that the makeup of the structures in the epidural space is actually adipose tissue collections which are distorted by injectate and that any unilateral spread is most likely due to needle and catheter misplacement.2,3 Regardless of its composition, it is important to note that a PMD may not be the most important or only factor responsible for unilateral spread of local anesthetic.\n\nThe patient had intractable neoplasm-related sacral and pelvic pain secondary to compression and inflammation of nerves by tumors. Using dual epidural catheters with PCEA proved to be an effective and necessary technique in this patient to achieve bilateral analgesia. The decision to place bilateral epidural catheters was made only after ruling out malposition of the catheter and using a large volume test dose to confirm persistent unilateral analgesia. The advantages to the epidural analgesia technique include a proven history for the effectiveness for terminal cancer pain, the ability to confirm bilateral analgesia prior to the patient leaving the procedure room, and the ability to titrate dosing to maximize analgesia and minimize side effects. Disadvantages to placing two external catheters are that there is a potential increased risk of infection and complications associated with placement when compared to using a single catheter. Alternatives to this procedure could include a single intrathecal phenol ablation of spinal nerves or increasing oral opiate dosing. Another option could have been to remove the epidural catheter and replace it with a single intrathecal catheter for a direct infusion of analgesics into the CSF. Some limitations of these techniques include possible elimination of motor function and higher chance of intolerability of opiate side effects. Ultimately the patient received effective pain control for the remainder of her life. The dual epidural catheter technique for controlling terminal cancer pain should be considered in patients who receive insufficient analgesia from oral opioid and other palliative treatments.\n\nAcknowledgment\nThe abstract of this paper was presented as a poster presentation at the North American Neuromodulation Society Annual Conference 2017.15\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Anteroposterior fluoroscopic image of contrast injected through the first epidural catheter which was placed showing spread only to right-sided nerve roots.\n\nFigure 2 Anteroposterior fluoroscopic image of contrast injected through the second epidural catheter which was placed on the left side of the epidural space showing spread only to the left-sided nerve roots.\n==== Refs\nReferences\n1 Asato F Goto F Radiographic findings of unilateral epidural block Anesth Analg 1996 83 3 519 522 8780273 \n2 Hogan Q Epidural anatomy: new observations Can J Anaesth 1998 45 5 Pt 2 R40 R48 9599675 \n3 Hogan Q Epidural catheter tip position and distribution of injectate evaluated by computed tomography Anesthesiology 1999 90 4 964 970 10201664 \n4 Hogan Q Lumbar epidural anatomy. A new look by cryomicrotome section Anesthesiology 1991 75 5 767 775 1952201 \n5 Savolaine ER Pandya JB Greenblatt SH Conover SR Anatomy of the human lumbar epidural space: new insights using CT-epidurography Anesthesiology 1988 68 2 217 220 3341575 \n6 Srivastava U Pilendran S Dwivedi Y Shukla V Radiographic evidence of unilateral epidural anesthesia J Anaesthesiol Clin Pharmacol 2013 29 4 571 572 24250011 \n7 Visser WA Lee RA Gielen MJ Factors affecting the distribution of neural blockade by local anesthetics in epidural anesthesia and a comparison of lumbar versus thoracic epidural anesthesia Anesth Analg 2008 107 2 708 721 18633056 \n8 Gallart L Blanco D Samso E Vidal F Clinical and radiologic evidence of the epidural plica mediana dorsalis Anesth Analg 1990 71 6 698 701 2240645 \n9 Hermanides J Hollmann MW Stevens MF Lirk P Failed epidural: causes and management Br J Anaesth 2012 109 2 144 154 22735301 \n10 Usubiaga J Reis A Usubiaga L Case reports: epidural misplacement of catheters and mechanisms of unilateral blockade Anesthesiology 1970 32 2 158 161 5414293 \n11 Boezaart AP Computerized axial tomo-epidurographic documentation of unilateral epidural analgesia Obstetric Anesthesia Digest 1990 10 2 117 \n12 Park WY Factors influencing distribution of local anesthetics in the epidural space Reg Anesth 1988 13 2 49 57 \n13 Yaeger MP Bae EE Parra MC Barr PA Bonham AK Sites BD Fluoroscopy-assisted epidural catheter placement: an exploratory analysis of 303 pre-operative epidurograms Acta Anaesthesol Scand 2016 60 4 513 519 \n14 Harrison GR Topographical anatomy of the lumbar epidural region: an in vivo study using computerized axial tomography Br J Anaesth 1999 83 2 229 234 10618934 \n15 Padalia RB Padalia DM Reeves CJ Case report: bilateral tunneled epidural catheters to prevent unilateral analgesia for cancer-related pain Poster presented at: North American Neuromodulation Society Annual Conference 2017 January 21, 2017\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1178-7112",
"issue": "10()",
"journal": "Local and regional anesthesia",
"keywords": "cancer; pain management; palliative care; regional techniques",
"medline_ta": "Local Reg Anesth",
"mesh_terms": null,
"nlm_unique_id": "101566276",
"other_id": null,
"pages": "79-82",
"pmc": null,
"pmid": "28790864",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "10201664;2240645;18633056;2582567;5414293;26508378;22735301;3341575;1952201;24250011;28790864;10618934;9599675;8780273",
"title": "Case report: bilateral tunneled epidural catheters to prevent unilateral analgesia for cancer-related pain.",
"title_normalized": "case report bilateral tunneled epidural catheters to prevent unilateral analgesia for cancer related pain"
} | [
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"abstract": "Chronic pain is often managed using a multidisciplinary, biopsychosocial approach. Interventions targeting the biological, psychological, and social aspects of both the patient and the pain have been demonstrated to provide objective and subjective improvement in chronic pain symptoms. The mechanism by which pain attenuation occurs after these interventions remains to be elucidated. While there is a relatively large body of empirical literature suggesting that functional and structural changes in the peripheral and central nervous systems are key in the development and maintenance of chronic pain states, less is known about changes that take place in the nervous system as a whole after biopsychosocial interventions. Using as a model the unique case of Mr. S, a patient suffering with chronic pain for 22 years who experienced a complete resolution of pain after a lucid dream following 2 years of biopsychosocial treatments, we postulate that central nervous system (CNS) reorganization (i.e., neural plasticity) serves as a possible mechanism for the therapeutic benefit of multidisciplinary treatments, and may set a neural framework for healing, in this case via a lucid dream.",
"affiliations": "Department of Physical Medicine and Rehabilitation, VA Greater Los Angeles Healthcare System, 11301 Wilshire Blvd, Los Angeles, CA 90073, USA. Electronic address: maurozappaterra@gmail.com.;Department of Physical Medicine and Rehabilitation, VA Greater Los Angeles Healthcare System, 11301 Wilshire Blvd, Los Angeles, CA 90073, USA.;Department of Physical Medicine and Rehabilitation, VA Greater Los Angeles Healthcare System, 11301 Wilshire Blvd, Los Angeles, CA 90073, USA.",
"authors": "Zappaterra|Mauro|M|;Jim|Lysander|L|;Pangarkar|Sanjog|S|",
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"issue": "82(3)",
"journal": "Medical hypotheses",
"keywords": null,
"medline_ta": "Med Hypotheses",
"mesh_terms": "D059350:Chronic Pain; D004325:Dreams; D006801:Humans; D008297:Male; D009473:Neuronal Plasticity",
"nlm_unique_id": "7505668",
"other_id": null,
"pages": "286-90",
"pmc": null,
"pmid": "24398162",
"pubdate": "2014-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Chronic pain resolution after a lucid dream: a case for neural plasticity?",
"title_normalized": "chronic pain resolution after a lucid dream a case for neural plasticity"
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"activesubstance": {
"activesubstancename": "TRAMADOL HYDROCHLORIDE"
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{
"abstract": "We describe a case of unintentional intoxication due to tramadol and propofol self administration, occurred in a middle aged man, healthcare provider, deceased despite advanced medical assistance an hour later the onset of severe and increasing dyspnea. Toxicological analysis performed with gas chromatography-mass spectrometry in blood sample, evidenced a lethal tramadol concentration and therapeutic level of Propofol. Quantitative determination was also performed in other specimens such as bile, tissues (liver, spleen, kidney) and pubic hair, to assess chronic exposure. Toxicological results and autopsy findings, supported by clinical and hematochemical data, suggested a myocardial damage, associated with respiratory failure.",
"affiliations": "Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Viale Regina Elena, 336-00161 Rome, Italy. giuliomann@tin.it",
"authors": "Mannocchi|Giulio|G|;Napoleoni|Francesca|F|;Napoletano|Simona|S|;Pantano|Flaminia|F|;Santoni|Mariangela|M|;Tittarelli|Roberta|R|;Arbarello|Paolo|P|",
"chemical_list": "D000701:Analgesics, Opioid; D006993:Hypnotics and Sedatives; D014147:Tramadol; D015742:Propofol",
"country": "England",
"delete": false,
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"issn_linking": "1752-928X",
"issue": "20(6)",
"journal": "Journal of forensic and legal medicine",
"keywords": "Cardiac arrest; GC–MS; Propofol; Toxicological; Tramadol",
"medline_ta": "J Forensic Leg Med",
"mesh_terms": "D000701:Analgesics, Opioid; D062787:Drug Overdose; D053593:Forensic Toxicology; D008401:Gas Chromatography-Mass Spectrometry; D006197:Hair; D006282:Health Personnel; D006323:Heart Arrest; D006801:Humans; D006993:Hypnotics and Sedatives; D057230:Limit of Detection; D008099:Liver; D008297:Male; D008875:Middle Aged; D015742:Propofol; D012131:Respiratory Insufficiency; D012646:Self Administration; D019966:Substance-Related Disorders; D014147:Tramadol",
"nlm_unique_id": "101300022",
"other_id": null,
"pages": "715-9",
"pmc": null,
"pmid": "23910868",
"pubdate": "2013-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fatal self administration of tramadol and propofol: a case report.",
"title_normalized": "fatal self administration of tramadol and propofol a case report"
} | [
{
"companynumb": "PHHY2013IT119390",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PROPOFOL"
},
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"druga... |
{
"abstract": "Parenteral ivermectin treatment of disseminated strongyloidiasis and hyperinfection is increasing, although not licensed in humans and with limited pharmacokinetic data available. Plasma and postmortem tissue analysis in an human immunodeficiency virus (HIV)/hepatitis C virus-positive man with disseminated strongyloidiasis suggests loading subcutaneous ivermectin doses are required, from which the central nervous system is protected.",
"affiliations": "University of New South Wales, Sydney, Australia.;University of New South Wales, Sydney, Australia.;University of New South Wales, Sydney, Australia.;University of Sydney, Sydney, Australia.;University of New South Wales, Sydney, Australia.;School of Biomedical Sciences, University of Queensland, Brisbane, Australia.;Pathology Queensland, Brisbane, Australia.",
"authors": "Konecny|Pamela|P|;Weatherall|Christopher J|CJ|;Adhikari|Suman|S|;Duflou|Johan|J|;Marjoniemi|Veli|V|;Pretorius|Carel J|CJ|;McWhinney|Brett|B|",
"chemical_list": "D000977:Antiparasitic Agents; D007559:Ivermectin",
"country": "United States",
"delete": false,
"doi": "10.4269/ajtmh.18-0387",
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"issn_linking": "0002-9637",
"issue": "99(6)",
"journal": "The American journal of tropical medicine and hygiene",
"keywords": null,
"medline_ta": "Am J Trop Med Hyg",
"mesh_terms": "D000328:Adult; D000818:Animals; D000977:Antiparasitic Agents; D001344:Autopsy; D003967:Diarrhea; D017809:Fatal Outcome; D015658:HIV Infections; D006526:Hepatitis C; D006801:Humans; D007279:Injections, Subcutaneous; D007418:Intestinal Pseudo-Obstruction; D007559:Ivermectin; D008297:Male; D013321:Strongyloides; D013322:Strongyloidiasis",
"nlm_unique_id": "0370507",
"other_id": null,
"pages": "1580-1582",
"pmc": null,
"pmid": "30334520",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22691685;8346648;27607192;14975065;19653954;23675546;23394259;19144377;25121962;19143887;28562417;12362927;18446504;26462990",
"title": "Case Report: Subcutaneous Ivermectin Pharmacokinetics in Disseminated Strongyloides Infection: Plasma and Postmortem Analysis.",
"title_normalized": "case report subcutaneous ivermectin pharmacokinetics in disseminated strongyloides infection plasma and postmortem analysis"
} | [
{
"companynumb": "PHHY2019AU000772",
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"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
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"dr... |
{
"abstract": "Catastrophic neurologic events occur rarely postoperatively and must be diagnosed quickly. A 63-year-old woman who had undergone uneventful total hip arthroplasty experienced obtundation after admission to the postanesthesia care unit. Cranial magnetic resonance imaging revealed multiple lesions consistent with ischemia or infarction, and fat cerebral embolism was diagnosed. We describe the numerous complications that may occur in patients in the postanesthesia care unit and review the differential diagnosis of altered mental status in such patients. Paradoxical cerebral fat embolization must be considered in the differential diagnosis of altered mental status after pelvic or long bone fracture or lower extremity major joint replacement, and this condition may occur despite normal pulmonary function and no patent foramen ovale or right-to-left intracardiac shunt. Magnetic resonance imaging with T2-weighted sequences is the cranial imaging study of choice for early evaluation of patients with sudden multifocal neurologic deficits and suspected fat embolism syndrome.",
"affiliations": "Division of Pulmonary Medicine, Mayo Clinic, Jacksonville, Fla 32224-1865, USA.",
"authors": "Ott|M C|MC|;Meschia|J F|JF|;Mackey|D C|DC|;Brodersen|M P|MP|;Burger|C|C|;Echols|J D|JD|;Fenton|D S|DS|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.4065/75.11.1209",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-6196",
"issue": "75(11)",
"journal": "Mayo Clinic proceedings",
"keywords": null,
"medline_ta": "Mayo Clin Proc",
"mesh_terms": "D000762:Anesthesia Recovery Period; D019644:Arthroplasty, Replacement, Hip; D003244:Consciousness Disorders; D003937:Diagnosis, Differential; D004620:Embolism, Fat; D005260:Female; D006801:Humans; D020766:Intracranial Embolism; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D011183:Postoperative Complications",
"nlm_unique_id": "0405543",
"other_id": null,
"pages": "1209-13",
"pmc": null,
"pmid": "11075754",
"pubdate": "2000-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cerebral embolization presenting as delayed, severe obtundation in the postanesthesia care unit after total hip arthroplasty.",
"title_normalized": "cerebral embolization presenting as delayed severe obtundation in the postanesthesia care unit after total hip arthroplasty"
} | [
{
"companynumb": "US-BAXTER-2014BAX077756",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PROPOFOL"
},
"drugadditional": null,
... |
{
"abstract": "In utero exposure to angiotensin II receptor blockers (ARBs) has fetotoxic effects including renal failure, oligohydramnios and lung hypoplasia. We present the case of a 24-year-old woman who presented to the maternity services in the 34th week of her first pregnancy. She was taking valsartan for hypertension. Ultrasound showed a structurally normal fetus with anhydramnios. The patient was admitted and valsartan was discontinued. She had spontaneous preterm delivery at 35 weeks' gestation of a baby girl. The baby's urine output was minimal in the first week of life and she was transferred to a paediatric hospital for specialist nephrology input. At 6 months of age, she requires ongoing nephrology follow-up and she remains on treatment for hypertension and anaemia. This case demonstrates the serious adverse effects resulting from ARB exposure in utero, and highlights the importance of avoiding fetotoxic medications in women of childbearing age.",
"affiliations": "Obstetrics and Gynaecology, Coombe Women and Infants University Hospital, Dublin, Ireland.;Obstetrics and Gynaecology, Coombe Women and Infants University Hospital, Dublin, Ireland.;Molecular, Genetic and Population Health Science, The University of Edinburgh Edinburgh Medical School, Edinburgh, UK ailbhemcgrath@gmail.com.;Maternal Fetal Medicine, Coombe Women and Infants University Hospital, Dublin, Ireland.",
"authors": "Petch|Sarah|S|;O'Connor|Emily|E|;McGrath|Ailbhe|A|http://orcid.org/0000-0003-1653-9556;Daly|Sean|S|",
"chemical_list": "D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000068756:Valsartan",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-240810",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(5)",
"journal": "BMJ case reports",
"keywords": "drugs: obstetrics and gynaecology; materno-fetal medicine; neonatal and paediatric intensive care",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D002648:Child; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007234:Infant, Premature; D016104:Oligohydramnios; D011247:Pregnancy; D051436:Renal Insufficiency, Chronic; D000068756:Valsartan; D055815:Young Adult",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34011666",
"pubdate": "2021-05-19",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Valsartan exposure in pregnancy with resultant anhydramnios and chronic kidney disease in a late preterm infant.",
"title_normalized": "valsartan exposure in pregnancy with resultant anhydramnios and chronic kidney disease in a late preterm infant"
} | [
{
"companynumb": "GB-TEVA-2021-GB-1924501",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LABETALOL\\LABETALOL HYDROCHLORIDE"
},
"drugadd... |
{
"abstract": "BACKGROUND\nThe combination of cyclophosphamide and glucocorticoids leads to remission in most patients with antineutrophil cytoplasm antibody (ANCA)-associated vasculitides. However, even when patients receive maintenance treatment with azathioprine or methotrexate, the relapse rate remains high. Rituximab may help to maintain remission.\n\n\nMETHODS\nPatients with newly diagnosed or relapsing granulomatosis with polyangiitis, microscopic polyangiitis, or renal-limited ANCA-associated vasculitis in complete remission after a cyclophosphamide-glucocorticoid regimen were randomly assigned to receive either 500 mg of rituximab on days 0 and 14 and at months 6, 12, and 18 after study entry or daily azathioprine until month 22. The primary end point at month 28 was the rate of major relapse (the reappearance of disease activity or worsening, with a Birmingham Vasculitis Activity Score >0, and involvement of one or more major organs, disease-related life-threatening events, or both).\n\n\nRESULTS\nThe 115 enrolled patients (87 with granulomatosis with polyangiitis, 23 with microscopic polyangiitis, and 5 with renal-limited ANCA-associated vasculitis) received azathioprine (58 patients) or rituximab (57 patients). At month 28, major relapse had occurred in 17 patients in the azathioprine group (29%) and in 3 patients in the rituximab group (5%) (hazard ratio for relapse, 6.61; 95% confidence interval, 1.56 to 27.96; P=0.002). The frequencies of severe adverse events were similar in the two groups. Twenty-five patients in each group (P=0.92) had severe adverse events; there were 44 events in the azathioprine group and 45 in the rituximab group. Eight patients in the azathioprine group and 11 in the rituximab group had severe infections, and cancer developed in 2 patients in the azathioprine group and 1 in the rituximab group. Two patients in the azathioprine group died (1 from sepsis and 1 from pancreatic cancer).\n\n\nCONCLUSIONS\nMore patients with ANCA-associated vasculitides had sustained remission at month 28 with rituximab than with azathioprine. (Funded by the French Ministry of Health; MAINRITSAN ClinicalTrials.gov number, NCT00748644; EudraCT number, 2008-002846-51.).",
"affiliations": "From the Département de Médecine Interne, Hôpital Cochin, Université Paris Descartes, Sorbonne Paris Cité, INSERM Unité 1016, Centre de Référence pour les Maladies Auto-immunes Rares (L.G., C.P., P.C., X.P., A.M., L.M.), Unité de Néphrologie, Hôpital Européen Georges-Pompidou, Université Paris Descartes (A.K.), Hôpital Bichat, Université Paris Diderot, Service de Néphrologie, INSERM Unité 699, Département Hospitalo-Universitaire FIRE (E.D.) and Département de Médecine Interne (T.P.), and Centre d'Epidémiologie Clinique, Hôpital Hôtel-Dieu, Université Paris Descartes, INSERM Unité 738 (P.R.), Assistance Publique-Hôpitaux de Paris, Paris, Service de Pneumologie, Centre de Référence pour Maladies Pulmonaires Rares, Hôpital Universitaire Louis Pradel (C.K.), and Service de Médecine Interne, Hôpital Edouard Herriot (J.N.), Lyon, Centre Hospitalier Universitaire, Hôpital Gabriel Montpied, Clermont-Ferrand (O.A.), Service de Médecine Interne, Hôpitaux privés de Metz, Metz (F.M.), Département de Médecine Interne, Hôpitaux Universitaires de Rennes, Hôpital Sud, Université Rennes I, IGDR-UMR 6290, Rennes (O.D.), Service de Médecine Interne et Néphrologie, Hôpital Général Henri Duffaut, Avignon (P. Gobert), Département de Néphrologie and Département de Médecine Interne, Centre Hospitalier de Valenciennes, Valenciennes (T.Q.), Service de Médecine Interne, Centre Hospitalier Général de Niort, Niort (C.B.-D.), Département de Médecine Interne, Centre Hospitalier Bretagne Atlantique de Vannes, Vannes (P. Godmer), Service de Néphrologie, Dialyse et Transplantation, Centre Hospitalier Universitaire de Grenoble, Grenoble (P.-L.C.), Service de Médecine Interne, Centre National de Référence de la Sclérodermie Systémique, Hôpital Claude Huriez, Université Lille Nord de France, Centre Hospitalier Universitaire de Lille, Lille (P.-Y.H.), Service de Médecine Interne, Centre de Référence Labellisé pour la Prise en Charge des C",
"authors": "Guillevin|Loïc|L|;Pagnoux|Christian|C|;Karras|Alexandre|A|;Khouatra|Chahera|C|;Aumaître|Olivier|O|;Cohen|Pascal|P|;Maurier|François|F|;Decaux|Olivier|O|;Ninet|Jacques|J|;Gobert|Pierre|P|;Quémeneur|Thomas|T|;Blanchard-Delaunay|Claire|C|;Godmer|Pascal|P|;Puéchal|Xavier|X|;Carron|Pierre-Louis|PL|;Hatron|Pierre-Yves|PY|;Limal|Nicolas|N|;Hamidou|Mohamed|M|;Ducret|Maize|M|;Daugas|Eric|E|;Papo|Thomas|T|;Bonnotte|Bernard|B|;Mahr|Alfred|A|;Ravaud|Philippe|P|;Mouthon|Luc|L|;|||",
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"mesh_terms": "D000328:Adult; D000368:Aged; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; D058846:Antibodies, Monoclonal, Murine-Derived; D001379:Azathioprine; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D007239:Infections; D053208:Kaplan-Meier Estimate; D060046:Maintenance Chemotherapy; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D000069283:Rituximab; D055502:Secondary Prevention",
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"title": "Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis.",
"title_normalized": "rituximab versus azathioprine for maintenance in anca associated vasculitis"
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"abstract": "Here, we report a case of neutrophilic eccrine hidradenitis (NEH) in a teenage male with synovial sarcoma associated with extracutaneous manifestations including myositis and splenomegaly secondary to pegfilgrastim. To the best of our knowledge, NEH has not been previously reported to occur in association with extracutaneous manifestations.",
"affiliations": "University of Kansas Hospital Kansas City Kansas.;University of Kansas Hospital Kansas City Kansas.;University of Kansas Hospital Kansas City Kansas.;University of Kansas Hospital Kansas City Kansas.",
"authors": "Puar|Neha|N|0000-0003-3552-3701;Scheele|Allek|A|0000-0001-7697-6008;Perez Marques|Francesca|F|0000-0002-3562-2665;Panicker|Jyoti|J|0000-0002-1081-9971",
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"doi": "10.1002/ccr3.1932",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.1932CCR31932Case ReportCase ReportsNeutrophilic eccrine hidradenitis secondary to pegfilgrastim in a patient with synovial sarcoma PUAR et al.Puar Neha http://orcid.org/0000-0003-3552-3701\n1\nScheele Allek http://orcid.org/0000-0001-7697-6008ascheele@kumc.edu \n1\nPerez Marques Francesca http://orcid.org/0000-0002-3562-2665\n1\nPanicker Jyoti http://orcid.org/0000-0002-1081-9971\n1\n\n1 \nUniversity of Kansas Hospital\nKansas City\nKansas\n* Correspondence\n\nAllek Scheele, Department of Pediatrics, University of Kansas Hospital, Kansas City, KS.\n\nEmail: ascheele@kumc.edu\n07 2 2019 3 2019 7 3 10.1002/ccr3.2019.7.issue-3533 536 27 7 2018 30 8 2018 12 9 2018 © 2018 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.Key Clinical Message\nHere, we report a case of neutrophilic eccrine hidradenitis (NEH) in a teenage male with synovial sarcoma associated with extracutaneous manifestations including myositis and splenomegaly secondary to pegfilgrastim. To the best of our knowledge, NEH has not been previously reported to occur in association with extracutaneous manifestations.\n\nfebrile neutrophilic dermatosisgranulocyte colony stimulating factorneutrophilic eccrine hidradenitissynovial sarcoma source-schema-version-number2.0component-idccr31932cover-dateMarch 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.6.1 mode:remove_FC converted:08.03.2019\n\n\nPuar \nN \n, \nScheele \nA \n, \nPerez Marques \nF \n, \nPanicker \nJ \n. Neutrophilic eccrine hidradenitis secondary to pegfilgrastim in a patient with synovial sarcoma . Clin Case Rep . 2019 ;7 :533 –536 . 10.1002/ccr3.1932\n==== Body\n1 INTRODUCTION\nThe neutrophilic dermatoses are uncommon in pediatric patients and are characterized by infiltration of neutrophils in the skin and occasionally in extracutaneous tissue.1 In neutrophilic eccrine hidradenitis (NEH), the neutrophilic infiltrate has a special predilection for the eccrine glands.1 Due to association with fever and similar clinical appearance to cellulitis, the diagnosis of NEH requires a skin biopsy.2 Additionally, infectious workup should be performed to rule out infectious etiology because the treatment would be different.2 Sweet Syndrome, another type of neutrophilic dermatosis, is classically associated with extracutaneous involvement including the central nervous system, bone marrow, heart, lung, muscles, and spleen.3 NEH, however, is not typically associated with extracutaneous disease. Resolution of skin lesions is usually spontaneous; however, recovery occurs much earlier if steroids or NSAIDs are given.\n\n2 CASE DESCRIPTION\nA 16‐year‐old male with a history of synovial sarcoma of the right posteromedial knee undergoing induction chemotherapy presented with a one‐day history of left upper quadrant abdominal pain and fever. Pain was not associated with eating, stooling, nausea, or vomiting and was only minimally relieved with oxycodone 5 mg. Physical examination revealed left upper quadrant tenderness, however, no guarding or rigidity. There were no other localizing signs of infection. The patient had his port accessed for labs recently, placing him at risk for bacteremia. Initial laboratory workup revealed a white blood cell count of 21 500, C‐reactive protein (CRP) of 3.01, and a normal lactate. Blood cultures and urine culture were also obtained prior to antibiotic initiation. He was hospitalized and started on cefepime. Abdominal tenderness was attributed to constipation due to recent history of hard stools and was treated with a bowel regimen.\n\nAfter three days of therapy, fever and abdominal pain persisted with a rising white cell count to 38 800 and CRP of 29.86. Blood cultures (including fungal culture) and urine culture showed no growth. Antibiotic coverage was expanded to include vancomycin. Abdominal CT was performed due to concern for an abscess, which revealed moderate retained fecal material, asymmetric thickening and edema of the left lateral abdominal wall musculature, reflecting myositis, and mild splenomegaly, however, no intra‐abdominal abscess. He also developed 2‐3 cm, tender, blanching erythematous patches on his abdomen and upper right arm (Figure 1). Workup was initiated for septic emboli and was negative. New lesions continued to erupt, with expanding size of previous lesions. This included a large plaque on the left abdomen/flank where his previous abdominal pain was located. Further history revealed that a similar lesion occurred on his left chest wall after his second cycle of chemotherapy during an admission for febrile illness and resolved after discharge (Figure 2). Chart review revealed that the patient had received pegfilgrastim twelve days prior to the onset of his current skin lesions and within eleven days of his initial eruption (Table 1). He received doxorubicin and ifosfamide in his first two cycles of chemotherapy and ifosfamide alone during his third cycle of chemotherapy (Table 1). During his hospitalization, he received cefepime for a total of six days and vancomycin for a total of three days. Despite broad‐spectrum antibiotics, he remained intermittently febrile and laboratory workup continued to demonstrate an upward trending CRP. Dermatology was consulted to perform a skin biopsy of his lesions. Per their recommendations, he was started on prednisone therapy to treat presumed acute febrile neutrophilic dermatosis and antibiotics were discontinued. Lesions started to rapidly resolve within 24‐48 hours of therapy initiation. Additionally, CRP started to improve within 48 hours of starting steroids. Dermatopathology revealed sparse neutrophilic infiltrate focally involving the eccrine unit, suggestive of NEH (Figure 3). Culture from the skin biopsy specimen showed no growth of aerobes, fungi, or Mycobacterium tuberculosis. He was discharged home after his clinical condition improved on a two‐week course of oral steroids. Because pegfilgrastim was determined as the likely causative agent, it was discontinued. He subsequently received four more cycles of ifosfamide and doxorubicin without pegfilgrastim and did not have recurrence of his skin lesions (Table 1). In retrospect, his initial eruption was also likely due to NEH given lack of improvement with antibiotics but improvement with steroids which were coincidentally given for nausea.\n\nFigure 1 Left sided erythematous abdominal plaque\n\nFigure 2 Erythematous plaques on right chest and lower abdomen which developed during previous hospitalization 11 d after G‐CSF administration\n\nTable 1 Patient's chemotherapy schedule and association with development of NEH\n\nDate\tAdministered drugs\t\nDoxorubicin\tIfosfamide\tPegfilgrastim\t\n1/17/2017\tX\tX\t\t\n1/18/2017\tX\tX\t\t\n1/19/2017\t\tX\t\t\n1/21/2017\t\t\tX\t\n2/6/2017\tX\tX\t\t\n2/7/2017\tX\tX\t\t\n2/8/2017\t\tX\tX\t\n2/10/2017\t\t\t\t\n2/21/2017\t\na\n\t\n2/25/2017\t\tX\t\t\n2/26/2017\t\tX\t\t\n2/27/2017\t\tX\t\t\n3/1/2017\t\t\tX\t\n3/13/2017\t\nb\n\t\n3/24/2017\t\tX\t\t\n3/25/2017\t\tX\t\t\n3/26/2017\t\tX\t\t\n5/8/2017\tX\tX\t\t\n5/9/2017\tX\tX\t\t\n5/10/2017\t\tX\t\t\n5/31/2017\tX\tX\t\t\n6/1/2017\tX\tX\t\t\n6/2/2017\t\tX\t\t\n6/21/2017\tX\t\t\t\n6/22/2017\tX\t\t\t\na Admission for fever with similar, but less intense rash which resolved likely secondary to steroids given for nausea.\n\nb Development of skin lesions seen in NEH described in case report.\n\nJohn Wiley & Sons, LtdFigure 3 Edema and rare neutrophils in the adventitial dermis around the secretory segment of the eccrine apparatus. Neutrophils noted with green arrows (H/E, X400 original magnification. Skin biopsy from anterior abdominal wall lesion)\n\n3 DISCUSSION\nNeutrophilic eccrine hidradenitis is a rare neutrophilic dermatosis characterized by the development of tender, edematous, erythematous papules and plaques.1 Histologic examination shows neutrophilic infiltration of the eccrine unit and necrosis of the eccrine coils and glands.2 It has been associated with malignancies such as acute myelogenous leukemia (AML), Wilms’ tumor, testicular carcinoma, osteosarcoma, Hodgkin's disease, and Non‐Hodgkin's lymphoma.4 Occurrence in the setting of synovial sarcoma, to our knowledge, has not previously been described. It has also been associated with chemotherapeutic agents including cytarabine, anthracyclines, bleomycin, cisplatin, and methotrexate.3 Seventy percent of chemotherapy‐related NEH occur after the first course of chemotherapy.3 Our patient did not develop NEH until after his second cycle of doxorubicin (an anthracycline) and moreover, received anthracyclines later in his course without development of NEH, making this less likely the cause of his NEH. Association with ifosfamide has not been previously described. Infections (HIV, Nocardia, Serratia, and Staphylococcus), Granulocyte colony‐stimulating factor (G‐CSF), systemic lupus erythematosus, and Behcet disease are other associated etiologies.1, 5, 6 In our patient's case, infection was unlikely the cause of his NEH as his blood cultures remained negative during his course and CRP continued to climb despite broad‐spectrum antibiotics, only improving after steroid administration.\n\n3.1 Pathophysiology\nNeutrophilic eccrine hidradenitis secondary to chemotherapy has been thought to represent a reaction to toxic drugs excreted in sweat.5 It has been suggested that G‐CSF induced NEH occurs secondary to enhanced chemotaxis of neutrophils and stimulation of neutrophilic progenitors.5 In healthy children with NEH, destruction of immature eccrine glands by high temperatures with resultant inflammatory infiltrate has been proposed as an additional pathogenetic mechanism.7 Another hypothesis is that NEH may be a hypersensitivity reaction within the spectrum of other neutrophilic dermatoses such as Sweet syndrome.8\n\n\n3.2 Clinical presentation\nPatients classically present with tender, erythematous and edematous papules and plaques and rarely, with purpuric lesions.5 Sites of involvement include the upper trunk, upper limbs, face (especially the periorbital area), palms, and soles.1, 2 The axillae and inguinal folds are classically spared. Many patients also present with a fever which may precede the onset of the lesions.4 Extracutaneous manifestations including myositis and splenomegaly (as seen in our patient) have been previously reported in Sweet syndrome, however, not in NEH.3, 9\n\n\n3.3 Diagnosis\nNeutrophilic eccrine hidradenitis can mimic cellulitis, and therefore, infection should be ruled out. The diagnosis is histologic, requiring a punch biopsy.2 The primary histologic feature is neutrophilic infiltrate in and around the eccrine glands.1 In neutropenic patients, the degree of infiltrate may be minimal. Therefore, in such patients, degenerative changes of the eccrine glands may be helpful in making the diagnosis.1 If a hematologic malignancy is suspected, a complete blood count should be obtained. In addition, medication intake should be reviewed for potential causative agents.1\n\n\n3.4 Treatment\nLesions typically resolve spontaneously within a few days or weeks of discontinuation of causative medications.5 Oral corticosteroids, colchicine, anti‐pyretics, and other non‐steroidal anti‐inflammatory drugs have been found to accelerate resolution.1, 3, 10\n\n\n4 CONCLUSIONS\nNeutrophilic eccrine hidradenitis is an acute febrile neutrophilic dermatosis associated with malignancies, chemotherapeutic agents, infections, and G‐CSF.1 Only a few cases of NEH have been previously reported in the pediatric population. NEH may clinically appear similar to infection and therefore must be distinguished by blood cultures and skin biopsy to guide appropriate therapy.2 Extracutaneous involvement, although seen in Sweet Syndrome, has not been previously reported in NEH.3, 9 Our patient with synovial sarcoma was a unique case of skin biopsy proven NEH who also developed extracutaneous involvement in the form of myositis and splenomegaly, likely secondary to G‐CSF.\n\nCONFLICT OF INTEREST\nThe authors listed have indicated they have no potential conflict of interests to disclose.\n\nAUTHOR CONTRIBUTION\nNP and AS: drafted the initial manuscript and reviewed and revised the manuscript. JP and FPM: conceptualized the case report and critically reviewed and revised the manuscript for important intellectual content. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.\n==== Refs\nREFERENCES\n1 \n\nBerk \nDR \n, \nBayliss \nSJ \n. Neutrophilic dermatoses in children . Pediatr Dermatol . 2008 ;25 (5 ):509 ‐519 .18950391 \n2 \n\nCopaescu \nA‐M \n, \nCastilloux \nJ‐F \n, \nChababi‐Atallah \nM \n, \nSinave \nC \n, \nBertrand \nJ \n. A classic clinical case: neutrophilic eccrine hidradenitis . Case Rep Dermatol . 2013 ;5 (3 ):340 ‐346 .24474918 \n3 \n\nCohen \nPR \n. Neutrophilic dermatoses occurring in oncology patients . Int J Dermatol . 2007 ;46 (1 ):106 ‐111 .17214733 \n4 \n\nKeane \nF \n, \nMunn \nE \n, \nBuckley \nA \n, \nHopster \nD \n, \nMuftit \nG \n, \ndu Vivier \nA \n. Neutrophilic eccrine hidradenitis in two neutropaenic patients . Clin Exp Dermatol . 2001 ;26 (2 ):162 ‐165 .11298106 \n5 \n\nBachmeyer \nC \n, \nAractingi \nS \n. Neutrophilic eccrine hidradenitis . Clin Dermatol . 2000 ;18 :319 ‐330 .10856664 \n6 \n\nBachmeyer \nC \n, \nChaibi \nP \n, \nAractingi \nS \n. Neutrophilic eccrine hidradenitis induced by granulocyte colony‐stimulating factor . Br J Dermatol . 1998 ;139 (2 ):354 ‐355 .9767267 \n7 \n\nAndreu‐Barasoain \nM \n, \nCalzado \nC \n, \nSalamanca \nJ \n, et al. Generalized idiopathic neutrophilic eccrine hidradenitis in a 7‐month‐old child . J Am Acad Dermatol . 2012 ;67 (4 ):133 ‐134 .\n8 \n\nGrillo \nE \n, \nVano‐Galvan \nS \n, \nGonzalez \nC \n, et al. Neutrophilic eccrine hidroadenitis with atypical findings . Dermatol Online J . 2011 ;17 (9 ):14 .\n9 \n\nAttias \nD \n, \nLaor \nR \n, \nZuckermann \nE \n, et al. Acute neutrophilic myositis in Sweet's syndrome: late phase transformation into fibrosing myositis and panniculitis . Hum Pathol . 1995 ;26 :688 ‐690 .\n10 \n\nLee \nSG \n, \nIn \nSG \n, \nShin \nJH \n, \nChoi \nGS \n, \nKim \nYC \n. Neutrophilic eccrine hidradenitis in non‐small cell lung cancer . Int J Dermatol . 2007 ;46 (1 ):59 ‐60 .17214722\n\n",
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"medline_ta": "Clin Case Rep",
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"title": "Neutrophilic eccrine hidradenitis secondary to pegfilgrastim in a patient with synovial sarcoma.",
"title_normalized": "neutrophilic eccrine hidradenitis secondary to pegfilgrastim in a patient with synovial sarcoma"
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"abstract": "BACKGROUND\nThe prothrombotic effect of combined oral contraceptives (COCs) is well-established, with a 3-6-fold increased risk of VTE compared to non-users. When initiation of COCs is considered, it is therefore of paramount importance to carefully evaluate all other potential risk factors for VTE. Based on a case of life-threatening COC-associated pulmonary embolism in a girl heterozygous for the prothrombin G20210A mutation and with a family history of thrombotic disease, we discuss the importance of assessing not just the genotype but also the phenotype when considering initiation of COCs in patients with thrombophilia.\n\n\nMETHODS\nA 14-year-old girl presented with acute onset of chest pain and dyspnea followed by syncope. She was hypoxic and hemodynamically compromised at admission. Computed tomography pulmonary angiography revealed a large central \"saddle\" pulmonary embolism causing nearly total occlusion of the right pulmonary artery, and several minor peripheral embolisms bilaterally. She was successfully treated with thrombolysis (alteplase) followed by aPTT-adjusted heparin infusion until adequate anticoagulation with warfarin was achieved. Two years earlier, the patient had been found heterozygote for the prothrombin G20210A mutation, and 9 months before admission she had initiated use of second-generation COCs.\n\n\nCONCLUSIONS\nHereditary thrombophilia and a family history of early-onset venous thromboembolism (VTE) each pose an increased risk of VTE and should be considered as separate, irreversible risk factors. Other contraceptive methods should be used when treatment with COCs is expected to result in an unacceptable high risk of VTE.",
"affiliations": "Clinical Pharmacology, Department of Public Health, University of Southern Denmark, Odense, Denmark.;Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.",
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"title": "Life-Threatening Contraceptive-Related Pulmonary Embolism in a 14-Year-Old Girl with Hereditary Thrombophilia.",
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{
"abstract": "Rash is one of the most common adverse events observed with mogamulizumab, an anti-C-C chemokine receptor 4 monoclonal antibody approved for previously treated mycosis fungoides (MF) and Sezary syndrome (SS). Given the nonspecific clinical presentations of this rash, histopathologic distinction from MF/SS is critical for informing clinical management. We performed a comprehensive characterization of the histopathologic findings in mogamulizumab-associated rash (MAR) with the integration of high-throughput sequencing of T-cell receptor (TCR) genes. Fifty-two biopsy specimens from 19 patients were evaluated retrospectively. Three major histologic reaction patterns were identified: spongiotic/psoriasiform dermatitis (33/52), interface dermatitis (11/52), and granulomatous dermatitis (8/52). Almost half of the specimens (21/52) showed at least 2 of these reaction patterns concurrently. Dermal eosinophils were not a consistent feature, being present in only half (27/52) of specimens and prominent in only 3. Features mimicking MF/SS, including lymphocyte exocytosis, lamellar fibroplasia, and adnexal involvement, were commonly seen but tended to be focal and mild. In 38/43 specimens with available immunohistochemistry, intraepidermal lymphocytes demonstrated a CD4:CD8 ratio ≤1 : 1. Low background levels of the patient's previously identified MF/SS-associated TCR sequence(s) were demonstrated in 20/46 specimens analyzed by high-throughput sequencing of TCR. We conclude that MAR may demonstrate diverse histologic features. Findings that may distinguish MAR from MF/SS include the inverted or normalized CD4:CD8 ratio within intraepidermal lymphocytes and demonstration of absent or nondominant levels of disease-associated TCR sequences. Correlation with the clinical findings and immunohistochemical and molecular characterization of the patient's MF/SS before mogamulizumab, when possible, may facilitate recognition of MAR.",
"affiliations": "Department of Dermatology, Stanford University School of Medicine, Redwood City.;Department of Dermatology, Stanford University School of Medicine, Redwood City.;Department of Dermatology, Stanford University School of Medicine, Redwood City.;Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA.;Department of Dermatology, Stanford University School of Medicine, Redwood City.;Department of Dermatology, Stanford University School of Medicine, Redwood City.;Department of Dermatology, Stanford University School of Medicine, Redwood City.;Department of Dermatology, Stanford University School of Medicine, Redwood City.;Department of Dermatology, Stanford University School of Medicine, Redwood City.;Department of Dermatology, Stanford University School of Medicine, Redwood City.",
"authors": "Wang|Jennifer Y|JY|;Hirotsu|Kelsey E|KE|;Neal|Tatiana M|TM|;Raghavan|Shyam S|SS|;Kwong|Bernice Y|BY|;Khodadoust|Michael S|MS|;Brown|Ryanne A|RA|;Novoa|Roberto A|RA|;Kim|Youn H|YH|;Rieger|Kerri E|KE|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C549035:mogamulizumab",
"country": "United States",
"delete": false,
"doi": "10.1097/PAS.0000000000001587",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0147-5185",
"issue": "44(12)",
"journal": "The American journal of surgical pathology",
"keywords": null,
"medline_ta": "Am J Surg Pathol",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D016516:CD4-CD8 Ratio; D003875:Drug Eruptions; D005076:Exanthema; D005260:Female; D019672:Genes, T-Cell Receptor; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D012867:Skin; D013601:T-Lymphocytes",
"nlm_unique_id": "7707904",
"other_id": null,
"pages": "1666-1676",
"pmc": null,
"pmid": "32976123",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Histopathologic Characterization of Mogamulizumab-associated Rash.",
"title_normalized": "histopathologic characterization of mogamulizumab associated rash"
} | [
{
"companynumb": "US-KYOWAKIRIN-2020BKK016246",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MOGAMULIZUMAB-KPKC"
},
"drugadditional": "3... |
{
"abstract": "We report safety, tolerability, and 12-week sustained virologic response with half-standard dose sofosbuvir and standard-dose simeprevir combination therapy in a hepatitis C virus genotype 1a-infected liver transplant recipient on hemodialysis - uncharted territory for sofosbuvir-based therapy. The patient was a non-responder to prior treatment with pegylated interferon plus ribavirin. Sofosbuvir efficacy was maintained despite pill-splitting and administration of half-standard dose, 200 mg per day. No drug-drug interactions were noted with tacrolimus-based immunosuppression. Laboratory tests remained stable or improved during therapy. Our observation, if reproduced in a larger study, may lead to significant improvement in clinical outcomes and cost savings in this patient population.",
"affiliations": "Division of Gastroenterology and Hepatology, Liver Transplant Program, Stanford University School of Medicine, Stanford, California, USA.",
"authors": "Perumpail|R B|RB|;Wong|R J|RJ|;Ha|L D|LD|;Pham|E A|EA|;Wang|U|U|;Luong|H|H|;Kumari|R|R|;Daugherty|T J|TJ|;Higgins|J P|JP|;Younossi|Z M|ZM|;Kim|W R|WR|;Glenn|J S|JS|;Ahmed|A|A|",
"chemical_list": "D000998:Antiviral Agents; D000069616:Simeprevir; D000069474:Sofosbuvir",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12348",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "17(2)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "direct-acting antivirals; hemodialysis; hepatitis C virus; liver transplantation; simeprevir; sofosbuvir",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000998:Antiviral Agents; D004359:Drug Therapy, Combination; D019698:Hepatitis C, Chronic; D006801:Humans; D007676:Kidney Failure, Chronic; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D006435:Renal Dialysis; D000069616:Simeprevir; D000069474:Sofosbuvir; D066027:Transplant Recipients; D016896:Treatment Outcome; D019562:Viral Load",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "275-8",
"pmc": null,
"pmid": "25641426",
"pubdate": "2015-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Sofosbuvir and simeprevir combination therapy in the setting of liver transplantation and hemodialysis.",
"title_normalized": "sofosbuvir and simeprevir combination therapy in the setting of liver transplantation and hemodialysis"
} | [
{
"companynumb": "US-ROCHE-1564766",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PEGINTERFERON ALFA-2A"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nPartial nephrectomy is the surgical standard of care for favorably located, small renal tumors. As the incidence of renal cell carcinoma (RCC) and detection of small kidney masses have increased over the past 20 years, minimally invasive management of these lesions has become more common. We report our single-institution experience with hand-assisted laparoscopic partial nephrectomy (HALPN) compared with open partial nephrectomy (OPN).\n\n\nMETHODS\nRelevant outcome and demographic information was collected prospectively for HALPNs (N = 60) and retrospectively for OPNs (N = 40). A p-value of < 0.05 denotes statistical significance.\n\n\nRESULTS\nAverage tumor size (2.6 cm HALPN versus 2.6 cm OPN, p = 0.97) was similar. Mean operative times were shorter for HALPN compared with OPN (161 versus 191 min, p = 0.027). HALPN was also associated with less blood loss (mean 120 cc versus 353 cc, p = 0.0003). Warm ischemia time was shorter for HALPN (mean 27.0 min versus 33.0 min, p = 0.035), as was hospital stay (mean 4.9 days versus 6.9 days, p = 0.007). Although four HALPN renal tumors required intraoperative margin re-excision (based on immediate gross evaluation by a pathologist), the final positive margin rate was 0%. A 5% final positive margin rate was observed in the OPN group. There were two conversions from HALPN to HAL radical nephrectomy and no conversions to an open technique. The HALPN minor complication rate was 18.3% versus 32.5% for OPN (p = 0.10). Complications included delayed bleeding (1, 2.5% OPN), urine leak (2, 5% OPN; 2, 3.3% HALPN), hypoxia, and nausea or fever lasting >3 days. Tumor pathology was as follows: 80.7% and 80% RCC, 12.3% and 8% oncocytoma, and 7% and 12% angiomyolipoma, for HALPN and OPN, respectively in each case.\n\n\nCONCLUSIONS\nHALPN is associated with diminished blood loss, operating time, warm ischemia time, positive margin rates, and length of stay compared with OPN. In our institution, HALPN is the standard approach for patients with small, surgically accessible renal tumors.",
"affiliations": "Department of Urology, Carolinas Medical Center, Charlotte, NC 28203, USA.",
"authors": "DeVoe|William B|WB|;Kercher|Kent W|KW|;Hope|William W|WW|;Lincourt|Amy E|AE|;Norton|H James|HJ|;Teigland|Chris M|CM|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00464-008-0135-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0930-2794",
"issue": "23(5)",
"journal": "Surgical endoscopy",
"keywords": null,
"medline_ta": "Surg Endosc",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D002292:Carcinoma, Renal Cell; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms; D010535:Laparoscopy; D008297:Male; D008875:Middle Aged; D009392:Nephrectomy",
"nlm_unique_id": "8806653",
"other_id": null,
"pages": "1075-80",
"pmc": null,
"pmid": "18830753",
"pubdate": "2009-05",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": "14569452;17574057;15821559;18294039;12796646;17070341;15910255;11325086;18340155;14680319;12352392;17574056;15351570;7714953;16153207;15448025;18222599;18287387;8345614;17070227;10799155",
"title": "Hand-assisted laparoscopic partial nephrectomy after 60 cases: comparison with open partial nephrectomy.",
"title_normalized": "hand assisted laparoscopic partial nephrectomy after 60 cases comparison with open partial nephrectomy"
} | [
{
"companynumb": "US-JNJFOC-20180231743",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FIBRINOGEN HUMAN\\THROMBIN HUMAN"
},
"drugadditio... |
{
"abstract": "Sarcoidosis is a multisystemic granulomatous disease with diverse and often non-specific symptoms during childhood. The clinical manifestations sometimes include endocrinopathies related to sarcoid infiltration of various endocrine organs, but more commonly due to the associated autoimmune endocrine disorders. There are only a few reports of multiple autoimmune and non-autoimmune endocrine problems occurring simultaneously in patients with sarcoidosis. We report a girl with probable sarcoidosis who also had Hashimoto's thyroiditis, Type 1 diabetes (T1D) and secondary adrenal insufficiency.\nA 9-year-old girl previously diagnosed with autoimmune hypothyroidism and vitamin D deficiency, presented with hypercalcemic pancreatitis after initiating vitamin D supplementation that lead to a diagnosis of probable sarcoidosis. Secondary adrenal insufficiency and T1D were subsequently diagnosed. Her angiotensin converting enzyme levels on 2 occasions were 106 and 135 nmol/mL/min (normal range 10 - 43). All investigations conducted to exclude several infectious and malignant conditions that may mimic sarcoidosis were negative. The patient showed a good response to treatment with hydrocortisone, levothyroxine, insulin and methotrexate.\nTo our knowledge, ours is the youngest ever patient reported in the literature with sarcoidosis to develop multiple autoimmune and non-autoimmune endocrinopathies.",
"affiliations": "Department of Paediatric Endocrinology, Alder Hey Children's Hospital, Liverpool, UK.;Department of Paediatric Endocrinology, Alder Hey Children's Hospital, Liverpool, UK.;Department of Paediatric Endocrinology, Alder Hey Children's Hospital, Liverpool, UK.;Department of Paediatric Rheumatology, Alder Hey Children's Hospital, Liverpool, UK.;Department of Paediatric Endocrinology, Alder Hey Children's Hospital, Liverpool, UK.;Department of Paediatric Rheumatology, Alder Hey Children's Hospital, Liverpool, UK.;Department of Paediatric Rheumatology, Alder Hey Children's Hospital, Liverpool, UK.;Department of Paediatric Rheumatology, Alder Hey Children's Hospital, Liverpool, UK.;Department of Paediatric Endocrinology, Alder Hey Children's Hospital, Liverpool, UK.",
"authors": "Dayal|Devi|D|;Pepper|Olivia|O|;Ramakrishnan|Renuka|R|;Baildam|Eileen|E|;Dharmaraj|Poonam|P|;Cleary|Gavin|G|;McCann|Liza|L|;Pain|Clare|C|;Senniappan|Senthil|S|",
"chemical_list": null,
"country": "Iran",
"delete": false,
"doi": "10.5812/ijem.57199",
"fulltext": "\n==== Front\nInt J Endocrinol MetabInt J Endocrinol Metab10.5812/ijem.KowsarInternational Journal of Endocrinology and Metabolism1726-913X1726-9148Kowsar 10.5812/ijem.57199Case ReportHypercalcaemic Pancreatitis, Adrenal Insufficiency, Autoimmune Thyroiditis and Diabetes Mellitus in a girl with Probable Sarcoidosis Dayal Devi 1drdevidayal@gmail.comPepper Olivia 1Ramakrishnan Renuka 1renuka.ramakrishnan@alderhey.nhs.ukBaildam Eileen 2eileen.baildam@alderhey.nhs.ukDharmaraj Poonam 1poonam.dharmaraj@alderhey.nhs.ukCleary Gavin 2gavin.cleary@alderhey.nhs.ukMcCann Liza 2liza.mccann@alderhey.nhs.ukPain Clare 2clare.pain@alderhey.nhs.ukSenniappan Senthil 1*senthilkss@yahoo.co.uk1 Department of Paediatric Endocrinology, Alder Hey Children’s Hospital, Liverpool, UK2 Department of Paediatric Rheumatology, Alder Hey Children’s Hospital, Liverpool, UK* Corresponding author: Dr. Senthil Senniappan MD, PhD, Consultant Paediatric Endocrinologist and Honorary Senior Lecturer, Department of Paediatric Endocrinology, Alder Hey Children’s Hospital NHS Trust, East Prescot Road, Liverpool, L14 5AB, UK. Tel: +44-1512525281, Fax: +44-1512824606, E-mail: senthilkss@yahoo.co.uk22 8 2017 10 2017 15 4 e5719905 4 2017 22 7 2017 25 7 2017 Copyright © 2017, International Journal of Endocrinology and Metabolism2017This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.Introduction\nSarcoidosis is a multisystemic granulomatous disease with diverse and often non-specific symptoms during childhood. The clinical manifestations sometimes include endocrinopathies related to sarcoid infiltration of various endocrine organs, but more commonly due to the associated autoimmune endocrine disorders. There are only a few reports of multiple autoimmune and non-autoimmune endocrine problems occurring simultaneously in patients with sarcoidosis. We report a girl with probable sarcoidosis who also had Hashimoto’s thyroiditis, Type 1 diabetes (T1D) and secondary adrenal insufficiency.\n\nCase Presentation\nA 9-year-old girl previously diagnosed with autoimmune hypothyroidism and vitamin D deficiency, presented with hypercalcemic pancreatitis after initiating vitamin D supplementation that lead to a diagnosis of probable sarcoidosis. Secondary adrenal insufficiency and T1D were subsequently diagnosed. Her angiotensin converting enzyme levels on 2 occasions were 106 and 135 nmol/mL/min (normal range 10 - 43). All investigations conducted to exclude several infectious and malignant conditions that may mimic sarcoidosis were negative. The patient showed a good response to treatment with hydrocortisone, levothyroxine, insulin and methotrexate.\n\nConclusions\nTo our knowledge, ours is the youngest ever patient reported in the literature with sarcoidosis to develop multiple autoimmune and non-autoimmune endocrinopathies.\n\nSarcoidosisHypercalcemiaPancreatitisType 1 DiabetesHashimoto’s ThyroiditisAdrenal Insufficiency\n==== Body\n1. Introduction\nSarcoidosis is a chronic multisystemic disease of unknown etiology characterized by granulomatous inflammation in lungs, liver, eyes, lymph nodes, skin, heart, nervous and musculoskeletal systems and gut (1). Diagnosis is typically confirmed in adults when three key features are present; positive radiological imaging (chest X-Ray), a suggestive clinical picture and the histological presence of non-caseating granulomas (2). However, there are no universal criteria especially in children and sarcoidosis is often a diagnosis of exclusion (3). The clinical value of using serum angiotensin converting enzyme (ACE) in diagnosis is debated as it can be raised non-specifically at moderately high levels in childhood. However, ACE is said to be elevated in 60% of patients with sarcoidosis and can be used to monitor disease activity (4).\n\nThe incidence of sarcoidosis varies worldwide as race, genetics and environment are implicated in the pathophysiology (5). The highest incidence is reported in Northern European and African-American individuals while Japanese populations are the least affected (6). The peak age of onset is between 25 - 45 years; paediatric presentations are very rare and often present a diagnostic challenge due to the nonspecific symptoms and the lack of specific biomarkers for diagnosis (7). The precise cause of sarcoidosis is still unknown. Current opinion suggests that exposure to antigens in genetically susceptible individuals may contribute to CD4+ T helper cell activation, triggering an abnormal immune response and leading to granuloma formation (8). Treatment with immunomodulatory drugs is often required.\n\nThe association of sarcoidosis with autoimmune disorders is well recognized and probably indicates a complex interplay of immunological and genetic mechanisms (8, 9). In general, autoimmune conditions are characterized by an immune response to self-antigens such as thyroperoxidase in Hashimoto’s thyroiditis (HT) or islet cell components in Type 1 diabetes (T1D). There is a polyclonal activation of B lymphocytes (delayed hypersensitivity, secondary autoimmunity) in response to one or several exogenous antigens in sarcoidosis (1, 8). Sarcoidosis may co-exist with several endocrine and non-endocrine autoimmune conditions (9). However, the reported cases with co-existing endocrine manifestations are rare in children.\n\nWe report a child who developed hypercalcemic pancreatitis after supplementation with vitamin D, subsequently leading to a diagnosis of sarcoidosis. Additionally, she was diagnosed with HT, T1D and secondary adrenal insufficiency. To our knowledge, such an unusual association of endocrinopathies has not been described previously in childhood sarcoidosis.\n\n2. Case Presentation\nA 9-year-old girl of mixed ethnic origin was referred to the endocrine team in view of hypercalcaemia, lethargy and weight loss. At 8 year of age, she was investigated elsewhere for lethargy, tiredness and reduced appetite and was diagnosed with autoimmune hypothyroidism and vitamin D deficiency (25-hydroxyvitamin D [25(OH)D] 11 nmol/L). At that point, she was also noted to have benign joint hypermobility and a functional cardiac murmur. There was no history of pain or swelling of joints. She did not complain of any significant ailments in the past and there was no history to suggest an endocrine or autoimmune disease in the family.\n\nShe was born at 42 weeks gestation with no neonatal concerns. Her symptoms had persisted despite satisfactory control of the hypothyroid state and intermittent vitamin D supplementation. She was treated with cholecalciferol (20,000 IU/d for 1 week and 800 IU/d later) for persistent vitamin D deficiency. A week later, she began to complain of low-grade fever and intermittent bouts of vomiting and abdominal pain. She was treated at the local hospital for a presumed abdominal infection in view of high C-reactive protein (CRP) levels but the screen for sepsis was negative. Her symptoms persisted and a weight loss of 4kg was noted over the preceding month. Additionally, she was detected to have hypercalcemia and was hospitalized.\n\nOn physical examination, her anthropometric parameters were normal for age. She was noted to have dark discoloration under the eyes and pallor. There was no goitre. The systemic examination was unremarkable. Investigations revealed hemoglobin of 96 g/L (normal, 115 - 155 g/L), erythrocyte sedimentation rate (ESR) 35 mm/h (normal, 3 - 13 mm/h) and platelet count was elevated at 685 × 109/L (normal, 140 – 400 × 109/L). Serum ferritin, CRP and albumin were 25 ng/mL (normal, 29 - 371 ng/mL), 44 mg/L and 25 g/L (normal, 35 - 55 g/L) respectively. Serial serum concentrations of calcium, phosphorus, alkaline phosphatase (ALP), parathyroid hormone (PTH), 25(OH)D and 1, 25 dihydroxy vitamin D [1, 25(OH)2D] are shown in Table 1. Serum magnesium was 0.58 mmol/L (normal, 0.7 - 1 mmol/L) and serum amylase was 395 U/L (normal, 23 - 85 U/L).\n\nTable 1. Biochemical Parameters Before, During and After the Episode of Hypercalcemic Pancreatitisa\nBiochemical Parameter\tBefore Episode\tDuring Hypercalcemic Episode\tAfter Episode\t\n\t1 y\t2 mo\t1 mo\tD1\tD3\tD4\tD5\t1 mo\t6 mo\t\n\nSerum calcium, mmol/L\n\t2.28\t2.33\t\t3.70\t3.78\t3.62\t2.55\t2.35\t2.36\t\n\nSerum phosphorus, mmol/L\n\t\t1.33\t\t1.46\t\t\t0.82\t1.36\t1.7\t\n\nSerum Alkaline phosphatase, IU/L\n\t\t\t\t133\t\t\t289\t393\t810\t\n\nSerum parathyroid hormone, pmol/L\n\t\t\t\t0.1\t0.7\t\t\t3.2\t3.6\t\n\nSerum 25(OH)D, nmol/L\n\t44\t29\t11\t65\t63\t\t\t69\t81\t\n\nSerum 1,25(OH)2D, pmol/L\n\t\t\t\t\t161\t\t\t102\t\t\n\nUrinary calcium/creatinine ratio, mmol/mmol\n\t\t\t\t3.03\t\t\t\t0.9\t\t\naNormal levels: calcium, 2.15 - 2.74 mmol/L; phosphorus, 0.97 - 1.94 mmol/L; alkaline phosphatase, 203 - 1151 IU/L; 25(OH)D, 50 - 125 nmol/L; 1,25(OH)2D, 43 - 143 pmol/L; parathyroid hormone, 1.1 - 6.9 pmol/L; urine calcium creatinine ratio, 0.08 - 0.79 mmol/mmol.\n\nAbdominal ultrasonogram (USG) showed a diffusely enlarged hypoechoic pancreas surrounded by free fluid, and minimal ascites but no cholelithiasis. A lower gut endoscopy and abdominal magnetic resonance imaging (MRI) showed no evidence of inflammatory bowel disease. Anti-tissue transglutaminase antibodies were negative. A clinical diagnosis of acute pancreatitis probably caused by hypercalcemia was considered.\n\nA rheumatological evaluation undertaken in view of her chronic non-specific symptoms revealed high ACE levels on 2 occasions (106 and 135 nmol/mL/min, normal range 10 - 43). Serum lactate dehydrogenase was 573 U/L (normal, 143 - 290 U/L). Tests for antinuclear antibody, anti-double-stranded DNA, perinuclear anti-neutrophil cytoplasmic antibodies and cytoplasmic anti-neutrophil cytoplasmic antibodies were negative. Ophthalmology examination showed no evidence of uveitis and conjunctival biopsy showed no granulomas.\n\nDetailed investigations were conducted to exclude infectious and malignant diseases that may mimic sarcoidosis. Radiograph and CT scan of the chest, and echocardiography were normal. Brain MRI including pituitary gland and pelvic USG showed no abnormality. Bone marrow examination was normal. Total human chorionic gonadotropin and α-fetoprotein levels were < 1 mIU/mL (normal, 0 - 5 mIU/mL) and 2.2 ng/mL (normal, < 5 ng/mL) respectively. Urinary vanillylmandelic acid level was normal. Mantoux test showed no induration. HIV serology and PCR for cytomegalovirus, adenovirus and Epstein-Barr virus were negative. Urine microscopy was made and culture was negative. Creatine kinase was 9U/L (normal, 22 - 198 U/L). Immunoglobulin and lipid profiles were normal. Serum complement C3 and C4 levels were 88 mg/dL (normal, 90 - 180 mg/dL) and 20 mg/dL (normal, 20 - 50 mg/dL) respectively. Plasma concentrations of ceruloplasmin, copper, mercury and lead were 0.33 g/L (normal, 0.32 - 0.57 g/L), 15 µmol/L (normal, 13.2 - 21.4 µmol/L), 3 nmol/L (normal, 0 - 20 nmol/L) and 1 µg/dL (normal, < 5 µg/dL) respectively.\n\nA short standard adrenocorticotropic hormone (ACTH) stimulation test showed serum cortisol concentrations of < 50, 320 and 378 nmol/L at baseline, 30 and 60 minutes respectively (normal stimulated peak concentration, > 500 nmol/L). Plasma ACTH level was < 1.1 pmol/L (normal, 2 - 11 pmol/L) suggestive of secondary adrenal insufficiency. Insulin-like growth factor-1 (IGF-1) level was < 3.3 nmol/L (normal, 4 - 20 nmol/L). The blood glucose concentrations during the 2nd week of hospital stay were ≥ 11.1 mmol/L on multiple occasions leading to a diagnosis of diabetes mellitus. Glycosylated hemoglobin (HbA1c) level was 31 mmol/mol (normal, < 42 mmol/mol). Titers of anti-thyroid peroxidase, anti-glutamic acid decarboxylase (GAD) and anti-adrenal antibodies were 253 IU/mL (normal, 0 - 60 IU/mL), 419 U/mL (normal, 0 - 5 U/mL) and negative (< 1 U/mL) respectively.\n\nThe vitamin D supplementation was stopped and intravenous hyperhydration was initiated along with intravenous furosemide for the management of hypercalcemia. On day 3 of hospitalization, a single subcutaneous dose of calcitonin (4 IU/kg) was administered in view of persistent hypercalcemia following which the hypercalcaemia gradually improved (Table 1) paralleling an improvement in abdominal symptoms. Hyperhydration was continued for another 2 days. Repeat USG of abdomen a week later showed resolving pancreatitis. There was no recurrence of hypercalcaemia over the next several months. Levothyroxine was continued. She was started on replacement oral hydrocortisone (10 mg/m2/day).\n\nSubsequently methotrexate (15 mg once a week) and oral prednisolone (40 mg once daily) was added for the management of sarcoidosis (hydrocortisone was discontinued whilst on prednisolone). A basal-bolus insulin regimen was commenced with good effect on glycaemic control. She has shown consistent clinical improvement in the year following diagnosis and her symptoms have significantly improved. Prednisolone was discontinued after 6 months and she was restarted on replacement hydrocortisone. Her current growth is optimal (weight 75th centile, height 50th centile) and she continues on hydrocortisone, levothyroxine, insulin (HbA1c 42 mmol/mol) and methotrexate.\n\n3. Discussion\nIn our patient, the diagnosis of sarcoidosis was based on the constellation of clinical features, with raised ESR and platelets and elevated ACE concentrations following exclusion of other conditions that mimic sarcoidosis (1, 3). Additionally, the low complement concentrations (10) and occurrence of hypercalcemia after routine doses of vitamin D (11) indicated the presence of granulomatous inflammation in the body. The serum levels of immunoglobulin and complement are usually low during disease activation due to their deposition in active sarcoid lesions and in circulating immune complexes (10).\n\nAn extensive radiological and laboratory workup and non-recurrence of symptoms over a fairly long-term follow-up helped exclude the usual chronic infectious and occult malignant disorders associated with hypercalcemia in children. However, the diagnosis of sarcoidosis remains probable, as the demonstration of granulomatous inflammation in tissues was not possible. Significant clinical improvement was noted on treatment with methotrexate and prednisolone.\n\nHypercalcemia occurs in 10% - 13% of patients with sarcoidosis and is due to dysregulated (non-PTH mediated) overproduction of 1,25(OH)2D by the granulomatous tissue and activated macrophages, that increases intestinal absorption of calcium (12). Hypercalcemia may also manifest after starting vitamin D supplements as the availability of more substrate 25(OH)D leads to its accelerated conversion to 1,25(OH)2D by autonomously produced 1 α-hydroxylases (11). Vitamin D levels are often low in sarcoidosis due to accelerated conversion of available 25(OH)D to 1,25(OH)2D (11, 13). In our patient, low vitamin D levels persisted despite routine cholecalciferol supplementation probably due to the enhanced utilization of 25(OH)D by 1 α-hydroxylases. Provision of higher doses of cholecalciferol had subsequently led to symptomatic hypercalcemia, similar to previous reports (11, 13). It may be mentioned that a diagnosis of sarcoidosis had not been entertained at the time of starting higher doses of cholecalciferol, similar to previous observations (11, 13).\n\nAcute pancreatitis that occurred in our patient could either be related to sarcoidosis or hypercalcaemia. The sarcoid infiltration of the pancreas, noted in about 1% of autopsy series, may manifest as acute or chronic pancreatitis (14, 15). Hypercalcaemic pancreatitis often manifests acutely and resolves after treatment of hypercalcemia, as seen in our patient, whereas sarcoidosis-induced pancreatitis requires steroids (14). The proposed mechanisms of hypercalcaemic pancreatitis include increased output and activation of pancreatic enzymes, intracellular activation of pancreatic proteases through cholecystokinin release, and increased permeability of pancreatic ducts causing leakage of enzymes (14). A notable feature of hypercalcaemic pancreatitis is that the short-term hypercalcaemia is more likely to be associated with acute pancreatitis than chronic hypercalcemia (11, 13, 14). Acute pancreatitis may also be associated with a number of rheumatic disorders such as systemic lupus erythematosus, rheumatoid arthritis, polyarteritis nodosas and Wegener’s granulomatosis (14) that were excluded in our patient by appropriate investigations. Drug-induced pancreatitis was not considered as the child had not received any drugs known to cause acute pancreatitis (16). Furthermore, a diagnosis of drug-induced pancreatitis is usually made if no other cause can be detected (16). Thus, the temporal association with administration of cholecalciferol resulting in acute hypercalcaemia and prompt resolution after lowering of serum calcium levels makes hypercalcemia as the most likely etiology of acute pancreatitis in our patient.\n\nHypothyroidism is a common co-existing endocrinopathy in sarcoidosis (1, 3). This may result from sarcoidotic infiltration of the thyroid gland that occurs in < 1% of cases (12), but is more often due to associated thyroid autoimmunity (3), as seen in our patient. Furthermore, high titers of anti-GAD 65 antibodies indicate autoimmune diabetes in our patient similar to previous reports (17), although involvement of pancreas in sarcoidosis is occasionally noted to result in diabetes mellitus (18).\n\nWe found secondary adrenal insufficiency in our patient that occurs rarely in sarcoidosis (19). This usually follows sarcoid infiltration of pituitary gland visible as an enlarged gland or mass lesion on MRI (19). Low IGF-1 levels also indicated anterior pituitary dysfunction. However the MRI pituitary was normal and it is difficult to attribute the pituitary dysfunction in our patient to either sarcoidosis or autoimmune destruction. It may be mentioned here that the IGF-1 levels were measured during the phase of hyperglycemia and could well be due to the uncontrolled diabetes at that time (20).\n\nIn conclusion, we report a rare association of multiple autoimmune and non-autoimmune endocrinopathies in a girl with probable sarcoidosis. The disease is currently controlled on a complex medical regime and the patient has returned to normal activities but the long-term outcome remains uncertain. To the best of our knowledge, ours is the youngest ever patient with sarcoidosis who developed such diverse endocrine abnormalities.\n==== Refs\n1 Prasse A The Diagnosis, Differential Diagnosis, and Treatment of Sarcoidosis. Dtsch Arztebl Int. 2016 113 33-34 565 74 10.3238/arztebl.2016.0565 27598883 \n2 Wessendorf TE Bonella F Costabel U Diagnosis of Sarcoidosis. Clin Rev Allergy Immunol. 2015 49 1 54 62 10.1007/s12016-015-8475-x 25779004 \n3 Iannuzzi MC Rybicki BA Teirstein AS Sarcoidosis. N Engl J Med. 2007 357 21 2153 65 10.1056/NEJMra071714 18032765 \n4 Khan AH Ghani F Khan A Khan MA Khurshid M Role of serum angiotensin converting enzyme in sarcoidosis. J Pak Med Assoc. 1998 48 5 131 3 9813973 \n5 Cozier YC Assessing the worldwide epidemiology of sarcoidosis: challenges and future directions. Eur Respir J. 2016 48 6 1545 8 10.1183/13993003.01819-2016 27903684 \n6 Valeyre D Prasse A Nunes H Uzunhan Y Brillet PY Muller-Quernheim J Sarcoidosis. Lancet. 2014 383 9923 1155 67 10.1016/S0140-6736(13)60680-7 24090799 \n7 Diaz Angarita T Morales Camacho W Lozano Neira L Plata Ortiz J Zarate Taborda L [Systemic sarcoidosis: a diagnostic challenge in pediatrics. Case report]. Arch Argent Pediatr. 2016 114 5 e323 8 10.5546/aap.2016.e323 27606655 \n8 Saidha S Sotirchos ES Eckstein C Etiology of sarcoidosis: does infection play a role? Yale J Biol Med. 2012 85 1 133 41 22461752 \n9 Papadopoulos KI Hornblad Y Liljebladh H Hallengren B High frequency of endocrine autoimmunity in patients with sarcoidosis. Eur J Endocrinol. 1996 134 3 331 6 8616531 \n10 Cagatay T Bilir M Gulbaran M Papila C Cagatay P The immunoglobulin and complement levels in the active pulmonary sarcoidosis. Kobe J Med Sci. 2003 49 5-6 99 106 15141145 \n11 Aujla K Majithia V Green A Extreme hypercalcemia leading to the diagnosis of extensive sarcoidosis. J Clin Rheumatol. 2014 20 6 328 9 10.1097/RHU.0000000000000143 25160018 \n12 Sharma OP Vucinic V Sarcoidosis of the thyroid and kidneys and calcium metabolism. Semin Respir Crit Care Med. 2002 23 6 579 88 10.1055/s-2002-36521 16088653 \n13 Amrein K Schilcher G Fahrleitner-Pammer A Hypercalcaemia in asymptomatic sarcoidosis unmasked by a vitamin D loading dose. Eur Respir J. 2011 37 2 470 1 10.1183/09031936.00136910 21282814 \n14 Delakidis S Elezoglou A Hypercalcemia, hyperlipidemia and rheumatic diseases: uncommon causes inducing acute pancreatitis. Ann Gastroenterol. 2007 13 2 \n15 Boruchowicz A Hachulla E Cortot A Paris JC Colombel JF Chronic pancreatitis: a complication of sarcoidosis? Eur J Gastroenterol Hepatol. 1996 8 11 1125 7 8944378 \n16 Nitsche C Maertin S Scheiber J Ritter CA Lerch MM Mayerle J Drug-induced pancreatitis. Curr Gastroenterol Rep. 2012 14 2 131 8 10.1007/s11894-012-0245-9 22314811 \n17 Yoshioka K Association of sarcoidosis, insulin-dependent diabetes mellitus, and ulcerative colitis. Arch Intern Med. 1997 157 4 465 10.1001/archinte.157.4.465 9046905 \n18 Sanchez-Lozada R Soriano-Rosas J Gutierrez-Vega R [Acute pancreatitis, diabetes, and sacoidosis. Case report and review of the literature]. Gac Med Mex. 2004 140 3 343 5 15259348 \n19 Alsahwi N Blavo D Karanchi H Systemic sarcoidosis with hypercalcaemia, hypothalamic-pituitary dysfunction and thyroid involvement. BMJ Case Rep. 2016 2016 10.1136/bcr-2016-216696 27495178 \n20 Raisingani M Preneet B Kohn B Yakar S Skeletal growth and bone mineral acquisition in type 1 diabetic children; abnormalities of the GH/IGF-1 axis. Growth Horm IGF Res. 2017 34 13 21 10.1016/j.ghir.2017.04.003 28482269\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1726-913X",
"issue": "15(4)",
"journal": "International journal of endocrinology and metabolism",
"keywords": "Adrenal Insufficiency; Hashimoto’s Thyroiditis; Hypercalcemia; Pancreatitis; Sarcoidosis; Type 1 Diabetes",
"medline_ta": "Int J Endocrinol Metab",
"mesh_terms": null,
"nlm_unique_id": "101235597",
"other_id": null,
"pages": "e57199",
"pmc": null,
"pmid": "29344035",
"pubdate": "2017-10",
"publication_types": "D002363:Case Reports",
"references": "27903684;18032765;27606655;25779004;22314811;25160018;24090799;27495178;27598883;16088653;8616531;15141145;8944378;9813973;22461752;15259348;9046905;28482269;21282814",
"title": "Hypercalcaemic Pancreatitis, Adrenal Insufficiency, Autoimmune Thyroiditis and Diabetes Mellitus in a girl with Probable Sarcoidosis.",
"title_normalized": "hypercalcaemic pancreatitis adrenal insufficiency autoimmune thyroiditis and diabetes mellitus in a girl with probable sarcoidosis"
} | [
{
"companynumb": "GB-PFIZER INC-2017546297",
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"activesubstancename": "PREDNISOLONE"
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{
"abstract": "OBJECTIVE\nA case of mycophenolate mofetil (MMF)-induced oral ulceration in a kidney transplant recipient is reported.\n\n\nCONCLUSIONS\nA 54-year-old man who had received a kidney transplant 7 months previously reported to our outpatient clinic with severe oral ulcers with odynophagia and was admitted to the hospital. His maintenance immunosuppressive agents at the time of admission consisted of tacrolimus and mycophenolate. The patient had stable renal function, with all laboratory values within normal ranges. After various alternative etiologies were ruled out, drug-induced oral ulceration was suspected, and the patient's tacrolimus dose was empirically reduced, resulting in reduction of the trough concentration from 10 ng/mL to 3.3 ng/mL without improvement of the ulceration. Mycophenolate-induced oral ulceration was suspected, and MMF was discontinued. Within 5 days of discontinuation, there was a remarkable improvement in both the size and severity of the ulceration, and the patient was discharged from the hospital. During the next clinic visit (a total of 12 days after MMF was discontinued), the patient's mouth and esophageal ulcers had completely healed. Six weeks after complete resolution of the ulcer, MMF at a dosage of 250 mg twice daily was initiated; the dosage was subsequently increased to 500 mg twice daily without a recurrence of ulceration.\n\n\nCONCLUSIONS\nA 54-year-old man developed oral ulceration after 7 months of MMF therapy. Discontinuation of therapy resulted in prompt resolution of the patient's ulcers, with no recurrence of ulceration at a lower MMF dose. This is the first case report indicating that mycophenolate-induced ulceration may be dose dependent.",
"affiliations": "Department of Pharmacy, St. Thomas Hospital West, Nashville, TN.;Department of Pharmacy, St. Thomas Hospital West, Nashville, TN.",
"authors": "Asare|Kwame|K|;Gatzke|Caroline Barone|CB|",
"chemical_list": "D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D016559:Tacrolimus",
"country": "England",
"delete": false,
"doi": "10.1093/ajhp/zxz358",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-2082",
"issue": "77(7)",
"journal": "American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists",
"keywords": "immunosuppressants; mycophenolate mofetil; mycophenolic acid; transplantation",
"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": "D004305:Dose-Response Relationship, Drug; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D019226:Oral Ulcer; D016559:Tacrolimus",
"nlm_unique_id": "9503023",
"other_id": null,
"pages": "523-528",
"pmc": null,
"pmid": "32058566",
"pubdate": "2020-03-24",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Mycophenolate-induced oral ulcers: Case report and literature review.",
"title_normalized": "mycophenolate induced oral ulcers case report and literature review"
} | [
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"companynumb": "US-MYLANLABS-2020M1056709",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBIDOPA\\ENTACAPONE\\LEVODOPA"
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"drugaddi... |
{
"abstract": "Purpose: There is limited clinical data evaluating anticoagulation with the direct oral anticoagulants (DOACs) in morbidly obese patients. We sought to examine the efficacy in preventing stroke or other systemic embolic events and safety of apixaban, dabigatran, and rivaroxaban, in comparison to warfarin in patients with either a body-mass index (BMI) over 40 kg/m2 and/or a weight over 120 kg.Methods: After approval from IRB, we collected retrospective data from our institution's records on 180 patients. We analyzed the rates of stroke and systemic embolic events as defined as ischemic stroke, pulmonary embolism (PE), deep vein thrombosis (DVT), and myocardial infarction (MI) as well as major bleeding in morbidly obese patients receiving apixaban, dabigatran, or rivaroxaban in comparison to warfarin for anticoagulation due to nonvalvular atrial fibrillation, postoperative thrombus prophylaxis, or DVT/PE treatment and/or reduction in risk for recurrence.Results: The final analysis included 90 patients in both arms. Fifty-two percent (n = 41) of patients in the DOAC group were on apixaban therapy, 12% (n = 11) on dabigatran, and 37% (n = 33) on rivaroxaban. The average BMI and weight in the DOAC group were 46.7 kg/m2 and 139.3 kg, respectively. In the warfarin group, average BMI and weight were 45.8 kg/m2 and 135.9 kg, respectively. There were 11 patients who developed a stroke or thromboembolic event in the DOAC group and 10 in the warfarin group (OR 1.11, 95% confidence interval [CI] 0.45-2.78; p = 0.82). The events in the DOAC group consisted of three patients who developed ischemic stroke, three patients who developed DVTs, one who developed a PE, and four patients who developed MIs. There were two major bleeding events in the DOAC group and three events in the warfarin group (p = 0.65).Conclusions: Anticoagulation therapy with DOACs in morbidly obese patients may be a safe and effective alternative to warfarin for prevention of stroke or systemic embolic events. However, additional studies are necessary to confirm these findings.",
"affiliations": "Pharmacy, Corpus Christi Medical Center, Corpus Christi, TX, USA.;Pharmacy, Corpus Christi Medical Center, Corpus Christi, TX, USA.;Pharmacy, Corpus Christi Medical Center, Corpus Christi, TX, USA.;Pharmacy, Corpus Christi Medical Center, Corpus Christi, TX, USA.;Pharmacy, Corpus Christi Medical Center, Corpus Christi, TX, USA.",
"authors": "Kalani|Charlene|C|;Awudi|Elizabeth|E|;Alexander|Thomas|T|;Udeani|George|G|;Surani|Salim|S|",
"chemical_list": "D000925:Anticoagulants; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban; D014859:Warfarin; D000069552:Rivaroxaban; D000069604:Dabigatran",
"country": "England",
"delete": false,
"doi": "10.1080/21548331.2019.1674586",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2154-8331",
"issue": "47(4)",
"journal": "Hospital practice (1995)",
"keywords": "Anticoagulation; apixaban; cardiovascular complications; dabigratan; direct oral anticoagulant; rivaroxaban; warfarin",
"medline_ta": "Hosp Pract (1995)",
"mesh_terms": "D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D001281:Atrial Fibrillation; D015992:Body Mass Index; D000069604:Dabigatran; D005260:Female; D006470:Hemorrhage; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction; D009767:Obesity, Morbid; D011655:Pulmonary Embolism; D011720:Pyrazoles; D011728:Pyridones; D012189:Retrospective Studies; D000069552:Rivaroxaban; D020521:Stroke; D020246:Venous Thrombosis; D014859:Warfarin; D055815:Young Adult",
"nlm_unique_id": "101268948",
"other_id": null,
"pages": "181-185",
"pmc": null,
"pmid": "31580732",
"pubdate": "2019-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Evaluation of the efficacy of direct oral anticoagulants (DOACs) in comparison to warfarin in morbidly obese patients.",
"title_normalized": "evaluation of the efficacy of direct oral anticoagulants doacs in comparison to warfarin in morbidly obese patients"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2019-BI-106638",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "BACKGROUND\nBevacizumab plus taxane chemotherapy improves progression-free survival (PFS) versus taxane monotherapy in the first-line treatment of HER2-negative metastatic breast cancer (MBC) and appears promising in the second-line setting. This retrospective analysis evaluated the efficacy and safety of this combination in a real-world setting.\n\n\nMETHODS\nEligible patients received bevacizumab (10 mg/kg days 1 and 15, every 28 days) plus paclitaxel (80 mg/m(2) days 1, 8, and 15, every 28 days) as first-line therapy for MBC, or as subsequent lines, including bevacizumab continuation therapy, at La Paz University Hospital between August 2007 and October 2012. End points included objective response rate (ORR), PFS, overall survival (OS), and safety.\n\n\nRESULTS\nSeventy-eight patients were included. Median PFS was 12.8 months for patients receiving first-line treatment and 9.3 months for subsequent lines. Forty-five patients (57.7%) continued bevacizumab after stopping paclitaxel, and had significantly longer PFS and OS than those who did not (hazard ratio [HR] 0.40, 95% confidence interval [CI] 0.248-0.653, P<0.001; HR 0.39, 95% CI 0.218-0.710, P=0.002; respectively). In the continuation phase, estrogen receptor-positive patients had longer PFS and OS when receiving hormone therapy plus bevacizumab versus patients receiving only bevacizumab (HR 0.50, 95% CI 0.24-1.04, P=0.06; HR 0.43, 95% CI 0.16-1.16, P=0.09; respectively). Thirty-five patients (44.9%) reported grade 3-4 adverse events.\n\n\nCONCLUSIONS\nBevacizumab plus paclitaxel was effective in HER2-negative MBC. Continuation of bevacizumab and addition of hormone therapy following paclitaxel therapy could be beneficial.",
"affiliations": "Medical Oncology Department, University Hospital La Paz (IdiPAZ), Madrid, Spain.;Medical Oncology Department, University Hospital La Paz (IdiPAZ), Madrid, Spain.;Medical Oncology Department, University Hospital La Paz (IdiPAZ), Madrid, Spain.;Medical Oncology Department, University Hospital La Paz (IdiPAZ), Madrid, Spain.;Medical Oncology Department, University Hospital La Paz (IdiPAZ), Madrid, Spain.;Medical Oncology Department, University Hospital La Paz (IdiPAZ), Madrid, Spain.;Medical Oncology Department, University Hospital La Paz (IdiPAZ), Madrid, Spain.;Translational Oncology and Molecular Pathology Laboratory, University Hospital La Paz (IdiPAZ), Madrid, Spain.;Pathology Department, University Hospital La Paz (IdiPAZ), Madrid, Spain.;Medical Oncology Department, University Hospital La Paz (IdiPAZ), Madrid, Spain.",
"authors": "Redondo|Andrés|A|;Martínez|Virginia|V|;Zamora|Pilar|P|;Castelo|Beatriz|B|;Pinto|Alvaro|A|;Cruz|Patricia|P|;Higuera|Oliver|O|;Mendiola|Marta|M|;Hardisson|David|D|;Espinosa|Enrique|E|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/OTT.S70654",
"fulltext": "\n==== Front\nOnco Targets TherOnco Targets TherOncoTargets and TherapyOncoTargets and therapy1178-6930Dove Medical Press 10.2147/OTT.S70654ott-7-2175Original ResearchContinuation of bevacizumab and addition of hormone therapy following weekly paclitaxel therapy in HER2-negative metastatic breast cancer Redondo Andrés 1*Martínez Virginia 1*Zamora Pilar 1Castelo Beatriz 1Pinto Alvaro 1Cruz Patricia 1Higuera Oliver 1Mendiola Marta 2Hardisson David 3Espinosa Enrique 11 Medical Oncology Department, University Hospital La Paz (IdiPAZ), Madrid, Spain2 Translational Oncology and Molecular Pathology Laboratory, University Hospital La Paz (IdiPAZ), Madrid, Spain3 Pathology Department, University Hospital La Paz (IdiPAZ), Madrid, Spain* These authors contributed equally to this work\n\nCorrespondence: Andrés Redondo, Medical Oncology Department, University Hospital La Paz (IdiPAZ), 261 Paseo de la Castellana, Madrid 28046, Spain, Tel +34 91 727 7516, Fax +34 91 358 5204, Email andres.redondos@uam.es2014 27 11 2014 7 2175 2181 © 2014 Redondo et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License2014The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Background\nBevacizumab plus taxane chemotherapy improves progression-free survival (PFS) versus taxane monotherapy in the first-line treatment of HER2-negative metastatic breast cancer (MBC) and appears promising in the second-line setting. This retrospective analysis evaluated the efficacy and safety of this combination in a real-world setting.\n\nPatients and methods\nEligible patients received bevacizumab (10 mg/kg days 1 and 15, every 28 days) plus paclitaxel (80 mg/m2 days 1, 8, and 15, every 28 days) as first-line therapy for MBC, or as subsequent lines, including bevacizumab continuation therapy, at La Paz University Hospital between August 2007 and October 2012. End points included objective response rate (ORR), PFS, overall survival (OS), and safety.\n\nResults\nSeventy-eight patients were included. Median PFS was 12.8 months for patients receiving first-line treatment and 9.3 months for subsequent lines. Forty-five patients (57.7%) continued bevacizumab after stopping paclitaxel, and had significantly longer PFS and OS than those who did not (hazard ratio [HR] 0.40, 95% confidence interval [CI] 0.248–0.653, P<0.001; HR 0.39, 95% CI 0.218–0.710, P=0.002; respectively). In the continuation phase, estrogen receptor-positive patients had longer PFS and OS when receiving hormone therapy plus bevacizumab versus patients receiving only bevacizumab (HR 0.50, 95% CI 0.24–1.04, P=0.06; HR 0.43, 95% CI 0.16–1.16, P=0.09; respectively). Thirty-five patients (44.9%) reported grade 3–4 adverse events.\n\nConclusion\nBevacizumab plus paclitaxel was effective in HER2-negative MBC. Continuation of bevacizumab and addition of hormone therapy following paclitaxel therapy could be beneficial.\n\nKeywords\nbevacizumabfirst linemaintenanceadvanced breast cancerhormone therapy\n==== Body\nIntroduction\nTreatment regimens involving the combination of antiangiogenic agents, such as bevacizumab with cytotoxic chemotherapy, have been extensively investigated in metastatic breast cancer (MBC).1–3 As highly proliferative tumors, such as those with triple-negative histology, have enhanced angiogenesis and increased vascular endothelial growth factor levels,4,5 the addition of bevacizumab to chemotherapy was a rational therapeutic approach in MBC.\n\nThe combination of bevacizumab with a taxane significantly improved progression-free survival (PFS) compared with taxane monotherapy in the first-line treatment of human epidermal growth factor receptor 2 (HER2)-negative MBC in a number of randomized, Phase III studies. In the pivotal E2100 study, median PFS was 11.8 months versus 5.9 months, respectively, for bevacizumab plus paclitaxel versus paclitaxel alone (hazard ratio [HR] 0.60, P<0.001).1 In addition, the AVADO study reported median PFS of 10.1 months versus 8.2 months for bevacizumab plus docetaxel versus docetaxel plus placebo, respectively (HR 0.77, P=0.006).2 Median PFS was increased from 8.0 months to 9.2 months (HR 0.64, P<0.001) with the combination of bevacizumab and taxanes versus taxanes alone in the RIBBON-1 study.3 However, it should be noted that although these studies in the first-line setting demonstrated a significant PFS benefit with the addition of bevacizumab to taxane chemotherapy, a significant overall survival (OS) benefit was not shown, possibly owing to the confounding effect of postprogression therapy, lack of power of the trials, or treatment crossover during the studies.6\n\nLimited data are available on the use of bevacizumab and chemotherapy in subsequent lines of treatment in patients with HER2-negative MBC. However, in the second-line setting, the RIBBON-2 trial demonstrated a PFS benefit for the combination of bevacizumab with chemotherapy versus chemotherapy alone (median PFS 7.2 versus 5.1 months, respectively, HR 0.78; P=0.0072).7 The aim of the current analysis was to determine the efficacy and long-term safety of weekly paclitaxel plus bevacizumab administered as different lines of treatment in patients with HER2-negative MBC in a real-world hospital setting.\n\nPatients and methods\nStudy design\nThis was a retrospective analysis of patients with HER2-negative MBC who received treatment with bevacizumab (Fritz Hoffmann-La Roche, Basel, Switzerland; 10 mg/kg on days 1 and 15, every 28 days) plus paclitaxel (Bristol-Myers Squibb, New York, NY, USA; 80 mg/m2 on days 1, 8, and 15, every 28 days) as first-line therapy, second-line therapy, or subsequent lines, including those who received bevacizumab continuation therapy after completion of paclitaxel, at La Paz University Hospital between August 2007 and October 2012. All analyses were approved by the local ethics committee.\n\nPatients\nAll patients who received bevacizumab plus paclitaxel in any line of therapy between August 2007 and October 2012 were evaluated. Patients were required to have sufficient follow-up time following treatment initiation (approximately 3 months) to be eligible for response evaluation.\n\nAssessments\nBaseline characteristics were collected for each patient, including disease-free interval (DFI), number of previous therapies, disease grade, and hormone-receptor status. PFS, OS, objective response rate (ORR; defined as the percentage of patients achieving a complete response [CR] or partial response [PR]) and clinical benefit (defined as the percentage of patients achieving a CR, PR, or stable disease for ≥6 months) were used to assess efficacy. Adverse events (AEs) were graded according to National Cancer Institute Common Toxicity Criteria version 4.0.\n\nStatistics\nStatistical significance was set at P=0.05. PFS and OS were analyzed using Kaplan–Meier methodology, and the log-rank test was used to compare differences in PFS and OS between the subgroups evaluated. A Cox proportional-hazard model was used to estimate the HRs and 95% confidence intervals (CIs). If overall medians could not be calculated because of insufficient PFS or OS events, a median would be calculated based on the events up to 60 months, with the remaining patients censored. ORR was determined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Statistical analysis was performed using IBM SPSS Statistics version 21 software.\n\nResults\nPatients\nData were analyzed from 78 patients. The median age was 54 years (range 33–76 years), and the majority of patients had hormone receptor-positive disease (Table 1). In total, eleven patients (14.1%) had triple-negative breast cancer (TNBC). Most patients (83.3%) had ductal infiltration, more than half (56.9%) had grade 3 disease, and the majority (75.6%) had a DFI >24 months or stage IV disease at diagnosis. Overall, 43 patients (51.1%) received bevacizumab plus paclitaxel as first-line therapy for HER2-negative MBC. The median treatment duration was 8.2 months (95% CI 0.56–44.62).\n\nA total of 45 patients (57.7%) received bevacizumab as continuation therapy after a variable number of cycles of paclitaxel plus bevacizumab. Of these, 40 patients (88.9%) had hormone receptor-positive disease, and 20 of these patients (44.4%) received hormone treatment plus bevacizumab during continuation therapy.\n\nEfficacy\nOf the 78 patients analyzed, nine achieved a CR and 33 achieved a PR, giving an ORR of 53.8% (Table 2). Clinical benefit was seen in 64 patients (82.1%). Median PFS was 12.8 months for patients receiving bevacizumab as first-line treatment and 9.3 months for those receiving bevacizumab in second or subsequent lines. Median OS was 39.0 months and 20.4 months, respectively. There were no significant differences in PFS or OS between patients with TNBC or hormone receptor-positive disease between any lines of treatment (median PFS 10.3 versus 8.3 months, P=0.242; and median OS 25.7 versus 21.6 months, P=0.991) or in PFS (P=0.247) or OS (P=0.175) among patients with grade 1, 2, or 3 disease.\n\nPatients who had not previously received taxanes had longer PFS than those who had received prior taxane therapy (13.7 versus 8.3 months, HR 0.63, 95% CI 0.39–1.02; P=0.062; Figure 1A), with no significant difference in OS (P=0.377). Previous treatment with anthracyclines had no influence on PFS (P=0.241) or OS (P=0.09). A significant difference in PFS (P=0.005) but not OS (P=0.783) was seen between patients with a DFI ≤24 months versus >24 months or stage IV disease at diagnosis. Median PFS was 7.5 months versus 11.7 months, respectively (HR 0.46, 95% CI 0.27–0.79) (Figure 1B). Patients with fewer than three metastatic sites had a significantly longer median PFS of 15.8 months compared with 8.2 months for patients with three or more metastatic sites or liver metastases (HR 0.37, 95% CI 0.22–0.62; P<0.001) (Figure 1C); there was no significant difference in OS (P=0.55).\n\nPatients who received bevacizumab as continuation therapy following completion of paclitaxel had a significantly longer PFS than those who did not (median 13.7 versus 5.4 months, HR 0.40, 95% CI 0.25–0.65; P<0.001) as well as a significantly longer OS (median 37.4 versus 13.9 months, HR 0.39, 95% CI 0.22–0.71; P=0.002) (Figure 2). In the subgroup of patients with estrogen receptor-positive disease receiving bevacizumab continuation therapy (n=40), median PFS was 21.9 months for patients who received hormone treatment plus bevacizumab compared with 10.6 months for those who did not receive hormone treatment (HR 0.50, 95% CI 0.24–1.04; P=0.065) (Figure 3A). Median OS was not yet reached in patients receiving concurrent hormone treatment versus 25.7 months for those without hormone treatment (HR 0.43, 95% CI 0.16–1.16; P=0.093) (Figure 3B).\n\nSafety\nA total of 35 patients (44.9%) across all treatment lines reported grade 3–4 AEs (Table 3); the most frequently reported of these were neutropenia (21.8%), asthenia (8.9%), and hypertension (7.6%). Bevacizumab treatment was discontinued in four patients due to AEs (severe epistaxis, digestive bleeding, brain stroke, and proteinuria).\n\nDiscussion\nThis retrospective analysis demonstrated that the combination of bevacizumab and paclitaxel was effective in a real-world setting in patients with HER2-negative MBC. The combination regimen achieved a high ORR (53.8%). Longer PFS was seen in the first-line treatment setting compared with administration in second or subsequent lines. This decrease in efficacy was as expected, since treatment efficacy generally declines with disease progression, due to such factors as increased tumor volume and drug resistance. Overall, these data are comparable with results obtained for first-line bevacizumab in combination with chemotherapy in randomized Phase III trials, with median PFS and ORR higher than those seen in the E2100 and ATHENA trials.1,8\n\nThe combination of bevacizumab and paclitaxel was also effective in both TNBC and hormone receptor-positive disease. Although bevacizumab and paclitaxel are effective in TNBC, patients with this type of MBC tend to have a worse prognosis than those with hormone receptor-positive disease, since TNBC has a more aggressive phenotype. In this study, there was no statistical difference in OS or PFS between TNBC and hormone receptor-positive disease, possibly due to the small sample size of TNBC patients. Although the size of the TNBC subgroup was too small to draw firm conclusions in this study, an analysis of the ATHENA trial also showed comparable OS in patients with hormone receptor-positive disease and TNBC when adjusted for prognostic factors.9\n\nThe combination regimen was generally well tolerated, with similar frequency and type of AEs (44.9% with grade 3–4 AEs, 7.6% hypertension, 5.1% proteinuria), as previously reported for bevacizumab plus taxane therapy. In the E2100 study, grade 3–4 hypertension occurred in 14.8% of patients and proteinuria in 3.5% of patients,1 whereas the AVADO trial reported grade 3–4 AEs in 38.1% of patients, with hypertension in 4.5% and proteinuria in 2.0%.2 The ATHENA trial of first-line bevacizumab and taxane chemotherapy reported grade ≥3 AEs in 51.5% of patients.8 The toxicity profile of bevacizumab is inherently linked to its mode of action; however, with adequate awareness and training, the side effects of bevacizumab-based regimens can be successfully managed without severe complications.\n\nVarious studies have investigated the prognostic and predictive factors of efficacy benefit in patients with MBC. Using an internally and externally validated score, Regierer et al reported DFI, location of metastases, and hormone-receptor status as significant prognostic factors for OS in MBC.10 Prior anthracycline and taxane treatment and number of metastatic sites/liver disease have also been shown to be important prognostic factors in MBC. These factors were confirmed by multivariate analysis to be associated with worse OS in the ATHENA study.9 Analysis of these risk factors (DFI, liver metastases, previous anthracycline/taxane treatment, and TNBC) led to the differentiation of three prognostic groups with progressively worse prognosis: those with one or no risk factors, those with two risk factors, and those with three or four risk factors.9 These prognostic groups were seen in both TNBC and hormone receptor-positive MBC. Our results, showing that DFI ≤24 months, three or more metastatic locations or liver metastases, and prior taxane therapy were associated with worse efficacy outcomes, are in agreement with these previous reports.\n\nPatients receiving bevacizumab continuation had a longer PFS than those who did not. This may have been because most patients receiving maintenance therapy also responded to first-line bevacizumab plus paclitaxel. In addition, some patients in the group not receiving maintenance may have stopped receiving bevacizumab before disease progression, due to toxicity or the investigator’s decision, which could also have contributed to the shorter PFS seen in this group. In a subgroup analysis of the ATHENA trial, patients who received bevacizumab maintenance therapy had longer PFS (11.6 months versus 6.7 months) and OS (30.0 months versus 18.4 months) than those who did not.11 Although the data may be biased because of the contributing factors surrounding patient selection for maintenance therapy (ie, inadvertently selecting responders), these results suggest that the use of maintenance bevacizumab continuation therapy could be beneficial for patients with MBC and warrants further investigation.\n\nThe addition of hormone therapy to bevacizumab continuation therapy in patients with estrogen receptor-positive disease is an important aspect of our analysis. Fabi et al reported a benefit of combination maintenance therapy, with patients receiving combined hormone therapy and bevacizumab maintenance therapy achieving a median PFS of 13.0 months compared with 4.1 months for patients treated with just bevacizumab maintenance therapy (P=0.05).12 These results were supported by a Phase II trial of first-line hormone therapy plus bevacizumab that reported a median PFS of 13.5 months.13 In the Phase III LEA study, the combination of hormone therapy and bevacizumab resulted in numerically but not significantly longer PFS compared with hormone therapy alone (19.3 versus 14.4 months, respectively).14 However, there are still limited conclusive data on whether bevacizumab plus hormone therapy as continuation therapy is superior to bevacizumab alone after stopping taxane-based therapy. In this retrospective analysis, patients with estrogen receptor-positive MBC who received bevacizumab plus hormone therapy had improved PFS and OS compared with patients who received bevacizumab monotherapy as continuation treatment, although the difference was not statistically significant because of the low patient numbers in these subgroups. The field of data remains inconclusive, and further research is warranted as to whether prescribing bevacizumab as continuation therapy alongside hormone therapy is the optimal treatment regimen in patients with HER2-negative MBC after weekly paclitaxel plus bevacizumab.\n\nOverall, while our real-world findings are aligned with results of previous clinical studies, such as the E2100 trial, this analysis adds some important information about the possible benefits of this regimen in second and subsequent lines of therapy, as well as the hypothesis of an increased PFS with the addition of hormone therapy to bevacizumab continuation therapy. Due to the small sample size in this single-institution setting, some of our results did not reach statistical significance; however, the data are promising and warrant further investigation in a multicenter setting.\n\nConclusion\nThe combination of bevacizumab plus paclitaxel was active in patients with MBC, as well as in subgroups of patients with TNBC and those with hormone receptor-positive disease, as observed in a real-world setting. Continuation of bevacizumab after stopping paclitaxel, and the addition of hormone therapy to bevacizumab, in patients with estrogen receptor-positive MBC could be beneficial, as shown by the longer PFS and OS observed. Additional research is needed to further confirm the use of bevacizumab and hormone therapy as continuation therapy for MBC.\n\nAcknowledgments\nThird-party medical writing assistance for this manuscript was provided by Joanna Musgrove of Gardiner-Caldwell Communications, funded by Fritz Hoffmann-La Roche.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 PFS stratified by (A) previous taxanes (no versus yes), (B) DFI (≤24 months versus >24 months or stage IV at diagnosis), and (C) number of metastatic sites (<3 versus ≥3 or liver metastases).\n\nAbbreviations: CI, confidence interval; DFI, disease-free interval; HR, hazard ratio; PFS, progression-free survival.\n\nFigure 2 PFS (A) and OS (B) stratified by continuation therapy (bevacizumab versus no bevacizumab).\n\nAbbreviations: CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival.\n\nFigure 3 PFS (A) and OS (B) stratified by hormone therapy use in the continuation treatment phase (yes versus no) in the subgroup with estrogen receptor-positive disease.\n\nNotes: *In the hormone-therapy group, the OS median was not reached (immature data); 56.3 months was the maximum value recorded in this group.\n\nAbbreviations: CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival.\n\nTable 1 Baseline characteristics (n=78)\n\nCharacteristic\tPatients, n (%)\t\nHistological subtype\t\n Ductal infiltration\t65 (83.3)\t\n Lobular infiltration\t9 (11.5)\t\n Others\t4 (5.1)\t\nHormone-receptor status\t\n ER-positive\t67 (85.9)\t\n ER- and PgR-positive\t57 (73.1)\t\n TNBC\t11 (14.1)\t\nGrade (n=58)\t\n 1\t7 (12.1)\t\n 2\t18 (31.0)\t\n 3\t33 (56.9)\t\nNumber of metastatic sites\t\n <3\t33 (42.3)\t\n ≥3 or liver metastases\t45 (57.7)\t\nPrevious treatment (adjuvant or metastatic setting)\t\n No anthracyclines or taxanes\t21 (26.9)\t\n Anthracyclines\t18 (23.1)\t\n Anthracyclines and taxanes\t39 (50.0)\t\nNumber of previous treatment lines for MBC\t\n 0\t43 (55.1)\t\n ≥1\t35 (44.9)\t\nAbbreviations: ER, estrogen receptor; MBC, metastatic breast cancer; PgR, progesterone receptor; TNBC, triple-negative breast cancer.\n\nTable 2 Tumor response (n=78)\n\nResponse\tPatients, n (%)\t\nOverall response rate\t42 (53.8)\t\nComplete response\t9 (11.5)\t\nPartial response\t33 (42.3)\t\nStable disease\t22 (28.2)\t\nProgressive disease\t13 (16.7)\t\nUnevaluable\t1 (1.3)\t\nTable 3 Summary of grade 3/4 adverse events\n\nAdverse event\tPatients, n (%)\t\nGrade 3/4 adverse events\t35 (44.9)\t\n Neutropenia\t17 (21.8)\t\n Asthenia\t7 (8.9)\t\n Hypertension\t6 (7.6)\t\n Febrile neutropenia\t4 (5.1)\t\n Proteinuria\t3 (5.1)\t\n Mucositis\t3 (3.8)\t\n Thrombocytopenia\t2 (2.5)\t\n Peripheral neuropathy\t2 (2.5)\t\n Bleeding\t2 (2.5)\t\n Thromboembolic disease\t1 (1.2)\t\n Brain stroke\t1 (1.2)\n==== Refs\nReferences\n1 Miller K Wang M Gralow J Paclitaxel plus bevacizumab vs paclitaxel alone for metastatic breast cancer N Engl J Med 2007 357 2666 2676 18160686 \n2 Miles DW Chan A Dirix LY Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer J Clin Oncol 2010 28 3239 3247 20498403 \n3 Robert NJ Diéras V Glaspy J RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer J Clin Oncol 2011 29 1252 1260 21383283 \n4 Liu Y Tamimi RM Collins LC The association between vascular endothelial growth factor expression in invasive breast cancer and survival varies with intrinsic subtypes and use of adjuvant systemic therapy: results from the Nurses’ Health Study Breast Cancer Res Treat 2011 129 175 184 21390493 \n5 Fakhrejahani E Toi M Tumor angiogenesis: pericytes and maturation are not to be ignored J Oncol 2012 2012 261750 22007214 \n6 Montero AJ Escobar M Lopes G Glück S Vogel C Bevacizumab in the treatment of metastatic breast cancer: friend or foe? Curr Oncol Rep 2012 14 1 11 22012632 \n7 Brufsky A Valero V Tiangco B Second-line bevacizumab-containing therapy in patients with triple-negative breast cancer: subgroup analysis of the RIBBON-2 trial Breast Cancer Res Treat 2012 133 1067 1075 22415477 \n8 Smith IE Pierga JY Biganzoli L First-line bevacizumab plus taxane-based chemotherapy for locally recurrent or metastatic breast cancer: safety and efficacy in an open-label study in 2,251 patients Ann Oncol 2011 22 595 602 20819780 \n9 Llombart-Cussac A Pivot XB Biganzoli L A prognostic factor (PF) index for overall survival in a HER2-negative endocrine-resistant metastatic breast cancer (MBC) population: analysis from the ATHENA trial J Clin Oncol 2013 31 555 \n10 Regierer AC Wolters R Ufen MP An internally and externally validated prognostic score for metastatic breast cancer: analysis of 2269 patients Ann Oncol 2014 25 633 638 24368402 \n11 Smith I Pierga JY Biganzoli L Final overall survival results and effect of prolonged (≥1 year) first-line bevacizumab-containing therapy for metastatic breast cancer in the ATHENA trial Breast Cancer Res Treat 2011 130 133 143 21830015 \n12 Fabi A Russillo M Ferretti G Maintenance bevacizumab beyond first-line paclitaxel plus bevacizumab in patients with Her2-negative hormone receptor-positive metastatic breast cancer: efficacy in combination with hormonal therapy BMC Cancer 2012 12 482 23083011 \n13 Yardley DA Burris HA 3rd Clark BL Hormonal therapy plus bevacizumab in postmenopausal patients who have hormone receptor-positive metastatic breast cancer: a phase II trial of the Sarah Cannon Oncology Research Consortium Clin Breast Cancer 2011 11 146 152 21665134 \n14 Loibl S De la Haba J von Minckwitz G Phase III trial evaluating the addition of bevacizumab to endocrine therapy as first-line treatment for advanced breast cancer Final analysis of the LEA study Poster presented at: 2013 European Cancer Congress September 27–October 1, 2013 Amsterdam\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1178-6930",
"issue": "7()",
"journal": "OncoTargets and therapy",
"keywords": "advanced breast cancer; bevacizumab; first line; hormone therapy; maintenance",
"medline_ta": "Onco Targets Ther",
"mesh_terms": null,
"nlm_unique_id": "101514322",
"other_id": null,
"pages": "2175-81",
"pmc": null,
"pmid": "25473300",
"pubdate": "2014",
"publication_types": "D016428:Journal Article",
"references": "20498403;22012632;20819780;23083011;22007214;18160686;21390493;21665134;24368402;21830015;22415477;21383283",
"title": "Continuation of bevacizumab and addition of hormone therapy following weekly paclitaxel therapy in HER2-negative metastatic breast cancer.",
"title_normalized": "continuation of bevacizumab and addition of hormone therapy following weekly paclitaxel therapy in her2 negative metastatic breast cancer"
} | [
{
"companynumb": "ES-ROCHE-1520703",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": null,
"dru... |
{
"abstract": "Immunodeficiency-related, vaccine-derived rubella virus (RuV) as an antigenic trigger of cutaneous and visceral granulomas is a rare, recently described phenomenon in children and young adults treated with immunosuppressant agents.\nTo perform a comprehensive clinical, histologic, immunologic, molecular, and genomic evaluation to elucidate the potential cause of an adult patient's atypical cutaneous granulomas.\nA prospective evaluation of skin biopsies, nasopharyngeal swabs, and serum samples submitted to the Centers for Disease Control and Prevention was conducted to assess for RuV using real-time reverse-transcriptase polymerase chain reaction (RT-PCR) and viral genomic sequencing. The samples were obtained from a man in his 70s with extensive cutaneous granulomas mimicking both cutaneous sarcoidosis (clinically) and CD8+ granulomatous cutaneous T-cell lymphoma (histopathologically). The study was conducted from September 2019 to February 2021.\nIdentification and genotyping of a novel immunodeficiency-related RuV-associated granulomatous dermatitis.\nImmunohistochemistry for RuV capsid protein and RT-PCR testing for RuV RNA revealed RuV in 4 discrete skin biopsies from different body sites. In addition, RuV RNA was detected in the patient's nasopharyngeal swabs by RT-PCR. The full viral genome was sequenced from the patient's skin biopsy (RVs/Philadelphia.PA.USA/46.19/GR, GenBank Accession #MT249313). The patient was ultimately diagnosed with a novel RuV-associated granulomatous dermatitis.\nThe findings of this study suggest that clinicians and pathologists may consider RuV-associated granulomatous dermatitis during evaluation of a patient because it might have implications for the diagnosis of cutaneous sarcoidosis, with RuV serving as a potential antigenic trigger, and for the diagnosis of granulomatous cutaneous T-cell lymphoma, with histopathologic features that may prompt an evaluation for immunodeficiency and/or RuV.",
"affiliations": "Department of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison.;Centers for Disease Control and Prevention, Division of Viral Diseases, Atlanta, Georgia.;Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia.;Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia.;Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia.;Centers for Disease Control and Prevention, Division of Viral Diseases, Atlanta, Georgia.;Centers for Disease Control and Prevention, Division of Viral Diseases, Atlanta, Georgia.;Centers for Disease Control and Prevention, Division of Viral Diseases, Atlanta, Georgia.;Centers for Disease Control and Prevention, Division of Viral Diseases, Atlanta, Georgia.;Department of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison.;Department of Dermatology, Medical College of Wisconsin, Milwaukee.;Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia.;Division of Infectious Diseases, University of Pennsylvania Perelman School of Medicine, Philadelphia.;Division of Infectious Diseases, University of Pennsylvania Perelman School of Medicine, Philadelphia.;Department of Dermatology, Medical College of Wisconsin, Milwaukee.;Division of Allergy and Immunology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.;Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia.",
"authors": "Shields|Bridget E|BE|;Perelygina|Ludmila|L|;Samimi|Sara|S|;Haun|Paul|P|;Leung|Thomas|T|;Abernathy|Emily|E|;Chen|Min-Hsin|MH|;Hao|LiJuan|L|;Icenogle|Joseph|J|;Drolet|Beth|B|;Wilson|Barbara|B|;Bryer|Joshua S|JS|;England|Ross|R|;Blumberg|Emily|E|;Wanat|Karolyn A|KA|;Sullivan|Kathleen|K|;Rosenbach|Misha|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1001/jamadermatol.2021.1577",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2168-6068",
"issue": "157(7)",
"journal": "JAMA dermatology",
"keywords": null,
"medline_ta": "JAMA Dermatol",
"mesh_terms": null,
"nlm_unique_id": "101589530",
"other_id": null,
"pages": "842-847",
"pmc": null,
"pmid": "34037685",
"pubdate": "2021-07-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Granulomatous Dermatitis Associated With Rubella Virus Infection in an Adult With Immunodeficiency.",
"title_normalized": "granulomatous dermatitis associated with rubella virus infection in an adult with immunodeficiency"
} | [
{
"companynumb": "US-009507513-2106USA002557",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugadditional": null,
... |
{
"abstract": "We report the case of a man affected by renal cell carcinoma with vertebral metastases, who presented a radiological complete response after systemic treatment with everolimus.",
"affiliations": "a Radioterapia , Azienda Ospedaliero-Universitaria Careggi , Florence , Italy.;a Radioterapia , Azienda Ospedaliero-Universitaria Careggi , Florence , Italy.;a Radioterapia , Azienda Ospedaliero-Universitaria Careggi , Florence , Italy.;a Radioterapia , Azienda Ospedaliero-Universitaria Careggi , Florence , Italy.;a Radioterapia , Azienda Ospedaliero-Universitaria Careggi , Florence , Italy.;a Radioterapia , Azienda Ospedaliero-Universitaria Careggi , Florence , Italy.;a Radioterapia , Azienda Ospedaliero-Universitaria Careggi , Florence , Italy.;a Radioterapia , Azienda Ospedaliero-Universitaria Careggi , Florence , Italy.;a Radioterapia , Azienda Ospedaliero-Universitaria Careggi , Florence , Italy.;a Radioterapia , Azienda Ospedaliero-Universitaria Careggi , Florence , Italy.;a Radioterapia , Azienda Ospedaliero-Universitaria Careggi , Florence , Italy.",
"authors": "Detti|Beatrice|B|;Francolini|Giulio|G|;Becherini|Carlotta|C|;Olmetto|Emanuela|E|;Giacomelli|Irene|I|;Scartoni|Daniele|D|;Greto|Daniela|D|;Baldazzi|Valentina|V|;Simontacchi|Gabriele|G|;Meattini|Icro|I|;Livi|Lorenzo|L|",
"chemical_list": "D000970:Antineoplastic Agents; D000068338:Everolimus",
"country": "England",
"delete": false,
"doi": "10.1080/1120009X.2016.1173869",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1120-009X",
"issue": "28(5)",
"journal": "Journal of chemotherapy (Florence, Italy)",
"keywords": "Everolimus; Metastases; Renal cancer",
"medline_ta": "J Chemother",
"mesh_terms": "D000970:Antineoplastic Agents; D002292:Carcinoma, Renal Cell; D000068338:Everolimus; D006801:Humans; D007680:Kidney Neoplasms; D008297:Male; D008875:Middle Aged; D011878:Radiotherapy; D013125:Spinal Neoplasms",
"nlm_unique_id": "8907348",
"other_id": null,
"pages": "432-4",
"pmc": null,
"pmid": "27376403",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Complete response in metastatic renal cell carcinoma after radiotherapy and everolimus: a clinical case and review of the literature.",
"title_normalized": "complete response in metastatic renal cell carcinoma after radiotherapy and everolimus a clinical case and review of the literature"
} | [
{
"companynumb": "IT-BAYER-2016-195264",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SORAFENIB"
},
"drugadditional": null,
"d... |
{
"abstract": "We describe the occurrence of a variant Ph chromosome (v-Ph) in a therapy-related acute leukemia (s-AL), developed after 8-year treatment for a NHL with alkylating agents, anthracyclines and topoisomerase II inhibitors. The v-Ph originated from a complex t(2;9;22) translocation, expressed a p190bcr-abl fusion protein, and was associated to other specific changes, such as dup(3) (q21q26) and -7. The s-AL, apparently not preceded by a dysplastic phase, presented with signs of trilineage dysplasia with 10% micromegakaryocytes; it was classified as M5 according to FAB. The complex genetic changes observed in the present case may reflect distinct leukemogenic effects by different chemotherapeutic agents.",
"affiliations": "Department of Human Biopathology, University La Sapienza, Rome, Italy.",
"authors": "Alimena|G|G|;Cedrone|M|M|;Nanni|M|M|;De Cuia|M R|MR|;Lo Coco|F|F|;De Sanctis|V|V|;Cimino|G|G|;Mancini|M|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0887-6924",
"issue": "9(9)",
"journal": "Leukemia",
"keywords": null,
"medline_ta": "Leukemia",
"mesh_terms": "D000208:Acute Disease; D000971:Antineoplastic Combined Chemotherapy Protocols; D002889:Chromosomes, Human, Pair 2; D002892:Chromosomes, Human, Pair 22; D002893:Chromosomes, Human, Pair 3; D002899:Chromosomes, Human, Pair 9; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D007938:Leukemia; D016393:Lymphoma, B-Cell; D008297:Male; D008875:Middle Aged; D016609:Neoplasms, Second Primary; D010677:Philadelphia Chromosome; D014178:Translocation, Genetic",
"nlm_unique_id": "8704895",
"other_id": null,
"pages": "1483-6",
"pmc": null,
"pmid": "7658716",
"pubdate": "1995-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Acute leukemia presenting a variant Ph chromosome with p190 expression, dup 3q and -7, developed after malignant lymphoma treated with alkylating agents and topoisomerase II inhibitors.",
"title_normalized": "acute leukemia presenting a variant ph chromosome with p190 expression dup 3q and 7 developed after malignant lymphoma treated with alkylating agents and topoisomerase ii inhibitors"
} | [
{
"companynumb": "IT-BAUSCH-BL-2018-012024",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": "3",
... |
{
"abstract": "Identification of risk factors for PRES after organ transplant can improve early detection and avoid permanent neurological injury. High calcineurin-inhibitor levels and hypertension are recognized risk factors for PRES in adult transplant recipients. Limited data exist regarding PRES after pediatric HTx, with studies limited to case reports. We performed a retrospective review of 128 pediatric HTx recipients to identify risk factors for PRES. Seven of 128 (5.5%) recipients developed PRES at a median of 10 days (5-57) after HTx. The median age of recipients with PRES was 10.0 yr (5.7-19.0), compared to 1.4 yr (0.0-19.8) for recipients without PRES (p = 0.010). Fewer than half of recipients with PRES had elevated post-transplant calcineurin-inhibitor levels (n = 3) and/or preceding severe hypertension (n = 3). Four of seven who developed PRES (57%) had pretransplant Glenn or Fontan physiology (G/F). G/F was a significant risk factor for PRES (RR 4.99, 95% CI: 1.19-21.0, p = 0.036). Two recipients (29%), both with severe PRES, had residual neurological symptoms. In summary, PRES occurred in 5.5% of pediatric HTx recipients and presented early after HTx. All recipients with PRES were > 5 yr. Patients with pretransplant G/F were at increased risk, a risks factor not previously described.",
"affiliations": "School of Medicine, University of Washington, Seattle, WA, USA.;Division of Pediatric Cardiology, Seattle Children's Hospital, University of Washington, Seattle, WA, USA.;Division of Pediatric Cardiology, Seattle Children's Hospital, University of Washington, Seattle, WA, USA.;Division of Pediatric Cardiothoracic Surgery, Seattle Children's Hospital, University of Washington, Seattle, WA, USA.;Division of Radiology, Seattle Children's Hospital, University of Washington, Seattle, WA, USA.;Division of Pediatric Cardiology, Seattle Children's Hospital, University of Washington, Seattle, WA, USA.",
"authors": "Eilers|Braiden|B|;Albers|Erin|E|;Law|Yuk|Y|;McMullan|D Mike|DM|;Shaw|Dennis|D|;Kemna|Mariska|M|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.12702",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "20(4)",
"journal": "Pediatric transplantation",
"keywords": "Fontan; heart transplantation; pediatric; posterior reversible encephalopathy syndrome",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D018729:Fontan Procedure; D016027:Heart Transplantation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D054038:Posterior Leukoencephalopathy Syndrome; D011183:Postoperative Complications; D015995:Prevalence; D012189:Retrospective Studies; D012307:Risk Factors; D055815:Young Adult",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "552-8",
"pmc": null,
"pmid": "27139146",
"pubdate": "2016-06",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Posterior reversible encephalopathy syndrome after pediatric heart transplantation: Increased risk for children with preexisting Glenn/Fontan physiology.",
"title_normalized": "posterior reversible encephalopathy syndrome after pediatric heart transplantation increased risk for children with preexisting glenn fontan physiology"
} | [
{
"companynumb": "US-WEST-WARD PHARMACEUTICALS CORP.-US-H14001-16-01244",
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"activesubstancename": "LEVETIRACETAM"
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{
"abstract": "Therapy for small cell cancer and high grade neuroendocrine tumours of the paranasal sinuses is extrapolated from the treatment of small cell lung cancer and paranasal cancer of different histologies. Prophylactic cranial irradiation has proven survival benefit in small cell lung cancer. Two patients with aggressive cancer of the paranasal sinuses received radiotherapy with simultaneous integrated prophylactic brain irradiation, using two sequential plans. Chemotherapy was given before, during and after radiotherapy. None of the patients had intracranial recurrence. One patient experienced severe, but transient encephalitis-like symptoms that could only be attributed to radiotherapy. No long term side effects in the CNS were observed. The treatment was feasible, but with possible severe, but transient side effects. It should be considered in cases with head and neck cancer, with a high risk of intracerebral metastasis, as well as a significant overlap between the primary irradiated volume and the brain.",
"affiliations": "Department of Oncology, Aarhus University Hospital, Denmark.;Department of Oncology, Aarhus University Hospital, Denmark.;Department of Pathology, Aarhus University Hospital, Denmark.;Department of Otorhinolaryngology, Head and Neck Surgery, Aarhus University Hospital, Denmark.;Medical Physics, Aarhus University Hospital, Denmark.",
"authors": "Jensen|Kenneth|K|;Sharma|Maja Bendtsen|MB|;Lenler-Eriksen|Simon|S|;Friis|Per|P|;Holm|Anne Ivalu Sander|AIS|",
"chemical_list": null,
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.ctro.2017.01.007",
"fulltext": "\n==== Front\nClin Transl Radiat OncolClin Transl Radiat OncolClinical and Translational Radiation Oncology2405-6308Elsevier S2405-6308(16)30048-910.1016/j.ctro.2017.01.007ArticleSimultaneous integrated prophylactic cranial irradiation in sino-nasal cancer Jensen Kenneth kennethjensen@dadlnet.dka⁎Sharma Maja Bendtsen aLenler-Eriksen Simon bFriis Per cHolm Anne Ivalu Sander da Department of Oncology, Aarhus University Hospital, Denmarkb Department of Pathology, Aarhus University Hospital, Denmarkc Department of Otorhinolaryngology, Head and Neck Surgery, Aarhus University Hospital, Denmarkd Medical Physics, Aarhus University Hospital, Denmark⁎ Corresponding author at: Department of Oncology, Aarhus University Hospital, Noerrebrogade 44, 8000 Aarhus C, Denmark.Department of OncologyAarhus University HospitalNoerrebrogade 448000 Aarhus CDenmark kennethjensen@dadlnet.dk20 2 2017 2 2017 20 2 2017 2 59 62 2 12 2016 20 1 2017 20 1 2017 © 2017 The Authors2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Therapy for small cell cancer and high grade neuroendocrine tumours of the paranasal sinuses is extrapolated from the treatment of small cell lung cancer and paranasal cancer of different histologies. Prophylactic cranial irradiation has proven survival benefit in small cell lung cancer.\n\nTwo patients with aggressive cancer of the paranasal sinuses received radiotherapy with simultaneous integrated prophylactic brain irradiation, using two sequential plans. Chemotherapy was given before, during and after radiotherapy.\n\nNone of the patients had intracranial recurrence. One patient experienced severe, but transient encephalitis-like symptoms that could only be attributed to radiotherapy. No long term side effects in the CNS were observed.\n\nThe treatment was feasible, but with possible severe, but transient side effects. It should be considered in cases with head and neck cancer, with a high risk of intracerebral metastasis, as well as a significant overlap between the primary irradiated volume and the brain.\n\nKeywords\nSino nasal cancerSmall cell neoplasmNeuroendocrine neoplasmRadiotherapyProphylactic craniel irradiation\n==== Body\nIntroduction\nSinonasal cancers are infrequent cancers with a grave prognosis. The cancers pose great challenges for both the surgical and radio-therapeutic management, due to the abundance of adjacent organs at risk. Small cell and high grade neuroendocrine cancer of the sinonasal area are rare entities [1] with an even poorer prognosis [2], including a high risk of intracranial expansion as well as haematogenous metastases to the brain. For small cell lung cancer (SCLC) the addition of prophylactic cranial irradiation (PCI) to the treatment leads to both a significant risk reduction of brain metastases and prolonged survival [3]. The risk of haematogenous metastases from small cell head and neck cancer is lower than that of SCLC, yet still significant, and PCI has been recommended for selected cases of small cell head and neck cancer [2], [4], [5], [6], [7]. Adding PCI after radiotherapy for sinonasal cancer is sub-optimal from a dosimetric point of view, as some areas of the brain already received a radiation dose from the primary tumour irradiation, that may cause late side effects, and probably has a low effect on tumour cells, as the dose per fraction is very low. Furthermore, studies on SCLC indicates, that PCI given during chemotherapy, has superior effect compared to delayed PCI [8]. In two cases we chose to use an integrated PCI during primary radiotherapy to the tumour areas. A description of the cases is given below with emphasis on the technique and results of the PCI.\n\nCase 1\nMale, 56 years, no significant comorbidity, but well controlled type II diabetes and hypertension. Two months prior to diagnosis he noticed a slight facial pain and nasal discharge.\n\nMRI and FDG-PET-CT showed a primary tumour of the left maxillary sinus with extension to anterior and posterior wall, gingiva and to the ipsilateral nasal cavity, ethmoid sinuses, orbital content and retromaxillary space. There were regional metastases to parapharyngeal-, retrostyloid- as well as level 1B and 2 lymph nodes. No distant metastasis, ie. T4aN2cM0\n\nPathology: The tumour was composed of irregular sheets of relatively small, rounded cells with prominent, hyperchromatic nuclei. Immunohistochemical analysis for CD45, S-100 and desmin were negative. Positive reactions were seen for cytokeratin (AE1/AE3 and KL-1), p16, CD56, and the neuroendocrine markers chromogranin A and synaptophysin. The tumour was negative for CK5/6 and p63. Proliferation index using Ki-67, was high (70%). The tumour was diagnosed as a small cell neuroendocrine carcinoma.\n\nDue to the advanced stage of the tumour nodes the patient was inoperable. Treatment with curative intent was initiated with chemotherapy: cisplatinum 75 mg/m2 i.v. day one and etoposide 120 mg/m2 i.v. day one to three every three weeks for a total of four series. Three weeks after initiation, he had grade 3 neutropenia (CTCAE 4.0) and the treatment was postponed one week. He subsequently received prophylactic G-CSF and received the remaining chemotherapy as planned without neutropenia. Ten days after initiation of chemotherapy he began radiotherapy.\n\nThe target was defined as gross tumour with a 5 mm margin for high dose clinical target given 66 Gy in 33 fractions. A further margin of 5 mm plus the remaining entire involved sinuses, was added for a high risk volume, treated with 60 Gy. No further elective volumes were included (Fig. 1). In addition, the entire brain was treated to 25.2 Gy for the last 14 fractions, as it was estimated, that at least 1.8 Gy per fraction was required to achieve a biological effect. No correction was made for fraction size to reach the biologic effect of 25 Gy in 10 fractions, which is standard at our institution for PCI with SCLC.Fig. 1 Target and beam angle selection for part 1 of radiotherapy. Case 1. CTV1 (66 Gy): dark blue and CTV2 (60 Gy): light blue. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)\n\n\n\nFor the first part of the treatment, 5 planar and 5 non-coplanar fields were used in order to minimize the dose to the brain. For the last part, 6 coplanar and 2 non-coplanar fields were chosen (Fig. 2A and B). As the left part of the visual pathways was partly included in the target volumes, constraints for the organs at risk could not be met. Because of the non-coplanar fields the bilateral parotid glands received a higher dose than typically allowed. Fixed beam angles were chosen over arcs, due to their superior dose distribution in the low dose volume, ie. the majority of the brain volume. The PCI was planned for the last fractions in order to estimate side effects and response for the first part of radiotherapy and chemotherapy.Fig. 2 (A) Treatment part 1. Brain sparing. Case 1. Target: CTV1 (66 Gy): dark blue and CTV2 (60 Gy) light blue Isodosecurves: Red: 36.1 Gy (95% PTV1). Orange: 32.8 Gy (95% PTV2). Yellow: 10 Gy. (B) Treatment part 2. Simultaneous integrated prophylactic cranial irradiation. Case 1. Target: CTV1 (66 Gy) dark blue and CTV2 (60 Gy): light blue. Brain: Green Isodosecurves: Red: 26.6 Gy (95% PTV1). Orange: 23.9 Gy (95% PTV Brain). Yellow: 10 Gy. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)\n\n\n\nOne month after initiation of radiotherapy, the patient was admitted 4 days due to dehydration, weight loss, pneumonia, oral candidiasis, mucositis and pain. He was treated with i.v. antibiotic, i.v. fluid and a nasogastric tube.\n\nAt the fourth series of chemotherapy, 14 days after cessation of radiotherapy, he had severe fatigue, but no neurological symptoms, still dependent on the nasogastric tube for sufficient nutrition, but the mucositis were healing as expected.\n\nThree weeks later he was admitted to a local hospital with fever and increasing fatigue. No neurological symptoms, no neutropenia, low c-reactive protein. He was treated with oral antibiotics and discharged the same day. At home he experienced continuous fever with temperatures reaching to 39 °C.\n\nEleven days later he returned to the department of oncology for an acute evaluation due to intermittent fever 38–39 °C, insomnia, intense dreams, headache and neck pain. Objectively his general condition had deteriorated and he was confused and dehydrated. He had no focal neurological symptoms objective abnormalities. MRI of the head and neck and CT of the thorax and abdomen showed regression of the tumour, with no new tumour manifestations. C-reactive protein was continuously low. Cerebrospinal fluid contained increased mononuclear cells, elevated protein and normal level of glucose. The patient was rehydrated and received antibacterial and antiviral treatment as well as high dose steroids on the suspicion of meningitis. No positive microbiology or serology were present. ECG showed unspecific signs of encephalopathy but not consistent with herpetic encephalitis, and CSF-autoimmune encephalitis antibodies were all negative. The patient was discharged after 5 days and continued high dose steroids. The neurological symptoms slowly regressed over months, with no lasting deficits.\n\nThe tumour evaluation with PET-CT and MRI performed 2 months after radiotherapy showed a partial response with diffuse oedema of the maxillary sinus and ethmoid cell but without excess FDG uptake. No nodal enlargement was observed, but one lymph node remained FDG avid. One month later a second evaluation PET-CT was performed, this time with no FDG positive changes.\n\nAfter the first and second evaluation the patient was offered a maxillectomy with left orbital exenteration, neck dissection and reconstruction with free flaps. The patient still suffered from minor neurological deficits with intermittent confusion and fatigue and refused surgery. Six months after therapy the patient was well and without clinical symptoms nor neurological deficits.\n\nTen months after initiation of therapy the initial symptoms recurred. He had a biopsy proven recurrence in the maxilla with metastasis to the neck and mediastinal nodes, lung and liver. He was in excellent clinical condition and started chemotherapy with carboplatinum and etoposide, with an early and pronounced response, but succumbed to the disease 16 months after initiation of primary therapy.\n\nCase 2\nMale, 55 years old, referred with epistaxis, nasal occlusion and anosmia. He had no significant co-morbidity.\n\nMRI and FDG-PET CT showed a FDG avid tumour in the right nasal cavity with extension to bilateral ethmoid and sphenoid cells and anterior fossa.\n\nPathology: The tumour was composed of densely packed medium sized to large tumour cells with pleomorphic nuclei, an increased mitotic rate and abnormal mitoses. There were widespread necrotic areas and interspersed were tumour areas with a tubular, intestinal adenocarcinoma appearance containing mucin. Immunohistochemistry showed positive reaction for cytokeratins (AE1/AE3, CK7, CK8, CK20), CDX-2, TTF-1, synaptophysin, CGA and CD56. Negative reaction for Vimentin, GFAP, TG, calcitonin and S-100. Proliferation index using Ki-67 was up to 80%. Histologically and immunophenotypically, the tumour was diagnosed as a poorly differentiated, non-small cell neuroendocrine carcinoma with differentiation towards an intestinal type adenocarcinoma (mixed adeno-neuroendocrine carcinoma, MANEC).\n\nThe patient was operated in one session with a dual approach: Initially the patient was operated with FESS technique where the nasal part of tumour was removed with a sphenoethmoidectomy to the scull base. The frontal sinuses were opened and tumour extension was removed. The area of tumour penetration through the scull base was localized. The neurosurgeons performed a bicoronal incision and removed the tumour extension to and through the dura, but no intra-cerebral extension was seen. The scull base was reconstructed with the fascia latae free flap. The postoperative period was uneventful. Due to dural invasion the disease was staged pT4bN0M0.\n\nFourteen days post operative the patient initiated chemotherapy with an identical schedule as case 1. Like patient 1, this patient had his second series postponed due to neutropenia (CTCAE 4.0 grade 2) and G-CSF was added for the remaining series.\n\nThe radiotherapy high risk CTV was defined as preoperative tumour extension plus 5 mm margin, treated with 60 Gy in 30 fractions. A moderate risk clinical target volume including the remaining, frontal, ethmoid, sphenoid and ipsilateral maxillary sinuses as well as ipsilateral nasal cavity was generated and treated to 54 Gy in 30 fractions. The entire brain was treated to 25.2 Gy for the last 14 fractions using an integrated volume. The treatment technique were comparable to case 1.\n\nThe patient had only moderate, expected side effects, including nausea during chemotherapy and a slight headache that responded to endoscopic cleansing of the sinuses post therapy. No lasting neurological deficits. There is no sign of relapse 24 months after therapy.\n\nDiscussion\nAggressive neuroendocrine sino-nasal tumours are very prone to recurrence both loco-regionally and distant, and should be treated with multimodality treatment whenever possible. Despite intense treatment, the prognosis is poor. The presented cases illustrates that even with intense treatment, loco-regional failure may occur. Intracerebral metastases poses a severe threat to the patient’s quality of life as well as survival. Based on retrospective data from head and neck cancer [4] as well as high level evidence extrapolated from SCLC, PCI will probably reduce that risk. From a dosimetric point of view, an integrated PCI in the primary radiotherapy treatment, may reduce the risk of late side effects due to superior conformity and homogeneity. As survival and late quality of life is the argument for PCI, we chose a very aggressive approach with chemotherapy given before, during and after radiotherapy and PCI integrated into the primary radiotherapy. This resulted in severe side effects, as one patient developed sign of radiotherapy induced encephalopathy that slowly but completely regressed during months. The acute side effects were, on the other hand, not unexpectedly high, taking the radiotherapy high-dose-target alone into consideration. None of the patients had an intracranial recurrence and simultaneous integrated PCI should be considered for head and neck cancer patients with a high risk for intracerebral metastasis from haematogenous spread, but only in cases with a significant dose overlap between the radiotherapy for the initial tumour manifestations and the brain.\n\nAcknowledgments\nThomas Ravnkilde for contributions with the dose plans.\n==== Refs\nReferences\n1 Bell D. Hanna E.Y. Weber R.S. DeMonte F. Triantafyllou A. Lewis J.S. Jr Neuroendocrine neoplasms of the sinonasal region Head Neck 38 Suppl. 1 2016 E2259 66 Epub;%2015 Jul 18.:E2259-E2266. 26041714 \n2 Rosenthal D.I. Barker J.L. Jr El-Naggar A.K. Glisson B.S. Kies M.S. Diaz E.M. Jr Sinonasal malignancies with neuroendocrine differentiation: patterns of failure according to histologic phenotype Cancer 101 11 2004 2567 2573 15517582 \n3 Zhang W. Jiang W. Luan L. Wang L. Zheng X. Wang G. Prophylactic cranial irradiation for patients with small-cell lung cancer: a systematic review of the literature with meta-analysis BMC Cancer 14 2014 793 25361811 \n4 De Felice F. Lei M. Guerrero Urbano T. Controversies in small cell carcinoma of the head and neck: prophylactic cranial irradiation (PCI) after primary complete initial remission Cancer Treat Rev 41 8 2015 725 728 26211602 \n5 Takahashi S. Miyashita T. Hoshikawa H. Haba R. Togami T. Shibata T. Accelerated hyperfractionated radiotherapy for small cell carcinoma of the nasopharynx Head Neck 37 5 2015 E63 E65 25270910 \n6 Yazici O. Ozdemir N.Y. Sendur M.A. Aksoy S. Zengin N. Current approaches for prophylactic cranial irradiation in extrapulmonary small cell carcinoma Curr Med Res Opin 30 7 2014 1327 1336 24628530 \n7 Franco P. Numico G. Migliaccio F. Catuzzo P. Cante D. Ceroni P. Head and neck region consolidation radiotherapy and prophylactic cranial irradiation with hippocampal avoidance delivered with helical tomotherapy after induction chemotherapy for non-sinonasal neuroendocrine carcinoma of the upper airways Radiat Oncol 7 21 2012 21 27 22336394 \n8 Sas-Korczynska B. Korzeniowski S. Wojcik E. Comparison of the effectiveness of “late” and “early” prophylactic cranial irradiation in patients with limited-stage small cell lung cancer Strahlenther Onkol 186 6 2010 315 319 20495970\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2405-6308",
"issue": "2()",
"journal": "Clinical and translational radiation oncology",
"keywords": "Neuroendocrine neoplasm; Prophylactic craniel irradiation; Radiotherapy; Sino nasal cancer; Small cell neoplasm",
"medline_ta": "Clin Transl Radiat Oncol",
"mesh_terms": null,
"nlm_unique_id": "101713416",
"other_id": null,
"pages": "59-62",
"pmc": null,
"pmid": "29658002",
"pubdate": "2017-02",
"publication_types": "D002363:Case Reports",
"references": "26041714;24628530;26211602;20495970;15517582;25361811;25270910;22336394",
"title": "Simultaneous integrated prophylactic cranial irradiation in sino-nasal cancer.",
"title_normalized": "simultaneous integrated prophylactic cranial irradiation in sino nasal cancer"
} | [
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"companynumb": "DK-MYLANLABS-2017M1083636",
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{
"abstract": "We describe the case of a healthy 67-year-old Caucasian female who developed a rare, reversible case of cystoid maculopathy without late leak on fluorescein angiogram. She presented initially with a 5-year history of bilateral, variable central scotomata. The visual acuities were 6/6, while foveal reflexes were abnormal. Fluorescein angiogram showed no leakage; however, optical coherence tomography (OCT) revealed cystic spaces in the fovea of both eyes. The patient had been taking niacin supplements averaging 100mg daily for 30 years. Niacin was discontinued, and 7 months later, her symptoms and OCT results improved. Although niacin-induced maculopathy is uncommon, the clinician should enquire about possible niacin supplementation in any patient with cystoid macular edema in the absence of late leakage on fluorescein angiography. We describe a new reason for niacin maculopathy due to chronic low dose niacin supplementation and a slower pattern of visual recovery than that previously suggested in the literature.",
"affiliations": "Moorfields Eye Hospital, NHS Foundation Trust, 162, City Road, London, EC1V 2PD, Royaume-Uni. waheeda.rahman@moorfields.nhs.uk",
"authors": "Rahman|W|W|;Errera|M-H|MH|;Egan|C|C|",
"chemical_list": "D009525:Niacin",
"country": "France",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0181-5512",
"issue": "36(2)",
"journal": "Journal francais d'ophtalmologie",
"keywords": null,
"medline_ta": "J Fr Ophtalmol",
"mesh_terms": "D000368:Aged; D019587:Dietary Supplements; D005260:Female; D005451:Fluorescein Angiography; D006801:Humans; D008269:Macular Edema; D009525:Niacin",
"nlm_unique_id": "7804128",
"other_id": null,
"pages": "e33-6",
"pmc": null,
"pmid": "23218599",
"pubdate": "2013-02",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "A rare case of cystoid maculopathy.",
"title_normalized": "a rare case of cystoid maculopathy"
} | [
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"companynumb": "GB-SUN PHARMACEUTICAL INDUSTRIES LTD-2013R1-74118",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NIACIN"
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"abstract": "Adverse events due to anticoagulation and antiplatelet therapy during left ventricular assistance device (LVAD) support are very common, and every effort must be made to reduce their impact. We report our experience using a low dose of double antiplatelet therapy for patients provided with the INCOR LVAD system as a bridge to transplantation. Twelve patients (10 males, 35-60 years old) with acute or end-stage heart failure were included in this study. The mean follow-up was 10 months (cumulative 4.9 years). For antiplatelet therapy, we use an association of variable doses of aspirin and clopidogrel. The use of a platelet aggregation test (PAT) allows reducing the dose of the drugs to the minimum needed. The primary end point was to check the safety of the therapy, analyzing the incidence of major and minor bleeding complications. The secondary end point was to check the effectiveness of the therapy, evaluating the incidence of major and minor thromboembolic events. We had three (25%) cases of early postoperative mediastinal bleeding. On the contrary, no episodes of major bleeding occurred during the follow-up period. The rate of minor bleeding complications was low: 0.2 events per patient/year. The rate of major and minor thromboembolic events was acceptable (respectively 0.09 and 0.2 per patient/year). During LVAD support, double antiplatelet therapy with a low dose of aspirin and clopidogrel was safe and effective. PAT allows reducing the dose of antiplatelet drugs, avoiding complications related to excessive or insufficient dose administration.",
"affiliations": "Division of Cardiac Surgery, San Giovanni Battista Hospital, University of Turin, C.so Bramante 88, 10127, Turin, Italy. matteoatti@libero.it",
"authors": "Attisani|Matteo|M|;Centofanti|Paolo|P|;La Torre|Michele|M|;Campanella|Antonio|A|;Sansone|Fabrizio|F|;Rinaldi|Mauro|M|",
"chemical_list": "D000925:Anticoagulants; D010975:Platelet Aggregation Inhibitors",
"country": "Japan",
"delete": false,
"doi": "10.1007/s10047-010-0527-7",
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"issue": "13(4)",
"journal": "Journal of artificial organs : the official journal of the Japanese Society for Artificial Organs",
"keywords": null,
"medline_ta": "J Artif Organs",
"mesh_terms": "D000328:Adult; D000925:Anticoagulants; D004359:Drug Therapy, Combination; D005260:Female; D006353:Heart-Assist Devices; D006470:Hemorrhage; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors; D013923:Thromboembolism; D016896:Treatment Outcome",
"nlm_unique_id": "9815648",
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"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": "18342745;19352331;427005;9576228;14056485;5081902;15799917;19476831;11726895",
"title": "Safety and effectiveness of low dosing of double antiplatelet therapy during long-term left ventricular support with the INCOR system.",
"title_normalized": "safety and effectiveness of low dosing of double antiplatelet therapy during long term left ventricular support with the incor system"
} | [
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"companynumb": "IT-SA-2014SA120446",
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"abstract": "It is estimated that early-onset multiple sclerosis multiple sclerosis (early-onset multiple sclerosis) approximately incorporates 3-5% of the multiple sclerosis population. In this report on early-onset multiple sclerosis, the authors aimed to define demographic, clinical and imaging features in a case-series of true-childhood multiple sclerosis and to compare its characteristics with juvenile multiple sclerosis. The authors inspected the records of multiple sclerosis patients who were registered by Isfahan MS Society. Clinical and demographic data of children with less than 16 years of age were reviewed retrospectively. Out of 4536 multiple sclerosis patients referred to the authors' center, 221 patients (4.8%) had multiple sclerosis starting at the age of 16 or less (11 true-childhood multiple sclerosis vs 210 juvenile-onset multiple sclerosis); the female to male ratio was 4.81:1. In the mean follow-up period of 6.2 years, 22 patients (10.5%) had positive family history of multiple sclerosis, 196 (88.6%) patients were classified as relapsing-remitting multiple sclerosis, the mean (± SD Expanded Disability Status Scale) was 1.5 ± 1.1 at the last evaluation. The most common initial presentation was optic nerve involvement (36.1%) and cerebellar sign and symptoms (14.6%). In all, 13 patients (5.8%) had experienced seizure in the course of multiple sclerosis. This study indicated that early-onset multiple sclerosis is not rare condition and overwhelmingly affects girls even at prepubertal onset. Physicians should consider multiple sclerosis in suspicious pediatric cases.",
"affiliations": "Department of Neurology, Medical School, Isfahan University of Medical Sciences, Isfahan, Iran Isfahan Research Committee of Multiple Sclerosis (IRCOMS), Isfahan University of Medical Sciences, Isfahan, Iran.;Department of Biological Science, California State University, Stanislaus, Turlock, CA, USA.;Medical School, Islamic Azad University, Najafabad Branch, Najafabad, Iran.;Isfahan Research Committee of Multiple Sclerosis (IRCOMS), Isfahan University of Medical Sciences, Isfahan, Iran Medical Students' Research Committee, Isfahan University of Medical Sciences, Isfahan, Iran.;Isfahan Research Committee of Multiple Sclerosis (IRCOMS), Isfahan University of Medical Sciences, Isfahan, Iran.;Isfahan Research Committee of Multiple Sclerosis (IRCOMS), Isfahan University of Medical Sciences, Isfahan, Iran.;Isfahan Research Committee of Multiple Sclerosis (IRCOMS), Isfahan University of Medical Sciences, Isfahan, Iran Institute of Neuropathology, University of Göttingen, Göttingen, Germany mf.esfahani@yahoo.com.",
"authors": "Etemadifar|Masoud|M|;Nourian|Sayed-Mohammadamin|SM|;Nourian|Niloofaralsadat|N|;Abtahi|Seyed-Hossein|SH|;Sayahi|Farnaz|F|;Saraf|Zahra|Z|;Fereidan-Esfahani|Mahboobeh|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/0883073816634853",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0883-0738",
"issue": "31(7)",
"journal": "Journal of child neurology",
"keywords": "early-onset multiple sclerosis; juvenile-onset multiple sclerosis; multiple sclerosis; true-childhood multiple sclerosis",
"medline_ta": "J Child Neurol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D002648:Child; D004185:Disability Evaluation; D005190:Family; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007492:Iran; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis; D012042:Registries; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "8606714",
"other_id": null,
"pages": "932-7",
"pmc": null,
"pmid": "26979097",
"pubdate": "2016-06",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Early-Onset Multiple Sclerosis in Isfahan, Iran: Report of the Demographic and Clinical Features of 221 Patients.",
"title_normalized": "early onset multiple sclerosis in isfahan iran report of the demographic and clinical features of 221 patients"
} | [
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"companynumb": "IR-BIOGEN-2018BI00506769",
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"abstract": "OBJECTIVE\nWe aimed to report the pattern of usage and efficacy of antiepileptic drugs (AEDs) in patients with autoimmune epilepsy (AE).\n\n\nMETHODS\nWe retrospectively studied the Mayo Clinic's electronic medical record of patients with AE in which seizures were the main presenting feature. Clinical data, including demographics, seizure characteristics, type of AED and immunotherapy used, presence of neural antibody, and treatment outcomes, were reviewed.\n\n\nRESULTS\nThe medical records of 252 adult patients diagnosed with autoimmune encephalitis and paraneoplastic disorders were reviewed. Seizure was the initial presentation in 50 patients (20%). Serum and/or CSF autoantibodies were detected in 41 (82%) patients, and 38 (76%) patients had neural autoantibodies. The majority (n = 43, 86%) received at least 1 form of immunotherapy in combination with AEDs, while the remainder received AEDs alone. Twenty-seven patients (54%) became seizure free: 18 (36%) with immunotherapy, 5 (10%) with AEDs alone, and 4 (8%) with AEDs after immunotherapy failure. Levetiracetam was the most commonly used (42/50); however, it was associated with 0% seizure-free response. AED seizure-free responses occurred with carbamazepine (n = 3) [3/16, 18.8%], lacosamide (n = 3) [3/18, 16.6%] with phenytoin (n = 1) [1/8, 12.5%], or oxcarbazepine (n = 2) [2/11, 18.1%]. Regardless of the type of therapy, voltage-gated potassium channel-complex antibody-positive patients were more likely to become seizure free compared with glutamic acid decarboxylase 65 antibody-positive cases (12/17 vs 2/10, p = 0.0183).\n\n\nCONCLUSIONS\nIn select patients, AEDs alone were effective in controlling seizures. AEDs with sodium channel blocking properties resulted in seizure freedom in a few cases. Prospective studies are needed to clarify AED selection and to elucidate their immunomodulatory properties in AE.",
"affiliations": "Department of Neurology (A.M.F., A.S.L.C.), Mayo Clinic, Jacksonville, FL; and Department of Neurology (J.W.B.), Mayo Clinic, Rochester, MN.;Department of Neurology (A.M.F., A.S.L.C.), Mayo Clinic, Jacksonville, FL; and Department of Neurology (J.W.B.), Mayo Clinic, Rochester, MN.;Department of Neurology (A.M.F., A.S.L.C.), Mayo Clinic, Jacksonville, FL; and Department of Neurology (J.W.B.), Mayo Clinic, Rochester, MN.",
"authors": "Feyissa|Anteneh M|AM|;López Chiriboga|A Sebastian|AS|;Britton|Jeffrey W|JW|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1212/NXI.0000000000000353",
"fulltext": "\n==== Front\nNeurol Neuroimmunol NeuroinflammNeurol Neuroimmunol NeuroinflammnnnNEURIMMINFLNeurology® Neuroimmunology & Neuroinflammation2332-7812Lippincott Williams & Wilkins Hagerstown, MD NEURIMMINFL201701244310.1212/NXI.000000000000035328461131ArticleAntiepileptic drug therapy in patients with autoimmune epilepsy Feyissa Anteneh M. MD, MScScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nLópez Chiriboga A. Sebastian MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nBritton Jeffrey W. MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nCo-investigator for clinical trial sponsored by Grifols pharmaceuticals for IVIG in VGKC encephalitis\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nMr. and Mrs. David Hawk charitable gift for epilepsy research\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nFrom the Department of Neurology (A.M.F., A.S.L.C.), Mayo Clinic, Jacksonville, FL; and Department of Neurology (J.W.B.), Mayo Clinic, Rochester, MN.Correspondence to Dr. Feyissa: Feyissa.Anteneh@mayo.eduFunding information and disclosures are provided at the end of the article. Go to Neurology.org/nn for full disclosure forms. The Article Processing Charge was funded by the Mayo Clinic.\n\n10 5 2017 7 2017 10 5 2017 4 4 e35307 2 2017 28 3 2017 Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology2017American Academy of NeurologyThis is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.Objective:\nWe aimed to report the pattern of usage and efficacy of antiepileptic drugs (AEDs) in patients with autoimmune epilepsy (AE).\n\nMethods:\nWe retrospectively studied the Mayo Clinic's electronic medical record of patients with AE in which seizures were the main presenting feature. Clinical data, including demographics, seizure characteristics, type of AED and immunotherapy used, presence of neural antibody, and treatment outcomes, were reviewed.\n\nResults:\nThe medical records of 252 adult patients diagnosed with autoimmune encephalitis and paraneoplastic disorders were reviewed. Seizure was the initial presentation in 50 patients (20%). Serum and/or CSF autoantibodies were detected in 41 (82%) patients, and 38 (76%) patients had neural autoantibodies. The majority (n = 43, 86%) received at least 1 form of immunotherapy in combination with AEDs, while the remainder received AEDs alone. Twenty-seven patients (54%) became seizure free: 18 (36%) with immunotherapy, 5 (10%) with AEDs alone, and 4 (8%) with AEDs after immunotherapy failure. Levetiracetam was the most commonly used (42/50); however, it was associated with 0% seizure-free response. AED seizure-free responses occurred with carbamazepine (n = 3) [3/16, 18.8%], lacosamide (n = 3) [3/18, 16.6%] with phenytoin (n = 1) [1/8, 12.5%], or oxcarbazepine (n = 2) [2/11, 18.1%]. Regardless of the type of therapy, voltage-gated potassium channel-complex antibody–positive patients were more likely to become seizure free compared with glutamic acid decarboxylase 65 antibody–positive cases (12/17 vs 2/10, p = 0.0183).\n\nConclusions:\nIn select patients, AEDs alone were effective in controlling seizures. AEDs with sodium channel blocking properties resulted in seizure freedom in a few cases. Prospective studies are needed to clarify AED selection and to elucidate their immunomodulatory properties in AE.\n\nOPEN-ACCESSTRUE\n==== Body\nAutoimmune epilepsy (AE) has been linked to both antineural antibodies targeting neural intracellular proteins (GAD65, ANNA-1, Ma, etc) and cell surface antigens (voltage-gated potassium channel–complex [VGKC-complex], NMDA receptor, AMPA, GABA-B, mGluR5, etc). AE can occasionally occur in the absence of detected neural antibodies as well.1 Valuable clinical clues for AE are subacute onset, an unusually high seizure frequency, intraindividual seizure variability or multifocality, antiepileptic drug (AEDs) resistance, personal or family history of autoimmunity, or history of recent or past neoplasia.2 Seizures occur as an early and prominent feature in AE, and these are characteristically refractory to conventional AED therapy.1\n\nAlthough intractability is a common feature in AE, some respond to AEDs, and they remain an important aspect of therapy. The role of AEDs in these patients is also relevant as even after controlling the inflammatory response, some patients remain at risk of recurrent seizures, particularly if cerebral damage occurred during the acute encephalitic phase of the illness. Some AEDs affect cellular and humoral immune responses.3–6 For example, carbamazepine and valproate have been shown to increase the serum levels of IL-1β, IL-2, IL-4, IL-6, IL-17, and tumor necrosis factor–alpha (TNFα) production.4,5 At this time, no single AED stands out as superior to others in AE, and the medically refractory nature of seizures in these patients is typically emphasized. However, occasional patients do respond to AED treatment, and it is not currently known if this occurs with medications featuring particular mechanisms of action. In this study, we aimed to explore the pattern of usage and relative efficacy of AEDs in patients with AE.\n\nMETHODS\nTo identify all relevant adult cases of AE, we searched the medical record index system of the Mayo Clinic, Rochester, for the terms “autoimmune encephalitis,” “autoimmune epilepsy,” “autoimmune seizure,” and “limbic encephalitis” from January 1, 2013, through December 31, 2015. Our search resulted in 252 cases. Among these, 50 patients were identified who fulfilled the following criteria: (1) seizures as the exclusive or predominant presenting complaint and (2) an autoimmune etiology suspected on the basis of clinical presentation, inflammatory CSF, MRI characteristics suggesting inflammation, or detection of serum and/or CSF neural autoantibody7 (figure 1). Demographic, clinical (seizure semiology, course, and associated symptoms), autoimmune serology, type of AED and immunotherapy used, EEG and radiologic characteristics, and treatment outcomes were reviewed.\n\nFigure 1 Flowchart showing methodology of study design\nAANA-1 = antineuronal nuclear antibody–1; AED = antiepileptic drug; EMR = electronic medical record; G-ACR = ganglionic acetylcholine receptor; GAD65 = glutamic acid decarboxylase 65; NMDAR = NMDA receptor; SSA = Sjögren's-syndrome-related antigen A; TPO = thyroid peroxidase; VGCC = voltage-gated calcium channel; VGKC-complex = voltage-gated potassium channel–complex.\n\nBaseline seizure frequency was determined by reviewing the seizure frequency stated in the clinical record prior to initiation of treatment and categorized as daily (>1 seizure per day), weekly (>1 seizure per week but not daily), or monthly (>1 seizure per month but not weekly). Response to AED with and without immunotherapy was determined by review of the record documenting course following treatment initiation.\n\nStatistical analysis.\nData were expressed as mean, range, and SD for continuous variables, and counts (percentages) for categorical variables. We compared treatment response by antibody type (VGKC-complex antibodies vs GAD65 vs antibody negative) using the Fisher exact test. All analyses were performed using SAS software (version 9.3). All statistical tests were 2 sided, and p < 0.05 was considered statistically significant.\n\nStandard protocol approvals, registrations, and patient consents.\nThe study was approved by the Mayo Clinic Institutional Review Board, and all patients consented to the use of their medical records for research purposes.\n\nRESULTS\nClinical characteristics.\nPatients age ranged from 10 to 87 years (mean age 41.3 years); 26 (52%) were men. The mean age at onset was 41 years. The median follow-up period was 18 months (range 3–44 months). Seizure types were focal seizures with and without loss of awareness, faciobrachial dystonic seizures, epilepsy partialis continua, and generalized tonic-clonic seizures with/without status. EEG was abnormal with interictal discharges or documented seizure activity in the majority of cases. MRI data were abnormal in 23 patients. Brain PET CT was performed in 4 patients, and it was abnormal in each. Summary of clinical characteristics of the 50 patients is provided in table 1.\n\nTable 1 Summary of clinical characteristics of 50 patients with suspected AE\n\nAutoantibody evaluation.\nNeural autoantibodies were identified in 38 patients (76%), of which 26 had antibodies targeting plasma membrane proteins: VGKC-complex antibody (n = 17) (LGI1 [11], CASPR2 [1], and double negative [5]); ganglionic acetylcholine receptor (G-AChR) (n = 5); NMDA receptor (n = 3); P/Q-type calcium channel (n = 1), and 12 had antibodies targeting cytoplasmic or nuclear proteins: P GAD65 (n = 10), ANNA-1 (n = 1), and ANNA-2 (n = 1). Three patients (6%) had non-neuronal antibodies (thyroid peroxidase [TPO], Ant-Ro, and anti–dsDNA), and nine patients (18%) were autoantibody negative.\n\nTreatments and response.\nThe majority (n = 43, 86%) received at least 1 form of immunotherapy in combination with AEDs, while the reminder received AEDs alone. The median number of AEDs used was 2 (range 1–6). Levetiracetam was the most common medication used (n = 42), followed by lacosamide (n = 18), carbamazepine (n = 16), oxcarbazepine (n = 11), lamotrigine (n = 11), and phenytoin (n = 8). Summary of AED use for the cohort is provided in figure 2. In addition, 4 patients received vagus nerve stimulation therapy, and 3 patients had unsuccessful epilepsy surgeries. The rationale for selecting one AED over the other was not clarified in the electronic medical record (EMR). Twenty-seven patients (54%) became seizure free: 18 (36%) with immunotherapy, 5 (10%) with AEDs alone, and 4 (8%) with AEDs after failing immunotherapy. Initiation of carbamazepine (n = 3) (3/16, 18.8%), lacosamide (n = 3) (3/18, 16.6%), phenytoin (n = 1) (1/8, 12.5%), or oxcarbazepine (n = 2) (2/11, 18.1%) resulted in seizure-free outcomes, while none of the patients became seizure free with levetiracetam (n = 0) (0/42, 0%). The timing of therapeutic response to AEDs (i.e., cessation of clinical seizures) was immediate: within 24 hours in 1 patient, within 1 week in 2, within 2 weeks in 3, and within 4 weeks in the remainder.\n\nFigure 2 Pattern of AED use in 50 patients with suspected AE\nAE = autoimmune epilepsy; AED = antiepileptic drug.\n\nAmong those who responded to AED therapy, 4 were VGKC-complex antibody positive (1 LGI1, 1 CASPR2, and 2 double negative), 1 was GAD65 antibody positive, 1 was AChR antibody positive, 1 was TPO antibody positive, and 2 were autoantibody negative. Regardless of the type of therapy, VGKC-complex antibody–positive patients were more likely to become seizure free compared with GAD65-positive and autoimmune antibody–negative cases (12/17 vs 2/10 vs 2/9 respectively, p < 0.05). Specifically, of the VGKC-complex antibody patients who became seizure free, 4 responded to AEDs (25%), while the remainder became seizure free with immunotherapy (75%). One patient with GAD65 ab-associated AE responded to carbamazepine, while the other became seizure free with immunotherapy. Two of the autoantibody-negative cases responded to AEDs (carbamazepine), and 2 became seizure free with immunotherapy. Details of patients who responded to AEDs alone or after failure of immunotherapy are summarized in table 2 and figure 3.\n\nTable 2 Clinical characteristics of patients who become seizure free with AED therapy\n\nFigure 3 Response to therapy by antibody status\nThe number of patients who responded per the total number of patients receiving individual therapy is provided in each bar. Ab negative = negative to antibody testing (n = 9); AED = antiepileptic drug; GAD65 = glutamic acid decarboxylase 65 (n = 10); VGKC-complex = voltage-gated potassium channel–complex (n = 17).\n\nDISCUSSION\nAlthough the seizures in AE are often considered to be medication resistant, and immunotherapy is often the focus of management,7 this study suggests that in select cases AEDs alone may confer seizure freedom.\n\nOf interest in our study, 9 patients became seizure free after the initiation of AEDs with sodium channel blocking properties7 (carbamazepine, n = 3; oxcarbazepine, n = 2; lacosamide alone, n = 3, or with phenytoin, n = 1). The response to AEDs was seen within 2–4 weeks of the initiation of therapy in all patients. In a few patients, AEDs alone were effective in controlling seizures. However, improvement of cognitive symptoms and other manifestations of autoimmune encephalitis in most patients requires immunotherapy.7 It is conceivable that these therapeutic responses could be secondary to immunomodulatory properties of these medications.4–6 For example, carbamazepine has been shown to reduce levels of proinflammatory cytokines IL-1β and TNFα in the hippocampus of rats4 and inhibits the development of different types of inflammation through dose-dependent reduction of prostaglandin E2 and substance P.5 Carbamazepine and oxcarbazepine have also been shown to decrease serum levels of IL-1 and IL-2 in healthy subjects.5 Although disruption of blood-brain barrier permeability has been suggested as a possible pathway for cytokines influencing seizures and epilepsy,8 the exact role of cytokines in human epilepsy is complex and not yet completely elucidated. Moreover, whether there are unique aspects of the pathophysiology of seizure onset in these patients which make them more susceptible to sodium channel blockage is not known. The observed response could also be due to the effectiveness of sodium channel blockers in focal onset epilepsy which is seen in 66% of patients in our cohort. Of note, while AED responders responded to sodium channel blockers, no patient responded to lamotrigine, which also has sodium channel properties.9 Therefore, if there is a unique responsivity of seizures in these patients to this class of medications, the response may not be uniform throughout the entire class. Studies are needed to elucidate whether any differential efficacy is based on their effect on seizure mechanisms or immunomodulatory properties.\n\nRegardless of the type of therapy, VGKC-complex antibody–positive patients were more likely to become seizure free compared with GAD65-positive and autoimmune antibody–negative cases (figure 2). This is consistent with previous observations of superior immunotherapy response in patients with neural surface–related autoantibody-mediated encephalitides as compared to those associated with intracellular antigen autoantibodies.1,7,10 Of note, among the patients who responded to AEDs in our cohort, the majority were VGKC-complex antibody positive (1 LGI1 positive; 1 CASPR2 positive, and 2 double negative). Two of these responded to oxcarbazepine, one to lacosamide, and the other to carbamazepine (figure 1). Indeed, sodium-channel blocking agents such as carbamazepine and phenytoin have been successfully used to treat autoimmune VGK channelopathies such as neuromyotonia11 and episodic ataxia type 1.12 These agents act by reducing neuronal repetitive firing through interaction with voltage-gated sodium channels.11,12 Perhaps, the observed favorable response of these agents in VGKC-complex ab–associated AE is attributable to this mechanism. In our series, one patient with GAD65 ab–associated AE became seizure free with carbamazepine after failing immunotherapy. This is in contrast to a similar report that found lack of AED response in patients with GAD65 antibody–positive AE following which it was postulated that GAD65 ab–associated AEs are intractable to AEDs.13 Regardless of the type of therapy, 4/9 (44.4%) autoantibody-negative patients become seizure free, 2 with AEDs (one with lacosamide and the other with carbamazepine after failing immunotherapy), while the other two responded to immunotherapy. Others have noted the potential for response in patients with seronegative AE to antiepileptic medication and immunotherapy.14\n\nThe rationale for selecting one AED over the other was not clarified in the EMR of our cohort. Levetiracetam was the most common used drug (42/50, figure 2); however, none of the patients in our series were rendered seizure free by this medication (0%). This finding is in contrast to previous reports suggesting that levetiracetam may have, at least in part, anti-inflammatory properties.3 The reason for the prevalent use of levetiracetam in our series is likely due to its ease of dosing and lack of drug-drug interactions.9 Certainly, AEDs with enzyme induction properties such as carbamazepine and phenytoin could alter the pharmacokinetics of immunosuppressive therapies and other agents used in these patients.9 Perhaps, newer AEDs with sodium channel blocking properties and more favorable pharmacokinetic profiles (such as oxcarbazepine and lacosamide) could be considered in this patient population. It is also imperative to monitor for hyponatremia (e.g., oxcarbazepine and carbamazepine) and allergic cutaneous reactions (e.g., carbamazepine and phenytoin), as these have been shown to occur at high rate in patients with VGKC-complex antibody.15 Prospective studies are needed to clarify AED selection and to elucidate their immunomodulatory properties in AE.\n\nThere are several limitations to our study. First, data collection for this retrospective study was based on the extraction of relevant patient information from EMRs. The lack of control group and the possible confounder of concomitant immunotherapy should also be acknowledged. In addition, selection bias could be present due to the tertiary nature of these patients. Finally, seizure quantification is only based on verbal report, thus recall bias could result in the event of amnestic seizures, and related to concurrent cognitive dysfunction that may have been present in a significant proportion of our cohort. Prospective studies are needed to clarify whether there is an optimal AED selection for AE. As the awareness of AE increases, finding effective strategies for seizure control is crucial.\n\nAUTHOR CONTRIBUTIONS\nStudy concept and design: Dr. Feyissa and Dr. Britton. Acquisition of data: Dr. Feyissa, Dr. Lopez, and Dr. Britton. Drafting of the manuscript: Dr. Feyissa and Dr. Lopez. Critical revision of the manuscript for important intellectual content: Dr. Feyissa and Dr. Britton.\n\nSTUDY FUNDING\nDr. Feyissa is supported by the Mayo Clinic Neuroscience Focused Research Team Program.\n\nDISCLOSURE\nDr. Feyissa and Dr. Lopez report no disclosures. Dr. Briton received research support from Grifols and Dr. and Mrs. David Hawk. Go to Neurology.org/nn for full disclosure forms.\n\nGLOSSARY\nAEautoimmune epilepsy\n\nAEDantiepileptic drug\n\nEMRelectronic medical record\n\nG-AChRganglionic acetylcholine receptor\n\nNMDARNMDA receptor\n\nTNFαtumor necrosis factor–alpha\n\nTPOthyroid peroxidase\n\nVGKC-complexvoltage-gated potassium channel–complex\n==== Refs\nREFERENCES\n1. Britton JW \nAutoimmune epilepsy . Handb Clin Neurol \n2016 ;133 :219 –245 .27112680 \n2. Bakpa OD , Reuber M , Irani SR \nAntibody-associated epilepsies: clinical features, evidence for immunotherapies and future research questions . Seizure \n2016 ;41 :26 –41 .27450643 \n3. Beghi E , Shorvon S \nAntiepileptic drugs and the immune system . Epilepsia \n2011 ;52 (suppl 3 ):40 –44 .21542845 \n4. Bianchi M , Rossoni G , Sacerdote P , Panerai AE , Berti F \nCarbamazepine exerts anti-inflammatory effects in the rat . Eur J Pharmacol \n1995 ;294 :71 –74 .8788417 \n5. Himmerich H , Bartsch S , Hamer H , et al \nModulation of cytokine production by drugs with antiepileptic or mood stabilizer properties in anti-CD3- and anti-Cd40-stimulated blood in vitro . Oxid Med Cell Longev \n2014 ;2014 :806162 .24757498 \n6. Gomez CD , Buijs RM , Sitges M \nThe anti-seizure drugs vinpocetine and carbamazepine, but not valproic acid, reduce inflammatory IL-1beta and TNF-alpha expression in rat hippocampus . J Neurochem \n2014 ;130 :770 –779 .24903676 \n7. Toledano M , Britton JW , McKeon A , et al \nUtility of an immunotherapy trial in evaluating patients with presumed autoimmune epilepsy . Neurology \n2014 ;82 :1578 –1586 .24706013 \n8. Li G , Bauer S , Nowak M , et al \nCytokines and epilepsy . Seizure \n2011 ;20 :249 –256 .21216630 \n9. French JA , Gazzola DM \nAntiepileptic drug treatment: new drugs and new strategies . Continuum (Minneap Minn) \n2013 ;19 :643 –655 .23739102 \n10. Tan KM , Lennon VA , Klein CJ , et al \nClinical spectrum of voltage-gated potassium channel autoimmunity . Neurology \n2008 ;70 :1883 –1890 .18474843 \n11. Ahmed A , Simmons Z \nIsaacs syndrome: a review . Muscle Nerve \n2015 ;52 :5 –12 .25736532 \n12. Rajakulendran S , Schorge S , Kullmann DM , Hanna MG \nEpisodic ataxia type 1: a neuronal potassium channelopathy . Neurotherapeutics \n2007 ;4 :258 –266 .17395136 \n13. Malter MP , Helmstaedter C , Urbach H , Vincent A , Bien CG \nAntibodies to glutamic acid decarboxylase define a form of limbic encephalitis . Ann Neurol \n2010 ;67 :470 –478 .20437582 \n14. von Rhein B , Wagner J , Widman G , Malter MP , Elger CE , Helmstaedter C \nSuspected antibody negative autoimmune limbic encephalitis: outcome of immunotherapy . Acta Neurol Scand \n2017 ;135 :134 –141 .26940288 \n15. Irani SR , Stagg CJ , Schott JM , et al \nFaciobrachial dystonic seizures: the influence of immunotherapy on seizure control and prevention of cognitive impairment in a broadening phenotype . Brain \n2013 ;136 (pt 10 ):3151 –3162 .24014519\n\n",
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"affiliations": "Departments of *Pediatrics †Immunobiology ‡Medicine §Pathology ∥University of Arizona Cancer Center, University of Arizona ¶Banner University Medical Center, Tucson, AZ.",
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"abstract": "Rhabdomyolysis is a serious and life-threatening condition which has many established causes including endocrine disturbances. Of those, thyroid, adrenal and pituitary deficiencies are the most commonly seen. Most cases of rhabdomyolysis with adrenal insufficiency that have been reported have been primary. Here, we report an encounter with a patient who presented with her second case of severe rhabdomyolysis in the setting of secondary adrenal insufficiency. The cause for corticotropic suppression was most likely autoimmune hypophysitis given the presence of other autoimmune comorbidities including a new diagnosis of autoimmune hepatitis. In addition to her case, we present a brief review of the literature pertaining to cases of rhabdomyolysis attributed to adrenal insufficiency.",
"affiliations": "General Medicine, Flinders Medical Centre, Bedford Park, South Australia, Australia.;General Medicine, Flinders Medical Centre, Bedford Park, South Australia, Australia.",
"authors": "Kennedy|Lisa|L|;Nagiah|Sureshkumar|S|http://orcid.org/0000-0003-0075-5799",
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"fulltext": "\n==== Front\nBMJ Case RepBMJ Case RepbmjcrbmjcasereportsBMJ Case Reports1757-790XBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR bcr-2018-22734310.1136/bcr-2018-227343Unusual Association of Diseases/Symptoms15061526Case ReportA case of severe rhabdomyolysis associated with secondary adrenal insufficiency and autoimmune hepatitis Kennedy Lisa http://orcid.org/0000-0003-0075-5799Nagiah Sureshkumar \nGeneral Medicine, Flinders Medical Centre, Bedford Park, South Australia, Australia\nCorrespondence to Dr Sureshkumar Nagiah, sureshkumar.nagiah@health.sa.gov.au2019 20 3 2019 20 3 2019 12 3 e22734315 2 2019 © BMJ Publishing Group Limited 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2019This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/Rhabdomyolysis is a serious and life-threatening condition which has many established causes including endocrine disturbances. Of those, thyroid, adrenal and pituitary deficiencies are the most commonly seen. Most cases of rhabdomyolysis with adrenal insufficiency that have been reported have been primary. Here, we report an encounter with a patient who presented with her second case of severe rhabdomyolysis in the setting of secondary adrenal insufficiency. The cause for corticotropic suppression was most likely autoimmune hypophysitis given the presence of other autoimmune comorbidities including a new diagnosis of autoimmune hepatitis. In addition to her case, we present a brief review of the literature pertaining to cases of rhabdomyolysis attributed to adrenal insufficiency.\n\nadrenal disorderspituitary disordersthyroid diseasemuscle diseasedrugs: musculoskeletal and joint diseasesspecial-featureunlocked\n==== Body\nBackground\nThis case represents an unusual presentation of rhabdomyolysis in secondary adrenal insufficiency as well as multiple autoimmune conditions occurring in the same patient. It highlights the importance of screening for endocrinopathies, in particular cortisol deficiency, in patients who present with rhabdomyolysis and an unclear precipitant. It is one of only few reported cases of secondary adrenal insufficiency causing rhabdomyolysis and thus represents an important clinical learning point. It also highlights the challenges and limitations in investigating the causes of hypopituitarism, and in particular, the diagnosis of autoimmune hypophysitis.\n\nCase presentation\nA 55-year-old woman was admitted to a tertiary hospital with a 4-day history of profound global weakness, light-headedness and cola-coloured urine following some moderate exertion which involved packing to move house. She was unable to walk or even lift her head off of the bed. Her swallow and respiratory effort were also impaired. She denied any preceding symptoms suggestive of an infection. She also denied any alcohol intake.\n\nHer medical history was significant for a previous episode of uncomplicated rhabdomyolysis 9 years prior. At that time, the peak creatine kinase (CK) was 9672 U/L and she was admitted for a short duration in a rural hospital. No obvious precipitant was found at that time and the only hormonal parameter tested was thyroid-stimulating hormone (TSH) which was normal. One month after that episode, her thyroid function tests were repeated and she was diagnosed with autoimmune hypothyroidism with a TSH of 5.3 mIU/L (reference 0.5–4.0), free thyroxine of 9 pmol/L (reference 10–25) with the detection of antithyroid peroxidase antibodies (238 IU/mL [reference <50]). She was commenced on levothyroxine. Her other comorbidities included well-controlled depression, anxiety and chronic degenerative back pain for which she was on long-term methadone. Her regular medications included thyroxine 75 µg, sertraline 200 mg and methadone 50 mg daily. She was a non-drinker, had never smoked and denied a history of illicit drug use.\n\nInvestigations\nBiochemical parameters for the current admission are shown in table 1. She was found to have severe rhabdomyolysis with a CK of 62 270 U/L. Screening bloods on presentation also revealed markedly elevated transaminases. Although this transaminase rise is likely due to her skeletal muscle damage, raised gamma-glutamyl transferase, alkaline phosphatase and bilirubin levels prompted us to screen for liver diseases. Her complete blood exam, renal function and electrolytes were normal.\n\nTable 1 Laboratory parameters for the current case\n\n\tCurrent case\tNormal range\t\nCK (U/L)\t62 270\t0–150\t\nSodium (mmol/L)\t137\t137–145\t\nPotassium (mmol/L)\t4.6\t3.5–4.9\t\nCreatinine (μmol/L)\t32\t50–100\t\nAlbumin (g/L)\t28\t34–48\t\nGlobulin (g/L)\t40\t21–41\t\nProthrombin time (s)\t15.4\t12–16\t\nProthrombin INR\t1.2\t0.9–1.2\t\nBilirubin (μmol/L)\t28\t2–24\t\nGamma-glutamyl transferase (U/L)\t204\t<60\t\nAlkaline phosphatase (U/L)\t153\t30–110\t\nAlanine transaminase (U/L)\t1210\t<55\t\nAspartate transaminase (U/L)\t3832\t<45\t\nTotal IgG (g/L)\t20.9\t6.5–16\t\nIgG1 (g/L)\t15.74\t3.76–7.96\t\nTSH (mIU/L)\t4.2\t0.5–4.0\t\nFree T4 (pmol/L)\t12\t10–25\t\n0900 Cortisol (nmol/L)\t16\t133–540\t\n0900 ACTH (ng/L)\t<10\t10–60\t\nIGF-1 (nmol/L)\t7\t7–24\t\nProlactin mIU/L\t456\t59–619\t\nFSH (IU/L)\t1\t>25 (postmenopausal)\t\nLH (IU/L)\t<1\t>8 (postmenopausal)\t\nCortisol post administration of synthetic ACTH (250 µg)\tBaseline\tAt 30 min\tAt 60 min\t\n11 nmol/L\t119 nmol/L\t230 nmol/L\t\nACTH, adrenocorticotropic hormone; CK, creatine kinase;FSH, follicle-stimulating hormone; IGF-1, insulin like growth factor-1; LH, luteinizing hormone; T4, thyroxine; TSH, thyroid-stimulating hormone.\n\nA screen for causes for rhabdomyolysis was undertaken. Myositis immunoblot was negative except for a positive Ro-52 which is not specific for autoimmune myositis. A muscle biopsy was not done given the paucity of other clinical signs to suggest an inflammatory myopathy. She had an elevated total IgG level, and in particular IgG1 was markedly raised (table 1). A screen for endocrinopathies is shown in table 1. Her thyroid function tests on presentation showed that she had slightly high TSH with thyroxine (T4) which was in the lower end of the normal range suggesting that she was under-replaced and her dose of levothyroxine was subsequently increased to 100 µg. A morning cortisol was 9 nmol/L, indicating profound adrenal insufficiency. A similar result was found on a repeat testing. The paucity of symptoms of adrenal insufficiency in this case was surprising and suggestive of a chronic process. A morning adrenocorticotropic hormone (ACTH) level was undetectable, indicating that the cortisol deficiency was secondary to hypopituitarism. The remainder of the pituitary screen revealed a suppressed follicle-stimulating hormone (FSH) and luteinizing hormone (LH) which strengthens the diagnosis, although there was sparing of the other axes. An MRI pituitary was unremarkable.\n\nOn further investigating the cause of the deranged liver function tests, an ultrasound abdomen showed a nodular heterogeneous liver, moderate ascites and moderate splenomegaly, suggestive of hepatic cirrhosis with portal hypertension. A screen for cause of liver disease revealed positive anti-soluble liver antigen (anti-SLA) antibodies and raised IgG suggestive of autoimmune hepatitis. All other liver autoantibodies were negative and the remainder of the screen did not reveal an alternate cause for the deranged liver function tests.\n\nTreatment\nShe was initially managed with intravenous hydration, general supportive measures and oral hydrocortisone replacement. Her clinical condition improved.\n\nOutcome and follow-up\nHer CK rapidly dropped over the first week and returned to the normal range within 3 months (figure 1). She was able to walk within 2 weeks and was discharged with rehabilitation in the home at this time. A liver biopsy several months into her treatment with hydrocortisone replacement found features of cirrhosis and inflammation that would be in keeping with, but not specific for, a partially treated autoimmune hepatitis.\n\nFigure 1 Trend in CK during week 1 and 2 months following presentation. CK, creatine kinase.\n\nDiscussion\nRhabdomyolysis can be a life-threatening condition with a mortality rate as high as 59% reported in critically ill patients with acute kidney injury (AKI).1 2 Clinical definitions vary, however, generally a serum CK of at least 10 times the upper limit of normal is considered diagnostic, particularly when followed by a fairly rapid descent to normal levels.3 The classical clinical presentation includes weakness, myalgia and pigmented urine, although this triad is seen in <10% of patients. With severe rhabdomyolysis, the most critical complication is AKI which is thought to be caused by myoglobin obstructing the tubules causing acute tubular necrosis.3 Other serious complications include metabolic disturbances and compartment syndrome. Causes for rhabdomyolysis are vast and include trauma, drugs, seizures, neuromuscular disorders, myopathies and hormonal abnormalities among others.3–5\n\nRhabdomyolysis in the setting of adrenal insufficiency is rarely seen. There are 12 other cases described in the literature, 7 being primary adrenal insufficiency alone, 1 being primary adrenal insufficiency with concurrent hypothyroidism and the remaining 4 found to be secondary to hypopituitarism. The characteristics of these cases are seen in table 2. Most of the cases described were associated with hyponatremia, which alone has also been implicated as a cause for rhabdomyolysis. This understandably led some authors to speculate that it may play a key role in the mechanism of rhabdomyolysis in adrenal insufficiency.6 However, the current case and several others show a markedly raised CK without hyponatremia which strongly points towards an alternative mechanism by which adrenal insufficiency leads to skeletal muscle breakdown. It certainly is known to present with a variety of other musculoskeletal complications including flexion contractures, myopathies, back pain, hyperkalemic neuromyopathy, Guillain-Barre syndrome, migratory myopathy and sciatica-like pain.7–9 It may be that cortisol deficiency, similar to the proposed mechanism in hypothyroidism,10–12 leads to muscle breakdown by impaired glycogenolysis or impaired mitochondrial oxidative metabolism. Another possibility is that the hypotension or shock associated with adrenal insufficiency may lead to muscle ischaemia.\n\nTable 2 Characteristics of previously reported cases of rhabdomyolysis with primary or secondary adrenal insufficiency\n\n\tAge/gender\tPeak CK (U/L)\tSodium (mmol/L)\tPrimary vs secondary\tComorbid endocrinopathies\t\nMor et al\n7\n\t44/F\t1670\t103\tPrimary\tNil\t\nJolobe and Sen47\n\t81/F\t3338\t138\tPrimary\tNil\t\nEgan et al\n6\n\t63/F\t21 490\t97\tPrimary\tNil\t\nde Witte et al\n48\n\t48/M\t438\tNormal*\tPrimary\tNil\t\nOki et al49\n\t52/M\t11 902\t118\tPrimary\tNil\t\nSolter et al\n50\n\t33/M\t12 560\t125\tPrimary\tNil\t\nLau et al\n9\n\t40/F\t30 779\t106\tPrimary\tNil\t\nMuir et al\n51\n\t22/M\t>25 000\t110\tPrimary\tHypothyroidism\t\nSoresi et al\n29\n\t64/F\t1377\t121\tSecondary\tPanhypopituitarism\t\nFoppiani et al\n52\n\t66/F\t4250\t123–127\tSecondary\tPanhypopituitarism\t\nSayarlioglu et al\n53\n\t58/F\t>40 000\t94\tSecondary\tPanhypopituitarism\t\nRobillon et al\n54\n\t31/F\t21 800\tNot given\tSecondary\tPanhypopituitarism\t\nCurrent case\t55/F\t62 270\t137\tSecondary\tTreated hypothyroidism\t\n*Absolute values not given.\n\nCK, creatine kinase; F, female; M, male.\n\nWith regards to the reported cases of rhabdomyolysis in the setting of both hypocortisolism and hypothyroidism, it is unclear which deficiency played the larger role in inducing muscle damage as they were both treated concurrently with resolution of signs and symptoms. Certainly hypothyroidism has a strong association with myopathy and it is a known cause of rhabdomyolysis.4 However, in the current case, the patient was already on treatment for hypothyroidism. At a mild degree of under-replacement as indicated by her low-normal T4 and mildly raised TSH, one would not expect to see such a severe degree of rhabdomyolysis. Thus, the current case suggests that the rhabdomyolysis seen in hypopituitarism or concurrent deficiencies in both cortisol and thyroid hormone is caused, to a meaningful degree, by the hypocortisolism.\n\nOne of the interesting aspects of this case is the coinciding diagnosis of liver disease. Liver disease does have an association with adrenal insufficiency through a number of mechanisms. For instance, hepatic cirrhosis has an established association with adrenal insufficiency via suppression of the hypothalamic–pituitary–adrenal axis,13 and conversely there are also documented cases of liver cirrhosis thought to be caused by hypopituitarism via changes akin to the development of metabolic syndrome leading to non-alcoholic fatty liver disease.14 The latter mechanism is a possibility in this case; however, the presence of anti-SLA antibodies and hypergammaglobulinaemia points more towards the diagnosis of an autoimmune hepatitis and she did not have clinical features of metabolic syndrome. The diagnosis of autoimmune liver disease in a patient with an established diagnosis of chronic autoimmune thyroiditis does then raise the suspicion of a predilection for autoimmune conditions as is seen in autoimmune polyglandular syndrome (APS). There are recorded case studies of autoimmune hepatitis in all three categories of APS.15–19 This has implications for screening for other autoimmune conditions and in this case raises the suspicion of an autoimmune cause for the adrenal insufficiency.\n\nWith regards to the profound chronic adrenal insufficiency in this case, the finding of low ACTH as well as low FSH and LH was diagnostic for a central endocrine pathology. Hypopituitarism has a number of causes including mass lesions, infiltrative disease, infarction, radiation, infection and autoimmunity. The hormonal deficiencies seen are highly variable, ranging from the classical panhypopituitarism to the loss of only one or two tropic axes.20 In the current case, in which there is a loss of the corticotropic and gonadotropic axes, the presence of concurrent autoimmune conditions and the paucity of radiological findings or features suggestive of an alternative cause, strongly points towards an autoimmune aetiology, that is, autoimmune hypophysitis.\n\nThe term autoimmune hypophysitis encompasses a spectrum of histopathological entities including granulomatous, lymphocytic and xanthomatous forms.21 Lymphocytic hypophysitis is the most common form.21 Histologically it is characterised by inflammation and cellular infiltration of the pituitary gland.22 It can present with symptoms of mass effect such as headache and diplopia, or with variable disturbances of the hypothalamic–pituitary axis.21 23 The most commonly affected axes include corticotropic, thyrotropic, lactotropic and gonadotropic.22 24While the precise pathogenesis of this condition is unknown, it has been associated with pregnancy and also certain immunological therapies.21 It also has an association with other autoimmune conditions, including autoimmune hepatitis,25 and has been seen in cases of APS.26MRI of the pituitary can be normal but is more often abnormal. Typical findings include thickening of the pituitary stalk with or without extension to the basal hypothalamus, diffuse enlargement of the gland which may resemble an adenoma, absence of bright spot of the posterior lobe on T1-weighted images, contrast enhancement, symmetrical sella floor and sellar mass.24 The availability and clinical utility of anti-pituitary antibodies (APAs) are evolving, but at present they are still predominantly restricted to the domain of clinical research.24 Presently, the limitations for clinical use include inconsistent methodology, low sensitivity and specificity.24 They can be positive in normal subjects as well as other pituitary conditions such as Sheehan syndrome and pituitary adenoma.24 In the current case, the MRI was non-diagnostic and there were no APA assays available for clinical use in the state. However, given the concurrent autoimmune diagnoses, the pattern of deficiency and the paucity of evidence for another cause for hypopituitarism, autoimmune hypophysitis is the most likely diagnosis.\n\nA delayed presentation of Sheehan syndrome was another diagnosis considered in this case. Sheehan syndrome is hypopituitarism resulting from ischaemia of the pituitary gland occurring at the time of childbirth usually where there has been postpartum haemorrhage and hypotension.27 It often presents acutely following birth with an Addisonian crisis but can also present subacutely with the first sign being an inability to lactate.28 There are also cases where the diagnosis has been made many years following birth when they have presented with chronic hypopituitarism.28 We found one such case in the literature in which the patient initially presented with rhabdomyolysis (table 3).29 She was found to be deficient in all of the anterior pituitary hormones and gave a history from many years ago of having had postpartum haemorrhage plus an inability to lactate following birth.29 There is another report of a late diagnosis of Sheehan syndrome causing acute renal failure but with only a mildly elevated CK (table 3).30 The renal failure was thought to be related to chronically low cortisol, and in that case they had elicited no history of peripartum complications, only an inability to breastfeed.30 In the current case, the patient did give birth over 20 years prior but did not report any complications and had been able to breastfeed. One could entertain a possibility of a variant of Sheehan syndrome with sparing of the lactotropic axis, and certainly in the current case, the prolactin level was in the normal range. However, while Sheehan syndrome cannot be entirely excluded, it is less likely than autoimmune hypophysitis.\n\nTable 3 Anterior pituitary parameters in reported cases of rhabdomyolysis or acute renal failure with secondary adrenal insufficiency\n\n\tSoresi et al\n29\n\tBhat et al\n30\n\tCurrent case\t\nAge/gender\t64 years/female\t56 years/female\t55 years/female\t\nCortisol (nmol/L)\t3.86\t<28\t16\t\nACTH (ng/L)\t17\tNot reported\t<10\t\nFree T4 (pmol/L)\t0.8\tNot reported\t12\t\nTotal T4 (μg/dL) \nRange (4–13)\tNot reported\t<1\tNot measured\t\nTSH (mIU/L)\t1.56\t3.53\t4.2\t\nFSH (IU/L)\t7.04\t3.53\t1\t\nLH (IU/L)\t3\t<0.5\t<1\t\nProlactin (mIU/L)\t30\t<21\t456\t\nACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone; LH, luteinizing hormone; T4, thyroxine; TSH, thyroid-stimulating hormone.\n\nHypopituitarism secondary to chronic methadone use is another possibility but is also less likely in this case. Most of the described cases are opiate-related hypogonadotropic hypogonadism rather than a deficiency in other anterior pituitary hormones.31 Opiate-induced secondary adrenal insufficiency is thought to be uncommon with only very few case reports in the literature but this may be due to under-reporting.32–37 Some believe that the prevalence of opiate-induced adrenal insufficiency due to suppression of hypothalamic–pituitary–adrenal suppression could be as high as 9%–29%.38 In the current case, as discussed above, the presence of other autoimmune tendency would favour an autoimmune hypophysitis over secondary adrenal insufficiency from opiate use although this cannot be entirely excluded. Also, as far we know, there is no known association with therapeutic opiate use and rhabdomyolysis. Most reported cases of rhabdomyolysis that have been described are in the setting of an opiate overdose resulting in immobilisation.39 40\n\nThere are isolated case reports of rhabdomyolysis in association with selective serotonin reuptake inhibitors (SSRIs) and in particularly with sertraline use.41 42 Almost all reported cases were seen within 4 months after commencing or uptitrating an SSRI and in the setting of strenuous exercise.41 43 Few other cases have also been reported with SSRI overdose.44 45 Our patient was on sertraline for several years, and there were no recent dose changes or a history of overdose. She also did not engage in strenuous exercise. Although a contribution from sertraline to rhabdomyolysis cannot be ruled out, it is less likely in our patient. We also could not find any clinical cases of adrenal insufficiency in association with SSRI use.\n\nThis dilemma highlights the need for improved diagnostic tools for hypopituitarism. Both the rarity and the wide spectrum of clinical manifestations of autoimmune hypophysitis make it difficult to achieve consistency in diagnosis. As discussed, contrast MRI and serum APAs may help to a limited degree. Histological confirmation by transsphenoidal biopsy can lead to a more definitive diagnosis and is the gold standard, but is usually only obtained in cases in which the mass effect is causing symptoms such as headache and visual disturbance and in these cases often surgery is being considered.46 Differentiating hypophysitis from tumour would be beneficial in these instances as the former may then be managed with corticosteroids, avoiding surgery and thus preserving remaining pituitary function.\n\nLearning points\nIf the cause of rhabdomyolysis is unclear after an initial workup and preliminary investigations, one should actively screen for cortisol deficiency.\n\nAlthough most recognised cases of adrenal insufficiency in association with rhabdomyolysis are primary, there seems to be an association with secondary adrenal insufficiency. The pathogenesis seems to be due to an autoimmune process.\n\nOnce rhabdomyolysis in association with cortisol deficiency is established, screening for other autoimmune diseases should be considered depending on the clinical suspicion and biochemical abnormalities.\n\nLK and SN contributed equally.\n\nContributor: LK and SN contributed equally.\n\nContributors: LK wrote parts of the case presentation, discussion and drafted the tables for the manuscript. LK also consented the patient for publication. SN initiated the write-up. He also wrote several parts of the discussion, edited the manuscript several times and inserted a number of references. He also answered all the reviewer comments. Both authors have contributed equally to this 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\nPatient consent for publication: Obtained.\n==== Refs\nReferences\n1 \nMcMahon GM , Zeng X , Waikar SS \nA risk prediction score for kidney failure or mortality in rhabdomyolysis . JAMA Intern Med \n2013 ;173 :1821 –7 . 10.1001/jamainternmed.2013.9774 \n24000014 \n2 \nde Meijer AR , Fikkers BG , de Keijzer MH , et al \nSerum creatine kinase as predictor of clinical course in rhabdomyolysis: a 5-year intensive care survey . Intensive Care Med \n2003 ;29 :1121 –5 . 10.1007/s00134-003-1800-5 \n12768237 \n3 \nZutt R , van der Kooi AJ , Linthorst GE , et al \nRhabdomyolysis: review of the literature . Neuromuscul Disord \n2014 ;24 :651 –9 . 10.1016/j.nmd.2014.05.005 \n24946698 \n4 \nHuerta-Alardín AL , Varon J , Marik PE \nBench-to-bedside review: rhabdomyolysis -an overview for clinicians . Crit Care \n2005 ;9 :158 –69 . 10.1186/cc2978 \n15774072 \n5 \nMelli G , Chaudhry V , Cornblath DR \nRhabdomyolysis: an evaluation of 475 hospitalized patients . Medicine \n2005 ;84 :377 –85 .16267412 \n6 \nEgan JJ , Davies AJ , Jones MK \nHyponatraemic rhabdomyolysis in Addison’s disease . Postgrad Med J \n1994 ;70 :830 –2 . 10.1136/pgmj.70.829.830 \n7824421 \n7 \nMor F , Green P , Wysenbeek AJ \nMyopathy in Addison’s disease . Ann Rheum Dis \n1987 ;46 :81 –3 . 10.1136/ard.46.1.81 \n3813679 \n8 \nShapiro MS , Trebich C , Shilo L , et al \nMyalgias and muscle contractures as the presenting signs of Addison’s disease . Postgrad Med J \n1988 ;64 :222 –3 . 10.1136/pgmj.64.749.222 \n2845381 \n9 \nLau SY , Yong TY \nRhabdomyolysis in acute primary adrenal insufficiency complicated by severe hyponatraemia . Intern Med \n2012 ;51 :2371 –4 . 10.2169/internalmedicine.51.7879 \n22975551 \n10 \nAltay M , Duranay M , Ceri M \nRhabdomyolysis due to hypothyroidism . Nephrol Dial Transplant \n2005 ;20 :847 –8 . 10.1093/ndt/gfh745 \n\n11 \nBarahona MJ , Mauri A , Sucunza N , et al \nHypothyroidism as a cause of rhabdomyolysis . Endocr J \n2002 ;49 :621 –3 . 10.1507/endocrj.49.621 \n12625411 \n12 \nMonzani F , Caraccio N , Siciliano G , et al \nClinical and biochemical features of muscle dysfunction in subclinical hypothyroidism . J Clin Endocrinol Metab \n1997 ;82 :3315 –8 . 10.1210/jcem.82.10.4296 \n9329360 \n13 \nFede G , Spadaro L , Tomaselli T , et al \nAdrenocortical dysfunction in liver disease: a systematic review . Hepatology \n2012 ;55 :1282 –91 . 10.1002/hep.25573 \n22234976 \n14 \nNyenwe EA , Williamson-Baddorf S , Waters B , et al \nNonalcoholic Fatty liver disease and metabolic syndrome in hypopituitary patients . Am J Med Sci \n2009 ;338 :190 –5 . 10.1097/MAJ.0b013e3181a84bde \n19745609 \n15 \nTeufel A , Weinmann A , Kahaly GJ , et al \nConcurrent autoimmune diseases in patients with autoimmune hepatitis . J Clin Gastroenterol \n2010 ;44 :208 –13 . 10.1097/MCG.0b013e3181c74e0d \n20087196 \n16 \nDieli-Crimi R , Núñez C , Estrada L , et al \nAn autoimmune polyglandular syndrome complicated with celiac disease and autoimmune hepatitis . Ann Hepatol \n2016 ;15 :588 –91 .27236159 \n17 \nYu H , Qiu H , Pan J , et al \nHashimoto’s thyroiditis concomitant with sequential autoimmune hepatitis, chorea and polyserositis: a new entity of autoimmune polyendocrine syndrome? \nIntern Med \n2013 ;52 :255 –8 . 10.2169/internalmedicine.52.6799 \n23318858 \n18 \nBiałkowska J , Zygmunt A , Lewiński A , et al \nHepatitis and the polyglandular autoimmune syndrome, type 1 . Arch Med Sci \n2011 ;7 :536 –9 . 10.5114/aoms.2011.23427 \n22312376 \n19 \nPatel T , Nystrom J , Pyrsopoulos N \nAutoimmune hepatitis as a part of polyglandular autoimmune syndrome type II: case report and literature review . Dig Dis Sci \n2010 ;55 :861 –4 . 10.1007/s10620-009-0796-2 \n19421855 \n20 \nSchneider HJ , Aimaretti G , Kreitschmann-Andermahr I , et al \nHypopituitarism . The Lancet \n2007 ;369 :1461 –70 . 10.1016/S0140-6736(07)60673-4 \n\n21 \nGuaraldi F , Giordano R , Grottoli S , et al. \nPituitary autoimmunity. Front Horm Res \n2017 ;48 :48 –68 .\n22 \nRao S , Mahadevan A , Maiti T , et al \nGranulomatous and lymphocytic hypophysitis - are they immunologically distinct? APMIS: acta pathologica, microbiologica, et immunologica Scandinavica . 2016 ;124 :1072 –7 .\n23 \nCaturegli P , Newschaffer C , Olivi A , et al. \nEndocr Rev \n2005 ;26 :599 –614 . 10.1210/er.2004-0011 \n15634713 \n24 \nHonegger J , Schlaffer S , Menzel C , et al \nDiagnosis of primary hypophysitis in Germany . J Clin Endocrinol Metab \n2015 ;100 :3841 –9 . 10.1210/jc.2015-2152 \n26262437 \n25 \nPiñol V , Cubiella J , Navasa M , et al \n[Autoimmune hepatitis associated with thyroiditis and hypophysitis. A case report] . Gastroenterol Hepatol \n2000 ;23 :123 –5 .10804689 \n26 \nHrubisková K , Jackuliak P , Vanuga P , et al \n[Autoimmune polyendocrine syndrome type 2 associated with autoimmune hypophysitis and coeliac disease] . Vnitr Lek \n2010 ;56 :1169 –76 .21250496 \n27 \nKilicli F , Dokmetas HS , Acibucu F \nSheehan’s syndrome . Gynecol Endocrinol \n2013 ;29 :292 –5 . 10.3109/09513590.2012.752454 \n23245206 \n28 \nShivaprasad C \nSheehan’s syndrome: newer advances . Indian J Endocrinol Metab \n2011 ;15 Suppl 3 (Suppl3 ):203 –S7 . 10.4103/2230-8210.84869 \n\n29 \nSoresi MB , Citarrella G.; , Banco R.; , et al \nLate onset Sheehan syndrome presenting with rhabdomyolisis and hyponatremia: a case report . Journal of Medical Case Reports \n2013 ;1 :227.\n30 \nBhat MA , Laway BA , Allaqaband FA , et al \nAcute renal failure: A rare presentation of Sheehan’s syndrome . Indian J Endocrinol Metab \n2012 ;16 :306 –9 . 10.4103/2230-8210.93777 \n22470876 \n31 \nReddy RG , Aung T , Karavitaki N , et al \nOpioid induced hypogonadism . BMJ \n2010 ;341 :c4462 –c . 10.1136/bmj.c4462 \n20807731 \n32 \nOltmanns KM , Fehm HL , Peters A \nChronic fentanyl application induces adrenocortical insufficiency . J Intern Med \n2005 ;257 :478 –80 . 10.1111/j.1365-2796.2005.01483.x \n15836666 \n33 \nSchimke KE , Greminger P , Brändle M \nSecondary adrenal insufficiency due to opiate therapy - another differential diagnosis worth consideration . Exp Clin Endocrinol Diabetes \n2009 ;117 :649 –51 . 10.1055/s-0029-1202851 \n19373753 \n34 \nLee AS , Twigg SM \nOpioid-induced secondary adrenal insufficiency presenting as hypercalcaemia . Endocrinol Diabetes Metab Case Rep \n2015;2015 ;2015 :150035 \n10.1530/EDM-15-0035 \n\n35 \nSingh N , Snyder R , Krishnamurthy M , et al \nAn Under-Recognized and Under-Reported Cause of Adrenal Insufficiency . International Journal of Case Reports in Medicine \n2014 :1 –4 . 10.5171/2014.524907 \n\n36 \nMüssig K , Knaus-Dittmann D , Schmidt H , et al \nSecondary adrenal failure and secondary amenorrhoea following hydromorphone treatment . Clin Endocrinol \n2007 ;66 :604 –5 . 10.1111/j.1365-2265.2007.02779.x \n\n37 \nPetre OA \nOpioid-induced secondary adrenal insufficiency . 20th European Congress of Endocrinology 19 , Barcelona, Spain , 2018 .\n38. \nDonegan D , Bancos I \nOpioid-Induced Adrenal Insufficiency . Mayo Clin Proc \n2018 ;93 :937 –44 . 10.1016/j.mayocp.2018.04.010 \n29976376 \n39 \nPrendergast BD , George CF \nDrug-induced rhabdomyolysis-mechanisms and management . Postgrad Med J \n1993 ;69 :333 –6 .8393995 \n40 \nde Gans J , Stam J , van Wijngaarden GK \nRhabdomyolysis and concomitant neurological lesions after intravenous heroin abuse . Journal of Neurology, Neurosurgery & Psychiatry \n1985 ;48 :1057 –9 . 10.1136/jnnp.48.10.1057 \n\n41 \nSnyder M , Kish T \nSertraline-induced rhabdomyolysis: A case report and literature review . American journal of therapeutics \n2016 ;23 :561 –5 .\n42 \nRichards S , Umbreit JN , Fanucchi MP , et al \nSelective serotonin reuptake inhibitor-induced rhabdomyolysis associated with irinotecan . South Med J \n2003 ;96 :1031 –3 . 10.1097/01.SMJ.0000084311.35864.D6 \n14570350 \n43 \nLabotz M , Wolff TK , Nakasone KT , et al \nSelective serotonin reuptake inhibitors and rhabdomyolysis after eccentric exercise . Med Sci Sports Exerc \n2006 ;38 :1539 –42 . 10.1249/01.mss.0000227643.06478.c6 \n16960512 \n44 \nGrundemar L , Wohlfart B , Lagerstedt C , et al \nSymptoms and signs of severe citalopram overdose . The Lancet \n1997 ;349 :1602 \n10.1016/S0140-6736(05)61630-3 \n\n45 \nBrendel DH , Bodkin JA , Yang J \nthe Department of Psychiatry MHBMA. Massive sertraline overdose . Annals of Emergency Medicine \n2000 ;36 :524 –6 .11054208 \n46 \nDe Bellis A , Bizzarro A , Bellastella A \nPituitary antibodies and lymphocytic hypophysitis . Best Pract Res Clin Endocrinol Metab \n2005 ;19 :67 –84 . 10.1016/j.beem.2004.11.007 \n15826923 \n47 \nJolobe O , Sen I \nHyponatraemic rhabdomyolysis in Addison’s disease . Postgrad Med J \n1995 ;71 :574 \n10.1136/pgmj.71.839.574 \n\n48 \nde Witte SA , Bonnet F , Morlat P , et al \nRhabdomyolysis as a consequence of adrenal insufficiency . Am J Med \n2003 ;114 :160 \n10.1016/S0002-9343(02)01319-0 \n\n49 \nOki K , Noda K , Kondo K , et al \nRhabdomyolysis associated with hyponatremia and adrenal insufficiency . Eur J Neurol \n2006 ;13 :e8 –e9 . 10.1111/j.1468-1331.2006.01389.x \n\n50 \nSolter M , Planinc D , Gabrić I , et al \nSevere rhabdomyolysis as a first symptom in Addison’s disease . J Endocrinol Invest \n2010 ;33 :206 –7 . 10.1007/BF03346584 \n19625758 \n51 \nMuir P , Choe MS , Croxson MS \nRapid development of anterotibial compartment syndrome and rhabdomyolysis in a patient with primary hypothyroidism and adrenal insufficiency . Thyroid \n2012 ;22 :651 –3 . 10.1089/thy.2011.0136 \n22568398 \n52 \nFoppiani L , Ruelle A , Quilici P , et al \nHypopituitarism in the elderly: two case-reports with heterogeneous presentation . Aging Clin Exp Res \n2009 ;21 :76 –81 . 10.1007/BF03324902 \n19225273 \n53 \nSayarlioglu H , Erkoc R , Sayarlioglu M , et al \nSheehan syndrome presented with acute renal failure associated with rhabdomyolysis and hyponatraemia . Nephrol Dial Transplant \n2006 ;21 :827 –8 . 10.1093/ndt/gfi234 \n16263736 \n54 \nRobillon JF , Jullien D , Drai E , et al \n[Iatrogenic rhabdomyolysis and hypothyroidism revealing Sheehan’s syndrome] . Presse Med \n1994 ;23 :628 .\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1757-790X",
"issue": "12(3)",
"journal": "BMJ case reports",
"keywords": "adrenal disorders; drugs: musculoskeletal and joint diseases; muscle disease; pituitary disorders; thyroid disease",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000309:Adrenal Insufficiency; D003402:Creatine Kinase; D003937:Diagnosis, Differential; D005260:Female; D019693:Hepatitis, Autoimmune; D006801:Humans; D006854:Hydrocortisone; D008875:Middle Aged; D012206:Rhabdomyolysis",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30898957",
"pubdate": "2019-03-20",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10804689;11054208;12586241;12625411;12768237;14570350;15634713;15716291;15774072;15826923;15836666;16263736;16267412;16960512;17038029;17371484;17467517;19225273;19373753;19421855;19625758;19745609;20087196;20807731;21250496;22029025;22234976;22312376;22470876;22568398;22975551;23245206;23318858;24000014;24083446;24946698;25581857;26161260;26262437;27236159;27704605;28245451;2845381;2997401;29976376;3813679;7479479;7824421;8029196;8393995;9174567;9329360",
"title": "A case of severe rhabdomyolysis associated with secondary adrenal insufficiency and autoimmune hepatitis.",
"title_normalized": "a case of severe rhabdomyolysis associated with secondary adrenal insufficiency and autoimmune hepatitis"
} | [
{
"companynumb": "AU-ACCORD-144180",
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVOTHYROXINE"
},
"drugadditional": "3",
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{
"abstract": "In recent years, the increasing number of asphyxiation cases due to helium inhalation is remarkable. All described cases in the literature where diagnosed as suicide. In this article, however, we describe a triple infant homicide in which helium, as balloon gas, was administered to three young children after sedation causing asphyxiation and death through the medical findings and toxicological analysis. During autopsy, in addition to standard toxicological samples, gas samples from lungs as well as lung tissue itself were directly collected into headspace vials. Besides routine toxicological analysis, which revealed toxic levels of doxylamine, qualitative analysis on gas and lung samples was performed using headspace gas chromatography-mass spectrometry. As carrier gas, the commonly used helium was replaced by nitrogen. In gas samples from lungs of all three children, no helium was found. Nevertheless, lung tissue samples were found positive on helium. Therefore, sedation followed by asphyxia due to helium inhalation can strongly be assumed as the cause of death of all three children.",
"affiliations": "KU Leuven Toxicology and Pharmacology, Campus Gasthuisberg, Onderwijs en Navorsing 2, Herestraat 49, PO box 922, 3000 Leuven, Belgium.;KU Leuven Toxicology and Pharmacology, Campus Gasthuisberg, Onderwijs en Navorsing 2, Herestraat 49, PO box 922, 3000 Leuven, Belgium.;KU Leuven Toxicology and Pharmacology, Campus Gasthuisberg, Onderwijs en Navorsing 2, Herestraat 49, PO box 922, 3000 Leuven, Belgium.;KU Leuven, Imaging and Pathology Department, Division Forensic Biomedical Sciences, University of Leuven (KU Leuven), Campus Sint-Rafaël, Kapucijnenvoer 33, 3000 Leuven, Belgium.;KU Leuven, Imaging and Pathology Department, Division Forensic Biomedical Sciences, University of Leuven (KU Leuven), Campus Sint-Rafaël, Kapucijnenvoer 33, 3000 Leuven, Belgium.;KU Leuven, Imaging and Pathology Department, Division Forensic Biomedical Sciences, University of Leuven (KU Leuven), Campus Sint-Rafaël, Kapucijnenvoer 33, 3000 Leuven, Belgium.;KU Leuven, Imaging and Pathology Department, Division Forensic Biomedical Sciences, University of Leuven (KU Leuven), Campus Sint-Rafaël, Kapucijnenvoer 33, 3000 Leuven, Belgium.;KU Leuven Toxicology and Pharmacology, Campus Gasthuisberg, Onderwijs en Navorsing 2, Herestraat 49, PO box 922, 3000 Leuven, Belgium.",
"authors": "Cuypers|Eva|E|;Rosier|Elien|E|;Loix|Sara|S|;Develter|Wim|W|;Van Den Bogaert|Wouter|W|;Wuestenbergs|Joke|J|;Van de Voorde|Wim|W|;Tytgat|Jan|J|",
"chemical_list": "D006634:Histamine H1 Antagonists; D006371:Helium; D004319:Doxylamine",
"country": "England",
"delete": false,
"doi": "10.1093/jat/bkx006",
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"fulltext_license": null,
"issn_linking": "0146-4760",
"issue": "41(4)",
"journal": "Journal of analytical toxicology",
"keywords": null,
"medline_ta": "J Anal Toxicol",
"mesh_terms": "D000280:Administration, Inhalation; D001237:Asphyxia; D001344:Autopsy; D004319:Doxylamine; D006371:Helium; D006634:Histamine H1 Antagonists; D006708:Homicide; D006801:Humans; D007223:Infant; D066088:Infant Death",
"nlm_unique_id": "7705085",
"other_id": null,
"pages": "347-349",
"pmc": null,
"pmid": "28168281",
"pubdate": "2017-05-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Medical Findings and Toxicological Analysis in Infant Death by Balloon Gas Asphyxia: A Case Report.",
"title_normalized": "medical findings and toxicological analysis in infant death by balloon gas asphyxia a case report"
} | [
{
"companynumb": "BE-SA-2021SA238430",
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"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LIDOCAINE"
},
"drugadditional": null,
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{
"abstract": "Hemophagocytic lymphohistiocytosis (HLH) comprises a group of severe immune function disorders that can lead to immune-mediated organ damage. There are two subtypes of HLH: primary and secondary. Secondary HLH is associated with infectious, oncologic, chemotherapeutic, and other underlying causes, and studies on HLH triggered by tumors have mainly focused on hematological malignancies. Secondary HLH in patients with solid tumors is rare. Here, we present two cases of gastric cancer complicated with HLH. The patient 1 was diagnosed as gastric cancer at stage I and got intractable fever after a distal subtotal gastrectomy without any evidence of infections or other complications. The patient 2 suffered from unresectable gastric adenocarcinoma and got fever, hemorrhagic rashes, and petechiae in mouth after six cycles of neoadjuvant chemotherapy. After detailed and comprehensive examinations, HLH was diagnosed in the two patients according to 2004 HLH diagnostic criteria, and the patients received treatment including immunosuppressive agents immediately. After therapy, the two patients showed partial remission, but both eventually died due to HLH relapse or progression of the primary tumor. The treatment regimen for HLH is intricate, and only a few relevant studies have focused on the treatment of cancer patients with HLH. The high mortality associated with this disease calls for more attention and additional research to improve the prognosis for these patients.",
"affiliations": "Department of Gastrointestinal Surgery, Peking University People's Hospital, Beijing, China.;Department of Gastrointestinal Surgery, Peking University People's Hospital, Beijing, China.;Department of Gastrointestinal Surgery, Peking University People's Hospital, Beijing, China.;Department of Gastrointestinal Surgery, Peking University People's Hospital, Beijing, China.;Department of Gastrointestinal Surgery, Peking University People's Hospital, Beijing, China.;Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China.;Department of Gastrointestinal Surgery, Peking University People's Hospital, Beijing, China.;Department of Gastrointestinal Surgery, Peking University People's Hospital, Beijing, China.",
"authors": "Zhou|Yu-Shi|YS|;Cui|Yan-Cheng|YC|;Yin|Mu-Jun|MJ|;Xie|Qi-Wei|QW|;Shen|Zhan-Long|ZL|;Shi|Hong-Xia|HX|;Ye|Ying-Jiang|YJ|;Liang|Bin|B|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.21037/jgo-20-432",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2078-6891",
"issue": "12(2)",
"journal": "Journal of gastrointestinal oncology",
"keywords": "Hemophagocytic lymphohistiocytosis (HLH); case report; chemotherapy; gastric cancer",
"medline_ta": "J Gastrointest Oncol",
"mesh_terms": null,
"nlm_unique_id": "101557751",
"other_id": null,
"pages": "892-899",
"pmc": null,
"pmid": "34012677",
"pubdate": "2021-04",
"publication_types": "D002363:Case Reports",
"references": "28214404;15864658;28621800;21936755;16937360;23838919;27238576;31296541;2058392;29741568;28031902;28471834;27244347;24290661;30012206;29871698;25758828;26479988;30668880;19953651;29087969;30287596;26583611;22718729;17675268;11564062;32009093;30828042;32191382",
"title": "Gastric cancer complicated with hemophagocytic lymphohistiocytosis: case report and a brief review.",
"title_normalized": "gastric cancer complicated with hemophagocytic lymphohistiocytosis case report and a brief review"
} | [
{
"companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-317656",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"d... |
{
"abstract": "Eradication of chronic hepatitis C virus (HCV) infection is now possible with all oral antiviral medications, including the combination of ombitasvir, paritaprevir, dasabuvir, and ritonavir (PrOD) with or without ribavirin. While high rates of sustained virologic response (SVR) can be achieved, a small subset of patients experience on-treatment liver enzyme elevations, in particular women using concurrent estradiol-containing oral contraceptive medications (OCPs). Herein, we describe four cases of liver enzyme elevations within 2-3 weeks of PrOD initiation in African-American men infected with HCV genotype 1a or 1b. Three patients with varying degrees of hepatic fibrosis received a full treatment course without medication modification, achieved SVR, and experienced resolution of liver enzyme abnormalities. One patient with cirrhosis was switched mid-treatment to an alternate HCV regimen, experienced subsequent resolution of liver enzyme abnormalities, and achieved SVR. In summary, these cases suggest that all HCV patients treated with PrOD, independent of gender or concurrent medications, should have laboratory monitoring for liver enzyme elevations, with a particular emphasis on early monitoring in cirrhotic patients.",
"affiliations": "Division of Infectious Diseases, Department of Medicine, Medical University of South Carolina, 135 Rutledge Avenue Suite 1209, MSC 752, Charleston, SC 29425, USA; Department of Pharmacy Services, Medical University of South Carolina, 150 Ashley Avenue, Charleston, SC 29425, USA.;Institute of Human Virology, University of Maryland School of Medicine, 725 West Lombard Street, Baltimore, MD 21201, USA.;Institute of Human Virology, University of Maryland School of Medicine, 725 West Lombard Street, Baltimore, MD 21201, USA.;Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of South Carolina, 114 Doughty Street Suite 249, MSC 702, Charleston, SC 29425, USA.;Division of Infectious Diseases, Department of Medicine, Medical University of South Carolina, 135 Rutledge Avenue Suite 1209, MSC 752, Charleston, SC 29425, USA.",
"authors": "Bean|Madelyne|M|0000-0003-0780-3685;Tang|Lydia|L|;Kottilil|Shyam|S|;Beavers|Kimberly L|KL|0000-0002-6614-7633;Meissner|Eric G|EG|0000-0002-5240-7115",
"chemical_list": null,
"country": "Egypt",
"delete": false,
"doi": "10.1155/2016/6151570",
"fulltext": "\n==== Front\nCase Rep Infect DisCase Rep Infect DisCRIIDCase Reports in Infectious Diseases2090-66252090-6633Hindawi Publishing Corporation 10.1155/2016/6151570Case ReportOn-Treatment Elevation in Hepatic Transaminases during HCV Treatment with Ombitasvir, Paritaprevir, Dasabuvir, Ritonavir, and Ribavirin: A Case Series http://orcid.org/0000-0003-0780-3685Bean Madelyne \n1\n\n2\nTang Lydia \n3\nKottilil Shyam \n3\nhttp://orcid.org/0000-0002-6614-7633Beavers Kimberly L. \n4\nhttp://orcid.org/0000-0002-5240-7115Meissner Eric G. \n1\n\n*\n1Division of Infectious Diseases, Department of Medicine, Medical University of South Carolina, 135 Rutledge Avenue Suite 1209, MSC 752, Charleston, SC 29425, USA2Department of Pharmacy Services, Medical University of South Carolina, 150 Ashley Avenue, Charleston, SC 29425, USA3Institute of Human Virology, University of Maryland School of Medicine, 725 West Lombard Street, Baltimore, MD 21201, USA4Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of South Carolina, 114 Doughty Street Suite 249, MSC 702, Charleston, SC 29425, USA*Eric G. Meissner: meissner@musc.eduAcademic Editor: Tomoyuki Shibata\n\n2016 26 5 2016 2016 615157024 3 2016 8 5 2016 Copyright © 2016 Madelyne Bean et al.2016This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Eradication of chronic hepatitis C virus (HCV) infection is now possible with all oral antiviral medications, including the combination of ombitasvir, paritaprevir, dasabuvir, and ritonavir (PrOD) with or without ribavirin. While high rates of sustained virologic response (SVR) can be achieved, a small subset of patients experience on-treatment liver enzyme elevations, in particular women using concurrent estradiol-containing oral contraceptive medications (OCPs). Herein, we describe four cases of liver enzyme elevations within 2-3 weeks of PrOD initiation in African-American men infected with HCV genotype 1a or 1b. Three patients with varying degrees of hepatic fibrosis received a full treatment course without medication modification, achieved SVR, and experienced resolution of liver enzyme abnormalities. One patient with cirrhosis was switched mid-treatment to an alternate HCV regimen, experienced subsequent resolution of liver enzyme abnormalities, and achieved SVR. In summary, these cases suggest that all HCV patients treated with PrOD, independent of gender or concurrent medications, should have laboratory monitoring for liver enzyme elevations, with a particular emphasis on early monitoring in cirrhotic patients.\n==== Body\n1. Introduction\nEradication of chronic hepatitis C virus (HCV) infection is now possible with all oral regimens composed of directly acting antiviral (DAA) agents. The combination of ombitasvir (an HCV NS5A inhibitor), paritaprevir (an NS3/4A protease inhibitor), dasabuvir (a nonnucleoside NS5B polymerase inhibitor), and ritonavir (collectively referred to as PrOD) with or without ribavirin is FDA approved for treatment of genotype 1a/1b in patients with HCV monoinfection and HIV/HCV coinfection [1]. High rates of sustained virologic response (SVR) are routinely achieved, with treatment duration and concomitant ribavirin use dependent upon genotype-1 subtype and presence of cirrhosis [2–5].\n\nAn increase in serum levels of aspartate transaminase (AST) and alanine transaminase (ALT) greater than 5 times the upper limit of normal (ULN) has been observed in a minority (~1%) of patients treated with PrOD in clinical trials [1]. Women taking concomitant estradiol-containing oral contraceptive pills (OCPs) during PrOD treatment have thus far been the primary identified risk group for liver enzyme elevation [1]. In HCV monoinfected subjects, on-treatment AST/ALT elevations were noted to be typically asymptomatic, with onset in the first 4 weeks of treatment and decline within 8 weeks during continued treatment [1]. In a small study of 63 HIV/HCV patients, only 1 patient treated with PrOD and ribavirin for 24 weeks had an AST value greater than 5 times the ULN, while 15 of 17 patients with bilirubin increases 3–10x ULN were taking concomitant atazanavir for HIV [5].\n\nAlthough hepatic transaminase elevation during PrOD treatment is well reported, there are as yet no published reports describing in detail the temporal changes in AST/ALT that can occur to help guide expectations for clinicians and aid in patient management. With the recent report of hepatic decompensation in a subset of cirrhotic patients treated with PrOD, particularly those with more advanced cirrhosis [6], understanding the clinical characteristics of this uncommon side effect is imperative. Here, we describe the detailed clinical course for 4 African-American male patients treated with PrOD with or without ribavirin who developed on-treatment elevation in AST/ALT, all of whom demonstrate a clinical scenario similar to that described for women on OCPs, and all of whom achieved SVR with treatment.\n\n2. Case Presentation\n2.1. Case 1\nA 62-year-old presented with treatment-naïve, HCV genotype 1b infection, and well-controlled HIV coinfection on a regimen of emtricitabine, tenofovir, atazanavir, and ritonavir with a CD4 count of 580 cells/mm3 and an HIV viral load < 40 copies/mL. Liver biopsy in 2004 revealed stage 0 disease, liver staging by Fibrosure in 2012 suggested F3-F4 disease (measured while taking atazanavir), and a 1.9 cm liver biopsy in 2013 again revealed stage 0 disease. Additional noninvasive staging revealed a FIB4 score of 2.3 and an APRI score of 0.89. Ultrasonography revealed normal liver size and echogenicity, with no evidence of portal hypertension or splenomegaly. Baseline labs included HCV viral load 61,251 IU/mL, platelets 158,000/mm3, ALT 83 IU/mL, AST 56 IU/mL, albumin 4.0 g/dL, and total bilirubin 2.0 IU/mL (bilirubin elevation likely due to atazanavir). He had no other significant past medical history or medication use, other than receiving azithromycin for chlamydia urethritis 3 days prior to initiating PrOD therapy for 12 weeks without ribavirin. Safety labs obtained at week 1 of treatment revealed an elevation in AST/ALT over pretreatment values (Figure 1(a)). During continued treatment, he remained asymptomatic and had frequent laboratory checks, including direct bilirubin to monitor for drug-induced liver injury, as baseline indirect bilirubin was elevated due to atazanavir. By week 7 hepatic transaminases had declined markedly from their peak (Figure 1(a)). No medication modifications were made during PrOD treatment, and he achieved SVR 12 weeks after treatment with liver enzymes in the normal range.\n\n2.2. Case 2\nA 61-year-old presented with treatment-naïve, HCV genotype 1a monoinfection with liver biopsy 3 years prior to treatment revealing stage 1-2 fibrosis and FibroScan 2 months prior to treatment showing a stiffness score of 9.5 kPa, suggesting F2-F3 disease. Additional noninvasive staging revealed a FIB4 score of 2.3 and an APRI score of 0.68. Baseline labs included HCV viral load 11.6 million IU/mL, platelets 162,000/mm3, ALT 52 U/L, AST 44 U/L, albumin 4.4 g/dL, and total bilirubin 0.9 mg/dL. Past medical history included spinal fusion surgery, hypertension (not on medications), and hyperlipidemia (on pravastatin 40 mg daily, a dose that did not require modification) [1]. PrOD was initiated for 12 weeks with weight-based ribavirin. At week 4 of treatment, an elevation in AST/ALT over baseline values was observed (Figure 1(b)). He reported mild side effects from therapy including fatigue, headache, insomnia, and itching that all resolved by week 4 of treatment. PrOD and ribavirin therapy were continued, he remained asymptomatic, and 12 weeks after treatment AST/ALT were in the normal range and HCV RNA was undetectable, indicating SVR.\n\n2.3. Case 3\nA 63-year-old presented with treatment-naïve, genotype 1a HCV monoinfection, with liver biopsy 4 years prior to treatment revealing stage 2-3 disease. Prior to treatment, noninvasive staging revealed a FIB4 score of 1.6 and an APRI score of 0.35. Baseline labs included HCV viral load 1.1 million IU/mL, platelets 194,000/mm3, ALT 28 U/L, AST 27 U/L, albumin 4.1 g/dL, and total bilirubin 1.5. Past medical history included hypertension, for which he took amlodipine and hydrochlorothiazide. PrOD was initiated for 12 weeks with weight-based ribavirin. At week 2 of treatment, labs revealed an elevation in AST/ALT over baseline values (Figure 1(c)). He was asymptomatic and treatment was continued without dose modification. By week 3, hepatic transaminases were declining and normalized by week 8. Hemoglobin and hematocrit remained stable throughout the treatment course and the patient achieved SVR.\n\n2.4. Case 4\nAn 82-year-old presented with treatment-naïve, genotype 1a HCV monoinfection with FibroScan 4 months prior to treatment revealing a stiffness score of 14 kPa, suggesting cirrhosis. Noninvasive staging scores were FIB4 4.6 and APRI 1.3. Liver ultrasound revealed changes consistent with cirrhosis and no concerning masses. Pretreatment labs included HCV viral load 46,382 IU/mL, platelets 160,000/mm3, ALT 86 U/L, AST 84 U/L, albumin 3.6 g/dL, and total bilirubin 1.5 U/L. Past medical history included hypertension (on hydrochlorothiazide), chronic idiopathic peripheral neuropathy (on gabapentin), and cecal adenocarcinoma treated surgically. Patient evaluation at treatment initiation did not reveal any signs of decompensated cirrhosis. Treatment with PrOD with weight-based ribavirin was initiated. At week 2, safety labs revealed unchanged AST/ALT values and a slight increase in total bilirubin (Figure 1(d)), as well as a decline in hemoglobin and hematocrit from 15.3/45.2 g/L to 13.5/38.3 g/L, respectively. He was asymptomatic and treatment was continued without dose modification. By week 4 of treatment, AST/ALT had increased while total bilirubin remained stable (Figure 1(d)) and he reported mild foot swelling, not present prior to treatment initiation. Physical exam confirmed bilateral 1+ pitting edema on the dorsum of his feet. At week 5 of treatment, hemoglobin and hematocrit had declined to 11.7/35.4, respectively, and bilateral pedal edema had increased to 2+. Ribavirin dose was reduced from 1200 mg/day to 600 mg/day. By week 7 of treatment, AST/ALT had increased further (Figure 1(d)), hemoglobin and hematocrit remained stable, and creatinine had increased from 1.34 at baseline to 2.15 mg/dL. He remained asymptomatic and had stable foot swelling that was relieved by use of compression stockings. PrOD and ribavirin therapy were stopped and the patient continued HCV therapy with ledipasvir-sofosbuvir. At week 10 of total HCV therapy (week 3 of ledipasvir-sofosbuvir) serum creatinine and AST/ALT had returned to baseline and remained normal thereafter (Figure 1(d)). He completed a total of 8 weeks of ledipasvir-sofosbuvir following the 7 weeks of PrOD and ribavirin. Foot swelling persisted throughout treatment but had resolved by 28 weeks after initiation of treatment when SVR was achieved.\n\n3. Discussion\nHerein, we present a detailed clinical description of AST/ALT elevations that can occur during PrOD therapy, with or without ribavirin, for chronic HCV genotype-1 infection. Although caution is recommended with concomitant use of estradiol-containing oral contraceptive medications [1], all 4 subjects in our series were African-American males with advancing age and differing degrees of hepatic fibrosis, including 1 patient with cirrhosis. All completed HCV treatment, with therapy modification in 1 case, and all achieved SVR. No medications or comorbidities were shared amongst these patients in terms of an alternate etiology for the observed pattern of hepatic transaminases.\n\nAside from a higher risk of AST/ALT elevations reported in women taking concomitant estrogen therapy during PrOD therapy, there are no reports of other specific patient factors related to an increased incidence of enzyme alterations that may help clinicians target patients for close monitoring or anticipate liver enzyme elevations. This report indicates and suggests that these abnormalities can occur in African-American men with advanced age and highlights the importance of close lab monitoring during treatment in cirrhotic patients in light of new FDA warnings for risk of liver toxicity with PrOD use. To determine whether age, race, and gender are significant risk factors for ALT elevation during PrOD therapy would require observation in a larger cohort of treated patients. Of note, none of our patients had a liver enzyme pattern suggestive of drug-induced liver injury. For case 4, therapy was switched during the peak of AST/ALT elevation and within the reported typical window of lab abnormality resolution, and thus it is challenging to know whether hepatic transaminases would have resolved without a switch in therapy.\n\nIn summary, these cases suggest that all PrOD patients should have monitoring as early as week 2 of treatment to monitor for abnormalities, with a particular emphasis on early monitoring in cirrhotic patients. While the patients with advanced liver disease who experienced liver injury associated with PrOD suggested that elevated transaminases were not as prominent a feature of their presentation as that reported in the package insert [6], close monitoring in the setting of cirrhosis remains a recommendation. For HIV/HCV coinfected patients on antiretroviral therapy containing atazanavir, direct bilirubin should be utilized to monitor for drug-induced liver injury given elevations in indirect bilirubin as a result of atazanavir use. Importantly, these cases also highlight that AST/ALT elevations for those without cirrhosis did not have an apparent clinical consequence and all patients progressed to achieve SVR.\n\nCompeting Interests\nDr. Meissner receives institutional research support from Gilead Sciences.\n\nFigure 1 Liver enzyme progression for individual patients. EOT: end of treatment; ALP: alkaline phosphatase.\n==== Refs\n1 Viekira Pak, AbbVie, Inc, Chicago, Ill, USA, December 2014 \n2 Feld J. J. Kowdley K. V. Coakley E. Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin The New England Journal of Medicine 2014 370 17 1594 1603 10.1056/nejmoa1315722 2-s2.0-84899068302 24720703 \n3 Poordad F. Hezode C. Trinh R. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis New England Journal of Medicine 2014 370 21 1973 1982 10.1056/NEJMoa1402869 2-s2.0-84901036125 24725237 \n4 Ferenci P. Bernstein D. Lalezari J. ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV The New England Journal of Medicine 2014 370 21 1983 1992 10.1056/nejmoa1402338 2-s2.0-84901044326 24795200 \n5 Sulkowski M. S. Eron O. J. Wyles D. Ombitasvir, paritaprevir co-dosed with ritonavir, dasabuvir, and ribavirin for hepatitis C in patients co-infected with HIV-1 a randomized trial JAMA-Journal of the American Medical Association 2015 313 12 1223 1231 10.1001/jama.2015.1328 2-s2.0-84925428093 \n6 U.S. Food and Drug Administration (FDA) FDA Drug Safety Communication: FDA warns of serious liver injury risk with hepatitis C treatments Viekira Pak and Technivie, October 2015, http://www.fda.gov/Drugs/DrugSafety/ucm468634.htm\n\n",
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"title": "On-Treatment Elevation in Hepatic Transaminases during HCV Treatment with Ombitasvir, Paritaprevir, Dasabuvir, Ritonavir, and Ribavirin: A Case Series.",
"title_normalized": "on treatment elevation in hepatic transaminases during hcv treatment with ombitasvir paritaprevir dasabuvir ritonavir and ribavirin a case series"
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"abstract": "BACKGROUND\nProton pump inhibitors (PPIs) are widely prescribed and generally well tolerated but can rarely cause severe allergic reactions, such as drug rash with eosinophilia and systemic symptoms (DRESS). We report a case of DRESS and renal injury induced by PPIs, and describe the therapeutic process.\nThe patient was a 66-year-old female who complained of fever, pruritus, desquamation, erythema multiforme, and anuria caused by omeprazole taken for 2 weeks to treat abdominal distention.\n\n\nMETHODS\nThe clinical history revealed a similar episode of PPI-induced fever, eosinophilia, and acute kidney injury more than 1 year ago. The present laboratory tests revealed eosinophilia and oliguric renal failure. The renal biopsy was performed subsequently and proved the diagnosis of PPI-induced DRESS.\n\n\nMETHODS\nAfter the suspected diagnosis of PPI-induced DRESS, omeprazole was discontinued and methylprednisolone infusion (40 mg qd) was initiated. Because of oliguric renal failure, the patient received intermittent hemodialysis.\n\n\nRESULTS\nThe patient initially responded to omeprazole discontinuation, hemodialysis, and glucocorticoids but later died from severe infection during the tapering of glucocorticoid therapy.\n\n\nCONCLUSIONS\nClinicians should remain on high alert for potential life-threatening complications when prescribing PPIs. If unexplained renal injury develops in a patient taking a PPI, renal biopsy may help in identifying the pathogenesis and might facilitate timely intervention.",
"affiliations": "Department of Nephrology, Beilun People's Hospital, Ning Bo.;Department of Nephrology, Beilun People's Hospital, Ning Bo.;Department of Nephrology, Beilun People's Hospital, Ning Bo.;Department of Nephrology, Beilun People's Hospital, Ning Bo.;Department of Nephrology, Beilun People's Hospital, Ning Bo.;Department of Nephrology, Beilun People's Hospital, Ning Bo.;Department of Nephrology, Beilun People's Hospital, Ning Bo.;Department of Nephrology, Beilun People's Hospital, Ning Bo.;Department of Nephrology, Beilun People's Hospital, Ning Bo.;Department of Nephrology, Beilun People's Hospital, Ning Bo.",
"authors": "He|Qien|Q|;Ying|Guanghui|G|;Fei|Xiapei|X|;Zha|Chenqin|C|;Chen|Zhaogui|Z|;Bao|Yishu|Y|;Long|Jiaorong|J|;Wang|Zhujun|Z|;He|Xuelin|X|;Xia|Min|M|",
"chemical_list": "D054328:Proton Pump Inhibitors; D009853:Omeprazole",
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"doi": "10.1097/MD.0000000000022509",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974 1536-5964 Lippincott Williams & Wilkins Hagerstown, MD \n\nMD-D-19-07835\n10.1097/MD.0000000000022509\n22509\n4000\nResearch Article\nClinical Case Report\nDrug rash with eosinophilia and systemic symptoms and severe renal injury induced by proton pump inhibitor therapy\nA case reportHe Qien BSa Ying Guanghui MSa Fei Xiapei MSa Zha Chenqin MSa Chen Zhaogui MSa Bao Yishu BSa Long Jiaorong MSa Wang Zhujun MSa He Xuelin MDabcd Xia Min MSa∗ Saranathan. Maya a Department of Nephrology, Beilun People's Hospital, Ning Bo\nb Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University\nc Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province\nd The Third Grade Laboratory under the National State, Administration of Traditional Chinese Medicine, Hangzhou, Zhejiang, China.\n∗ Correspondence: Min Xia, Department of Nephrology, Beilun People's Hospital, Ning Bo, Zhejiang, China (e-mail: xiamin9898@qq.com).\n16 10 2020 \n16 10 2020 \n99 42 e2250920 10 2019 3 7 2020 2 9 2020 Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.2020This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nIntroduction:\nProton pump inhibitors (PPIs) are widely prescribed and generally well tolerated but can rarely cause severe allergic reactions, such as drug rash with eosinophilia and systemic symptoms (DRESS). We report a case of DRESS and renal injury induced by PPIs, and describe the therapeutic process.\n\nPatient concerns:\nThe patient was a 66-year-old female who complained of fever, pruritus, desquamation, erythema multiforme, and anuria caused by omeprazole taken for 2 weeks to treat abdominal distention.\n\nDiagnosis:\nThe clinical history revealed a similar episode of PPI-induced fever, eosinophilia, and acute kidney injury more than 1 year ago. The present laboratory tests revealed eosinophilia and oliguric renal failure. The renal biopsy was performed subsequently and proved the diagnosis of PPI-induced DRESS.\n\nInterventions:\nAfter the suspected diagnosis of PPI-induced DRESS, omeprazole was discontinued and methylprednisolone infusion (40 mg qd) was initiated. Because of oliguric renal failure, the patient received intermittent hemodialysis.\n\nOutcomes:\nThe patient initially responded to omeprazole discontinuation, hemodialysis, and glucocorticoids but later died from severe infection during the tapering of glucocorticoid therapy.\n\nConclusion:\nClinicians should remain on high alert for potential life-threatening complications when prescribing PPIs. If unexplained renal injury develops in a patient taking a PPI, renal biopsy may help in identifying the pathogenesis and might facilitate timely intervention.\n\nKeywords\nDRESSsevere renal injuryPPINingbo city department level project2019 ky654Qien HeOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nDrug rash with eosinophilia and systemic symptoms (DRESS) is a severe delayed-type hypersensitivity syndrome associated with erythema multiforme-type drug eruption and life-threatening systemic manifestations that primarily involve the liver, kidneys, lungs, and pancreas.[1] DRESS is clinically divided into immediate and delayed types. Immediate-type DRESS is considered an immunoglobulin E (IgE)-mediated type-I hypersensitivity reaction,[2–4] whereas delayed-type DRESS is thought to involve a T cell-mediated hypersensitivity reaction.[5] Although proton pump inhibitors (PPIs) rarely cause DRESS,[6] these drugs have been reported to cause hypersensitivity reactions in 0.2% to 3% of cases,[7] with a mortality rate of 10%.[8] Previous studies have reported DRESS syndrome induced by a variety of PPIs, including rabeprazole, pantoprazole, esomeprazole, lansoprazole, and omeprazole.[5,9–12]\n\nHere, we present the case of a woman who died following the repeat occurrence of DRESS syndrome and renal failure caused by a 2-week course of omeprazole taken to treat symptoms of abdominal distention. The patient had developed DRESS syndrome in response to PPI therapy the previous year but had not received a renal biopsy or regular follow-up after the first episode. This case highlights the need for clinicians to remain on high alert for potential life-threatening complications when prescribing PPIs and to consider renal biopsy in cases of unexplained renal injury during therapy with a PPI.\n\n2 Case presentation\nOn August 28, 2015, a 66-year-old Chinese woman was admitted to Beilun People's Hospital (Ningbo, China) with symptoms of fever, rash, chest tightness, and anuria, and a provisional diagnosis of renal failure was made. The patient had started a course of oral omeprazole (20 mg qd; purchased from a drug store) 2 weeks before admission due to symptoms of abdominal distension. In the week prior to admission, the patient had gradually developed pruritus and a rash over her whole body (including the limbs), with features that included desquamation, papules, macules, partially integrated blisters, and scabs (Fig. 1).\n\nFigure 1 Pruritus and rash over the whole body (including the limbs) of the patient, with features that include desquamation, papules, macules, partially integrated blisters, and scabs.\n\nThe patient denied a history of chronic diseases, such as hypertension or diabetes, or the long-term use of traditional Chinese medicines (a potential cause of renal injury). However, the patient had developed DRESS and acute renal failure after PPI therapy more than 1 year before the current admission. Specific details of the previous episode of DRESS are as follows: On July 1, 2014, the patient was admitted to a local hospital because of cough and gastrointestinal symptoms, such as nausea and vomiting. No abnormalities were detected in basic renal function tests (serum creatinine concentration, 75 μmol/L) or in a routine urine test. Three days later, the patient developed fever, cough, abdominal pain, nausea, and vomiting. She was treated initially with omeprazole infusion (40 mg qd) and then with long-term (>1 month) PPI therapy that included omeprazole, pantoprazole, and esomeprazole, in succession. Subsequently, the patient developed a fever (>38.5 °C) without any rash. Routine blood tests revealed an increase in eosinophil count (as high as 2.55 × 109/L; normal range, 0.1–0.4 × 109/L) and eosinophil proportion (as high as 20.1%; normal range, 0.4%–3%). A routine urine test was positive for leukocytes (an eosinophil granulocyte test was not conducted) but negative for proteinuria and microscopic hematuria. The patient received continuous renal replacement therapy (CRRT) for oliguria and acute renal failure for more than 2 weeks, which restored her serum creatinine level to 100 μmol/L. However, the patient did not undergo a renal biopsy after the completion of CRRT and was not followed-up during the subsequent year.\n\nThe blood hematology and biochemistry findings on admission of the patient to our hospital were as follows: leukocyte count, 8.7 × 109/L (normal range, 3.6–11.0 × 109/L), eosinophil count, 0.83 × 109/L (normal range, 0.1–0.4 × 109/L), eosinophil proportion, 9.6% (normal range, 0.4%–3%), hemoglobin concentration, 56 g/L (normal range, 115–165 g/L), platelet count, 108 × 109/L (normal range, 140–400 × 109/L), serum creatinine concentration, 1181 μmol/L (normal range, 45–84 μmol/L), blood urea nitrogen, 57.9 mmol/L (normal range, 2.5–7.0 mmol/L), and K+ concentration 7.17 mmol/L (normal range, 3.5–5.5 mmol/L). Erythrocyte sedimentation rate was normal. Arterial blood gas analysis showed severe metabolic acidosis (pH, 7.03 [normal range, 7.36–7.44]; HCO3−, 2 mmol/L [normal range, 22–28 mmol/L]; base excess, 28 mmol/L [normal range, ± 2 mmol/L]); and hyponatremia (Na+, 123 mmol/L; normal range, 133–146 mmol/L). Color Doppler ultrasonography of the urinary system showed that the sizes of the two kidneys were 102 × 48 mm and 98 × 47 mm, respectively, and that the bilateral renal cortex was about 4 mm in thickness. Routine urine tests were positive for glucose (2+), protein (+), and red blood cells (+ or 2+). The concentration of urinary α1-microglobulin was 21.9 mg/dL, and that of urinary micro-albumin was 36 mg/dL. Tests for the presence of anti-myeloperoxidase (MPO) antibody in peripheral blood produced weak positive results on two occasions. Tests for perinuclear and cytoplasmic anti-neutrophil cytoplasmic antibodies (p-ANCA and c-ANCA) were negative. Blood culture and echocardiography showed no abnormalities, and there was no swelling of the superficial lymph nodes. The patient subsequently received intermittent hemodialysis.\n\nA diagnosis of PPI-induced DRESS was suspected based on the rapid development of fever, rash, and acute renal failure after the patient had started taking omeprazole. The skin lesions were also considered to be a drug rash upon consultation with dermatologists.\n\nThe criteria suggested by the Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) are widely used for assessing the probability of an adverse drug reaction.[13] According to this scoring system, a case for DRESS can be estimated as follows: fever ≥38.5 °C (0 point), enlarged lymph nodes (0 point), eosinophilia >1.5 × 109/L (2 point), atypical lymphocytes (0 point), organ involvement (2 points), resolution ≥15 days (0 point), skin rash >50% of the body surface area (1 point), skin rash suggesting DRESS (1 point), organ involvement including the kidneys and digestive system (2 point), and negative evaluation of other potential causes (1 point). The RegiSCAR score of 9 points indicates that the case presented here was definitely of DRESS.\n\nA renal biopsy on day 18 of hospitalization revealed severe and chronic injury to the renal tubules and interstitium, accompanied by glomerular ischemia and shrinkage. Immunohistochemical analysis showed that most renal interstitial lymphocytes were CD3+/MPO+ neutrophils with a small number of CD20+ lymphocytes and CD38+ interstitial cells. Furthermore, there was diffuse atrophy of kidney tubules, proliferation of interstitial collagen fibers, and infiltration of lymphocytes, and occasional presence of eosinophils (see Figs. 2 and 3 for details). Electron microscopy showed vacuolar degeneration of the capillary endothelium and narrowing of the lumen of capillaries.\n\nFigure 2 Hematoxylin and eosin staining of renal biopsy specimens showing chronic tubular-interstitial inflammation, diffuse atrophy of the renal tubular epithelium, extensive lymphocytic infiltration of the renal interstitial, and occasionally eosinophils (200×).\n\nFigure 3 Periodic acid–Schiff staining showing glomerular ischemic changes; fibrosis can be seen around the balloon, and the capillary vasospasm is contracted by ischemia. Renal tubular epithelial cells showing vacuoles, granule degeneration, and a small amount of protein casts and diffuse atrophy. Renal interstitial showing lymphocytes and mononuclear cell infiltration with fibrosis, vitreous changed in the wall of the arterioles, increased thickness of the wall of small arteries, intimal hyperplasia, stenosis of the lumen, no cellulose-like necrosis (200×).\n\nTreatment with methylprednisolone infusion (40 mg qd) was initiated on day 7 of hospitalization, and the rash resolved after 1 week of therapy. The medication was switched from glucocorticoid to oral prednisone (40 mg qd) after 2 weeks of methylprednisolone therapy. Subsequently, a series of investigations demonstrated a decrease in the count and proportion of eosinophils to normal levels, an increase in urinary volume, a fall in serum creatinine to 262 to 276 μmol/L, and a glomerular filtration rate (GFR; estimated using the Modification of Diet in Renal Disease [MDRD] formula) of 25 mL/min. Dialysis was successfully discontinued after 3 weeks of steroid therapy (hemodialysis was given intermittently for a total of 10 sessions). The patient was discharged on day 28 (September 25, 2015) of hospitalization and prescribed prednisone tablets at an initial dose of 35 mg/day, with tapering of the dose by one tablet (5 mg) every 2 weeks. However, severe pulmonary infection and respiratory failure developed ∼2 months after the initiation of steroid therapy. The patient was admitted to hospital, the trachea was cannulated, and a diagnosis of invasive pulmonary aspergillosis (IPA) was made following bronchial brushing during bronchoscopy. Despite the initiation of anti-fungal therapy with caspofugin (Cancidas) and fluconazol, the patient exhibited progressive deterioration of renal function and died on December 8, 2015.\n\n3 Discussion\nWhile dermatologists usually focus on the varied cutaneous manifestations of DRESS, nephrologists are concerned with the renal injury that results from drug-induced acute interstitial nephritis (AIN). DRESS often affects the function of the renal tubules and interstitium and, thus, results in polyuria and glycosuria; however, the syndrome rarely results in kidney failure. Omeprazole-induced AIN was first described in 1992,[14] and all PPIs currently on the market, including pantoprazole,[15] omeprazole,[16] rabeprazole,[17] esomeprazole,[18] and lansoprazole,[19] have been reported to induce AIN. The incidence of PPI-induced AIN is 2 to 20 per 100,000[7,20] and is not related to the drug dosage, suggesting the importance of individual factors, such as an allergic predisposition.[20] The pathogenesis of PPI-induced DRESS is not fully characterized but may involve the deposition of a hapten with the drug (or its metabolite) in the tubulointerstitium, direct stimulation of the abnormal expression of T-cells, or Th1- and Th17-mediated inflammatory processes.[21] Furthermore, genetic polymorphism of CYP2C19 that slows the metabolism of PPIs is thought to increase the risk of acute renal injury.[5,20,22]\n\nThe case reported here relates to the recurrence of DRESS syndrome and impaired renal function after the repeated use of PPIs. On both occasions, the patient developed renal failure that required renal replacement therapy. Generally, renal injury occurs within 2 to 6 weeks after exposure to the causative drug. In this case, the patient relapsed 1 year after the initial episode of DRESS due to re-administration of a PPI, which, to the best of our knowledge, has not been described previously. The patient in this case report was found to have chronic interstitial nephritis, whereas the pathologic manifestations of PPI-induced acute renal injury are generally those of acute allergic intestinal nephritis.[7,14–19]\n\nAcute renal injury caused by PPIs is histologically manifested as an infiltration of mixed inflammatory cells (lymphocytes, eosinophils, plasma cells, and isolated groups of neutrophils) in the renal interstitium.[7,17,23] Geevasinga et al identified 18 cases of biopsy proven PPI-induced AIN causing AKI in a retrospective case review.[17] A growing body of literature and case reports confirms that PPI therapy is linked to acute kidney injury, which can potentially lead to chronic kidney disease (CKD) and end-stage renal disease (ESRD).[24–26]\n\nThe pathologic changes underlying the development of chronic interstitial nephritis in the present case may have involved the initial occurrence of AIN and edema (during the first episode of PPI-induced DRESS), which then gradually progressed to renal interstitial fibrosis, tubular atrophy, and glomerular sclerosis.[27] The pathological finding in the present case is in line with the role of acute injury in CKD, as reported in literature. The exact pathology of CKD caused by PPIs has not been previously reported for any case.\n\nOne of the factors that likely contribute to the development of chronic interstitial nephritis in patients with PPI-induced AIN is a missed or delayed diagnosis due to the atypical clinical manifestations of hypersensitivity reactions caused by PPIs. For example, fewer than half of the cases have fever, <10% develop a rash, about one-third manifest hypereosinophilia, and only 5% to 10% present with typical symptoms of a hypersensitivity reaction.[28] Because it can take several weeks or even months to confirm a diagnosis of AIN after the development of symptoms, some patients inevitably develop chronic renal interstitial fibrosis before treatment can be initiated.[28,29]\n\nIt has been reported that renal function does not recover to the baseline in a substantial proportion of patients with PPI-induced AIN despite discontinuation of the causative drug and treatment with steroids.[7] Furthermore, long-term administration of PPIs may increase the risk of chronic renal injury. For example, when compared with H2 receptor antagonists, long-term PPI use is associated with a higher risk of renal disease that progresses to CKD and ESRD.[24,30,31] We suggest that renal biopsy may represent a useful technique for characterizing the pathological changes underlying the progression of AIN to chronic renal injury.[30,32] Furthermore, the use of renal biopsy could help in increasing our understanding of the factors influencing the prognosis of renal disease caused by long-term PPI use and the ability of renal function to recover after discontinuation of the drug.\n\nThere is also cross-reactivity in PPI-induced AIN, necessitating a skin prick test before the use of an alternative PPI and systemic desensitization for those who must use it.[3] A recent case report described acute renal injury caused by the administration of two different PPIs (omeprazole first, pantoprazole later) to the same individual.[33] The present case reported the prior use of three different PPIs (omeprazole, pantoprazole, and esomeprazole), suggesting that cross-reactivity may have contributed to the development of renal injury. Only two previous case reports have suggested that omeprazole[34] and pantoprazole[35] can induce ANCA-related vasculitis, and immunofluorescence microscopy of renal biopsy specimens demonstrated deposition of oligoimmune complex in a patient treated with pantoprazole.[35] The renal biopsy specimens from the patient reported here were positive for IgM antibody but negative for other antibodies, such as IgG and IgA, which is consistent with the deposition of oligoimmune complex. However, the underlying mechanism is still unclear. In this case, the patient also tested positive for the anti-MPO antibody, which was deposited in the renal interstitium (see Fig. 4 for details). To the best of our knowledge, this is a novel finding that has not been described in previous studies.\n\nFigure 4 Myeloperoxidase staining of the renal interstitium. The arrow indicates the positively stained cells (200×).\n\nThe established treatment of drug-induced AIN involves discontinuation of the drug and administration of a glucocorticoid as an immunosuppressant.[36,37] Early intervention with a glucocorticoid agent upon confirmation of renal pathology is thought to reduce the risk of renal interstitial fibrosis and facilitate the recovery of impaired renal function[38] However, early diagnosis and intervention to prevent renal failure require close cooperation between physicians from different departments, in particular nephrology and pathology. Pathologic markers to guide therapy (such as the ratio of glomerular sclerosis to renal tubular atrophy, the degree of renal arteriolar occlusion, or the extent of interstitial fibrosis) are yet to be established. Nonetheless, it is envisaged that the development of standardized methods to evaluate the severity of interstitial nephritis and disease chronicity will facilitate decision-making by clinicians in the future.\n\nPPIs are over-the-counter drugs that are widely used without prescription.[28] Many clinicians have expressed concerns about the safety implications of the misuse of PPIs due to widespread availability of these drugs and a lack of regulation.[20,39,40] PPIs are more frequently used by the elderly population than by the young people, which may contribute to a higher prevalence of AIN and CKD as well as a higher proportion of patients in need of dialysis.[29]\n\nThe following factors may significantly affect the clinical outcomes—lack of the awareness of PPI-induced AKI or other types of allergic manifestations, individual allergic idiosyncrasy, time of identification after the onset of PPI hypersensitivity reaction, therapeutic drug reaction to this syndrome.[41]\n\nMost patients with PPI-induced DRESS can achieve a good prognosis if confirmation of the diagnosis, discontinuation of the PPI, and initiation of glucocorticoid-based therapy are performed in a timely manner.[11] However, the early diagnosis and treatment of PPI-induced DRESS requires a multidisciplinary approach. The present case highlights the need for clinicians to remain on high alert for potential life-threatening complications when prescribing PPIs. Furthermore, renal biopsy may help in identifying the pathogenesis and facilitate timely intervention in patients who develop unexplained renal injury after starting a course of PPI therapy.\n\nAuthor contributions\nConception and design: Min Xia.\n\nAdministrative support: Min Xia, Xuelin He.\n\nProvision of study materials or patients: Guanghui Ying, Xiapei Fei, Chenqin Zha, haogui Chen, Yishu Bao.\n\nCollection and assembly of data: Qien He, Zhujun Wang,Min Xia.\n\nData analysis and interpretation: Qien He.\n\nManuscript writing: All authors.\n\nFinal approval of manuscript: All authors.\n\nAbbreviations: AIN = acute interstitial nephritis, c-ANCA = cytoplasmic anti-neutrophil cytoplasmic antibodies, CRRT = continuous renal replacement therapy, DRESS = drug rash with eosinophilia and systemic symptoms, IgE = immunoglobulin E, IPA = invasive pulmonary aspergillosis, MPO = anti-myeloperoxidase, p-ANCA = perinuclear cytoplasmic anti-neutrophil cytoplasmic antibodies, PPIs = proton pump inhibitors.\n\nHow to cite this article: He Q, Ying G, Fei X, Zha C, Chen Z, Bao Y, Long J, Wang Z, He X, Xia M. Drug rash with eosinophilia and systemic symptoms and severe renal injury induced by proton pump inhibitor therapy: A case report. Medicine. 2020;99:42(e22509).\n\nThis study was supported by Ningbo City Department Level project [2019 ky654].\n\nWritten informed consent was obtained from the patient/her relative for publication of this report.\n\nThe authors have no conflicts of interest to disclose.\n\nThis is a case report, and the relevant case information has been fully provided in the article.\n\nThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nData sharing not applicable to this article as no datasets were generated or analyzed during the current study.\n\nAll data generated or analyzed during this study are included in this published article [and its supplementary information files]\n\nThe data that support the findings of this study are available from a third party, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are available from the authors upon reasonable request and with permission of the third party.\n==== Refs\nReferences\n[1] Lin CY Wang CW Hui CR \nDelayed-type hypersensitivity reactions induced by proton pump inhibitors: a clinical and in vitro T-cell reactivity study\n. Allergy \n2018 ;73 :221 –9\n.28658503 \n[2] Kepil Özdemir S Öner Erkekol F Ünal D \nManagement of hypersensitivity reactions to proton pump inhibitors: a retrospective experience\n. Int Arch Allergy Immunol \n2016 ;171 :54 –60\n.27838693 \n[3] Otani IM Banerji A \nImmediate and delayed hypersensitivity reactions to proton pump inhibitors: evaluation and management\n. Curr Allergy Asthma Rep \n2016 ;16 :17 .26810177 \n[4] Lobera T Navarro B Del Pozo MD \nNine cases of omeprazole allergy: cross-reactivity between proton pump inhibitors\n. J Investig Allergol Clin Immunol \n2009 ;19 :57 –60\n.\n[5] Bose S Guyer A Long A \nEvaluation and management of hypersensitivity to proton pump inhibitors\n. Ann Allergy Asthma Immunol \n2013 ;111 :452 –7\n.24267357 \n[6] Lombardo C Bonadonna P \nHypersensitivity reactions to proton pump inhibitors\n. Curr Treat Options Allergy \n2015 ;2 :110 –23\n.\n[7] Simpson IJ Marshall MR Pilmore H \nProton pump inhibitors and acute interstitial nephritis: report and analysis of 15 cases\n. Nephrology (Carlton) \n2006 ;11 :381 –5\n.17014549 \n[8] Roujeau JC Stern RS \nSevere adverse cutaneous reactions to drugs\n. N Engl J Med \n1994 ;331 :1272 –85\n.7794310 \n[9] Kepil Özdemir S Yilmaz I Aydin Ö \nImmediate-type hypersensitivity reactions to proton pump inhibitors: usefulness of skin tests in the diagnosis and assessment of cross-reactivity\n. Allergy \n2013 ;68 :1008 –14\n.23895584 \n[10] Caboni S Gunera-Saad N Ktiouet-Abassi S \nEsomeprazole-induced DRESS syndrome. Studies of cross-reactivity among proton-pump inhibitor drugs\n. Allergy \n2007 ;62 :1342 –3\n.17711546 \n[11] Bourneau-Martin D Leclech C Jamet A \nOmeprazole-induced drug reaction with eosinophilia and systemic symptoms (DRESS)\n. Eur J Dermatol \n2014 ;24 :413 –5\n.24751668 \n[12] Barbaud A Collet E Milpied B \nA multicentre study to determine the value and safety of drug patch tests for the three main classes of severe cutaneous adverse drug reactions\n. Br J Dermatol \n2013 ;168 :555 –62\n.23136927 \n[13] Kardaun SH Sidoroff A Valeyrie-Allanore L \nVariability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist?\n\nBr J Dermatol \n2007 ;156 :609 –11\n.17300272 \n[14] Ruffenach SJ Siskind MS Lien YH \nAcute interstitial nephritis due to omeprazole\n. Am J Med \n1992 ;93 :472 –3\n.1341422 \n[15] Ra A Tobe SW \nAcute interstitial nephritis due to pantoprazole\n. Ann Pharmacother \n2004 ;38 :41 –5\n.14742791 \n[16] Post AT Voorhorst G Zanen AL \nReversible renal failure after treatment with omeprazole\n. Neth J Med \n2000 ;57 :58 –61\n.10924942 \n[17] Geevasinga N Coleman PL Roger SD \nRabeprazole-induced acute interstitial nephritis\n. Nephrology (Carlton) \n2005 ;10 :7 –9\n.15705174 \n[18] Geevasinga N Kairaitis L Rangan GK \nAcute interstitial nephritis secondary to esomeprazole\n. Med J Aust \n2005 ;182 :235 –6\n.15748135 \n[19] Jose J Saravu K Khera K \nAcute interstitial nephritis related to lansoprazole administration\n. J Pak Med Assoc \n2008 ;58 :206 –7\n.18655432 \n[20] Nast CC \nMedication-induced interstitial nephritis in the 21st century\n. Adv Chronic Kidney Dis \n2017 ;24 :72 –9\n.28284382 \n[21] Berney-Meyer L Hung N Slatter T \nOmeprazole-induced acute interstitial nephritis: a possible Th1-Th17-mediated injury?\n\nNephrology (Carlton) \n2014 ;19 :359 –65\n.24629073 \n[22] Corsonello A Lattanzio F Bustacchini S \nAdverse events of proton pump inhibitors: potential mechanisms\n. Curr Drug Metabol \n2018 ;19 :142 –54\n.\n[23] Torpey N Barker T Ross C \nDrug-induced tubulo-interstitial nephritis secondary to proton pump inhibitors: experience from a single UK renal unit\n. Nephrol Dial Transplant \n2004 ;19 :1441 –6\n.15004262 \n[24] Lazarus B Chen Y Wilson FP \nProton pump inhibitor use and the risk of chronic kidney disease\n. JAMA Int Med \n2016 ;176 :238 –46\n.\n[25] Toth-Manikowski S Grams ME \nProton pump inhibitors and kidney disease—GI upset for the nephrologist?\n\nKidney Int Rep \n2017 ;2 :297 –301\n.28845467 \n[26] Klatte DCF Gasparini A Xu H \nAssociation between proton pump inhibitor use and risk of progression of chronic kidney disease\n. Gastroenterology \n2017 ;153 :702 –10\n.28583827 \n[27] Joyce E Glasner P Ranganathan S \nTubulointerstitial nephritis: diagnosis, treatment, and monitoring\n. Pediatr Nephrol \n2017 ;32 :577 –87\n.27155873 \n[28] Geevasinga N Coleman PL Webster AC \nProton pump inhibitors and acute interstitial nephritis\n. Clin Gastroenterol Hepatol \n2006 ;4 :597 –604\n.16630752 \n[29] Muriithi AK Leung N Valeri AM \nClinical characteristics, causes and outcomes of acute interstitial nephritis in the elderly\n. Kidney Int \n2015 ;87 :458 –64\n.25185078 \n[30] Xie Y Bowe B Li T \nProton pump inhibitors and risk of incident CKD and progression to ESRD\n. J Am Soc Nephrol \n2016 ;27 :3153 –63\n.27080976 \n[31] Muriithi AK Leung N Valeri AM \nBiopsy-proven acute interstitial nephritis, 1993-2011: a case series\n. Am J Kidney Dis \n2014 ;64 :558 –66\n.24927897 \n[32] Morschel CF Mafra D Eduardo JCC \nThe relationship between proton pump inhibitors and renal disease\n. J Bras Nefrol \n2018 ;40 :301 –6\n.30010692 \n[33] Torlot FJ Whitehead DJ \nAcute interstitial nephritis caused by two different proton pump inhibitors\n. Br J Hosp Med (Lond) \n2016 ;77 :50 –1\n.26903459 \n[34] Singer S Parry RG Deodhar HA \nAcute interstitial nephritis, omeprazole and antineutrophil cytoplasmic antibodies\n. Clin Nephrol \n1994 ;42 :280 .7834928 \n[35] Jacobs-Kosmin D Derk CT Sandorfi N \nPantoprazole and perinuclear antineutrophil cytoplasmic antibody-associated vasculitis\n. J Rheumatol \n2006 ;33 :629 –32\n.16482642 \n[36] Clarkson MR Giblin L O’Connell FP \nAcute interstitial nephritis: clinical features and response to corticosteroid therapy\n. Nephrol Dial Transplant \n2004 ;19 :2778 –83\n.15340098 \n[37] Prendecki M Tanna A Salama AD \nLong-term outcome in biopsy-proven acute interstitial nephritis treated with steroids\n. Clin Kidney J \n2017 ;10 :233 –9\n.28396740 \n[38] González E Gutiérrez E Galeano C \nEarly steroid treatment improves the recovery of renal function in patients with drug-induced acute interstitial nephritis\n. Kidney Int \n2008 ;73 :940 –6\n.18185501 \n[39] Gross M Labenz J \nPrescription of PPI in Germany: too often, too long, too much?\n\nMMW Fortschr Med \n2018 ;160 :37 –40\n.\n[40] Leven C Hudier L Picard S \nProspective study of drug-induced interstitial nephritis in eleven French nephrology units\n. Presse Med \n2014 ;43 :e369 –76\n.25218248 \n[41] Arora P Gupta A Golzy M \nProton pump inhibitors are associated with increased risk of development of chronic kidney disease\n. BMC Nephrol \n2016 ;17 :112 Published 2016 Aug 3 .27487959\n\n",
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"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D063926:Drug Hypersensitivity Syndrome; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D009853:Omeprazole; D054328:Proton Pump Inhibitors",
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"title": "Drug rash with eosinophilia and systemic symptoms and severe renal injury induced by proton pump inhibitor therapy: A case report.",
"title_normalized": "drug rash with eosinophilia and systemic symptoms and severe renal injury induced by proton pump inhibitor therapy a case report"
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"abstract": "Background: Although increasing cerebral perfusion pressure (CPP) is commonly accepted to improve brain tissue oxygen pressure (PbtO2), it remains unclear whether recommended CPP targets (i. e., >60 mmHg) would result in adequate brain oxygenation in brain injured patients. The aim of this study was to identify the target of CPP associated with normal brain oxygenation. Methods: Prospectively collected data including patients suffering from acute brain injury and monitored with PbtO2, in whom daily CPP challenge using vasopressors was performed. Initial CPP target was >60 mmHg; norepinephrine infusion was modified to have an increase in CPP of at least 10 mmHg at two different steps above the baseline values. Whenever possible, the same CPP challenge was performed for the following days, for a maximum of 5 days. CPP \"responders\" were patients with a relative increase in PbtO2 from baseline values > 20%. Results: A total of 53 patients were included. On the first day of assessment, CPP was progressively increased from 73 (70-76) to 83 (80-86), and 92 (90-96) mmHg, which resulted into a significant PbtO2 increase [from 20 (17-23) mmHg to 22 (20-24) mmHg and 24 (22-26) mmHg, respectively; p < 0.001]. Median CPP value corresponding to PbtO2 values > 20 mmHg was 79 (74-87) mmHg, with 2 (4%) patients who never achieved such target. Similar results of CPP targets were observed the following days. A total of 25 (47%) were PbtO2 responders during the CPP challenge on day 1, in particular if low PbtO2 was observed at baseline. Conclusions: PbtO2 monitoring can be an effective way to individualize CPP values to avoid tissue hypoxia. Low PbtO2 values at baseline can identify the responders to the CPP challenge.",
"affiliations": "Department of Intensive Care, Hopital Erasme, Université Libre de Bruxelles, Brussels, Belgium.;Department of Intensive Care, Hopital Erasme, Université Libre de Bruxelles, Brussels, Belgium.;Department of Intensive Care, Hopital Erasme, Université Libre de Bruxelles, Brussels, Belgium.;Department of Neurosurgery, Hopital Erasme, Université Libre de Bruxelles, Brussels, Belgium.;Department of Intensive Care, Hopital Erasme, Université Libre de Bruxelles, Brussels, Belgium.;Department of Intensive Care, Hopital Erasme, Université Libre de Bruxelles, Brussels, Belgium.;Department of Intensive Care, Hopital Erasme, Université Libre de Bruxelles, Brussels, Belgium.;Department of Intensive Care, Hopital Erasme, Université Libre de Bruxelles, Brussels, Belgium.;Department of Intensive Care, Hopital Erasme, Université Libre de Bruxelles, Brussels, Belgium.",
"authors": "Kovacs|Matyas|M|;Peluso|Lorenzo|L|;Njimi|Hassane|H|;De Witte|Olivier|O|;Gouvêa Bogossian|Elisa|E|;Quispe Cornejo|Armin|A|;Creteur|Jacques|J|;Schuind|Sophie|S|;Taccone|Fabio Silvio|FS|",
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"doi": "10.3389/fneur.2021.732830",
"fulltext": "\n==== Front\nFront Neurol\nFront Neurol\nFront. Neurol.\nFrontiers in Neurology\n1664-2295\nFrontiers Media S.A.\n\n10.3389/fneur.2021.732830\nNeurology\nOriginal Research\nOptimal Cerebral Perfusion Pressure Guided by Brain Oxygen Pressure Measurement\nKovacs Matyas 1\nPeluso Lorenzo 1 *\n\nNjimi Hassane 1\nDe Witte Olivier 2\n\nGouvêa Bogossian Elisa 1\n\nQuispe Cornejo Armin 1\n\nCreteur Jacques 1\nSchuind Sophie 1\nTaccone Fabio Silvio 1\n1Department of Intensive Care, Hopital Erasme, Université Libre de Bruxelles, Brussels, Belgium\n2Department of Neurosurgery, Hopital Erasme, Université Libre de Bruxelles, Brussels, Belgium\nEdited by: Anders Lewén, Uppsala University, Sweden\n\nReviewed by: Teodor Mikael Svedung Wettervik, Uppsala University, Sweden; Minjee Kim, Northwestern University, United States\n\n*Correspondence: Lorenzo Peluso lorenzopeluso80@gmail.com\nThis article was submitted to Neurocritical and Neurohospitalist Care, a section of the journal Frontiers in Neurology\n\n28 10 2021\n2021\n12 73283029 6 2021\n29 9 2021\nCopyright © 2021 Kovacs, Peluso, Njimi, De Witte, Gouvêa Bogossian, Quispe Cornejo, Creteur, Schuind and Taccone.\n2021\nKovacs, Peluso, Njimi, De Witte, Gouvêa Bogossian, Quispe Cornejo, Creteur, Schuind and Taccone\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.\nBackground: Although increasing cerebral perfusion pressure (CPP) is commonly accepted to improve brain tissue oxygen pressure (PbtO2), it remains unclear whether recommended CPP targets (i. e., >60 mmHg) would result in adequate brain oxygenation in brain injured patients. The aim of this study was to identify the target of CPP associated with normal brain oxygenation.\n\nMethods: Prospectively collected data including patients suffering from acute brain injury and monitored with PbtO2, in whom daily CPP challenge using vasopressors was performed. Initial CPP target was >60 mmHg; norepinephrine infusion was modified to have an increase in CPP of at least 10 mmHg at two different steps above the baseline values. Whenever possible, the same CPP challenge was performed for the following days, for a maximum of 5 days. CPP “responders” were patients with a relative increase in PbtO2 from baseline values > 20%.\n\nResults: A total of 53 patients were included. On the first day of assessment, CPP was progressively increased from 73 (70–76) to 83 (80–86), and 92 (90–96) mmHg, which resulted into a significant PbtO2 increase [from 20 (17–23) mmHg to 22 (20–24) mmHg and 24 (22–26) mmHg, respectively; p < 0.001]. Median CPP value corresponding to PbtO2 values > 20 mmHg was 79 (74–87) mmHg, with 2 (4%) patients who never achieved such target. Similar results of CPP targets were observed the following days. A total of 25 (47%) were PbtO2 responders during the CPP challenge on day 1, in particular if low PbtO2 was observed at baseline.\n\nConclusions: PbtO2 monitoring can be an effective way to individualize CPP values to avoid tissue hypoxia. Low PbtO2 values at baseline can identify the responders to the CPP challenge.\n\nbrain injury\nbrain oxygenation\noptimal perfusion\nindividualized therapy\ntraumatic brain injury\nintracranial hemorrhage\nsubarachnoid hemorrhage\n==== Body\npmcIntroduction\n\nMonitoring of patients with critical illness has expanded significantly over the past several decades. As for hemodynamics, respiratory or renal functions, several studies have underlined the importance of monitoring brain function, not only in patients with a primary brain injury [i.e., traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), post-anoxic brain injury], but also in those with a systemic disease, such as sepsis, acute pancreatitis, or cardiogenic shock, who may present different alterations of cerebral function and potentially may develop secondary brain injuries (1), which can impact on long-term functional and cognitive recovery (2).\n\nIn patients suffering from TBI, the combination of intracranial pressure (ICP) and cerebral perfusion pressure (CPP)-guided therapy is recommended for the current management of these patients (3); similarly, ICP and CPP are the cornerstone of management of severe non-traumatic brain injury patients, although the evidence suggesting that such approach might impact on long-term outcomes remain limited (4). Importantly, increased ICP could be a late and insensitive indicator of some secondary brain injuries (5, 6); in particular, the occurrence of tissue hypoxia may occur even in the absence of intracranial hypertension and, when untreated or refractory to therapeutic interventions, is associated with an increased risk of poor neurological outcome in brain injured patients (7, 8). As such, rather than protocolizing therapies to target fixed ICP and CPP values for all patients, independently from the underlying brain injury, comorbid diseases, and the severity of brain edema, the implementation of brain tissue oxygen pressure (PbtO2) monitoring could be helpful to individualize ICP and CPP values based on cerebral oxygenation.\n\nAlthough higher than recommended CPP targets (i.e., >60 mmHg) have been associated with adequate PbtO2 values in heterogeneous populations of brain injured patients, few prospective studies have evaluated the effects of increasing CPP using vasopressors on PbtO2 in such patients. In one small study (n = 11) on TBI patients, increasing CPP from 70 to 90 mmHg with norepinephrine resulted in a significant increase in PbtO2 (from 17 ± 8 to 22 ± mmHg), despite brain metabolism was only marginally affected (8). In another study including 14 TBI patients, increasing CPP resulted also in a significant increase in PbtO2, although this was measured after a challenge of inspired oxygen at 100% on the ventilator (9). However, all these studies did not specifically investigate the proportion of patients requiring higher than recommended CPP to obtain adequate PbtO2 values, neither whether this CPP target would change along the hospital stay.\n\nThe aim of this study was therefore to evaluate which level of CPP corresponds to an adequate PbtO2 in an heterogeneous population of brain injured patients. Secondary aims were to assess: (a) whether this level of CPP change over time and (b) the characteristics of patients requiring higher than recommended CPP targets to have optimal brain oxygenation values.\n\nMethods\n\nStudy Population\n\nThis was an analysis of prospectively collected data including all adult (>18 years of age) patients with an acute primary brain injury admitted to the ICU of Erasme Hospital, Brussels, Belgium, between January 2016 and December 2020. Eligible patients were those: (a) having a PbtO2 monitoring catheter, which was inserted according to the decision of senior ICU physician and an experienced neurosurgeon; (b) receiving vasopressors to target a CPP of at least 60–70 mmHg; (c) who underwent daily CPP challenge as part of routine patient management (see below). Data for all measurements were recorded into the patient management data system (PDMS, Picis Critical Care Manager; Picis Inc., Wakefield, MA, USA). Exclusion criteria were a malfunctioning PbtO2 catheter, the absence of vasopressor therapy, elevated ICP (>25 mmHg) refractory to different interventions (i.e., sedation, osmotic therapy, and hyperventilation), clinical contraindication to increased CPP (i.e., frequent arrhythmias or acute heart failure). The study was approved by the ethical committee of the Erasme Hospital (Comité d'Ethique Hospitalo-Facultaire Erasme – ULB; P2021/038), which waived the need of informed consent given the observational design of the study analyzing recorded data into the PDMS.\n\nPatients' Management and CPP Challenge\n\nPatients were managed according to local protocols, based on international recommendations (3, 4, 10, 11). A triple lumen bolt allowing the insertion of a PbtO2 probe (IM3.ST_EU; Integra LifeSciences Corporation, Plainsboro, NJ, USA), alone or in association with an eight-contact depth EEG electrode and a microdialysis catheter, was placed in the operating room by a neurosurgeon in patients with TBI, subarachnoid hemorrhage (SAH), or intracranial hemorrhage (ICH), who had indications for ICP monitoring (i.e., abnormal CT-scan findings and a Glasgow Coma Score on admission <9). The bolt was positioned in the normal-appearing brain area of the injured side or, in case of aneurysmal SAH, on either the ipsilateral side of the aneurysm (i.e., anterior circulation) or on the right side (i.e., no aneurysm identified or aneurysm located in the posterior circulation). Other continuously monitored variables included electrocardiogram, mean arterial pressure (MAP), peripheral oxygen saturation, end-tidal carbon dioxide and body temperature (i.e., with urinary or esophageal probes), as a routine approach in all severe brain injured patients.\n\nFor patients requiring vasopressors, initial CPP and PbtO2 targets are >60 mmHg and >20 mmHg, respectively. Cerebral perfusion pressure (CPP) was calculated as the difference between MAP and ICP; MAP was zeroed at the level of the left atrium (i.e., with patient at 30° recumbent position). After the initial daily assessment of the patient, which can also include the evaluation of pupillary function using an automated pupillometry (NeurOptics NPi-200; Neuroptics, Irvine, CA, USA) to calculate the Neurological Pupil Index (NPi), or brain flow velocities with Transcranial Doppler (TCD) to measure mean flow velocities (mFV) and the pulsatility index (PI) (12), CPP was set around 60–70 mmHg (i.e., if not already within these ranges) and norepinephrine infusion was modified to have an increase in CPP of at least 10 mmHg at two different steps above the baseline values. At each CPP level (i.e., stabilized for at least 5 min), PbtO2, ICP, NPi, mFV, and PI were collected and results used to adjust vasopressor infusion daily in order to define CPP goals according to PbtO2 values (i.e., target ≥ 20 mmHg) and/or guide further interventions. This CPP challenge was part of the routine management of patients, as it had a short duration (i.e., 10–15 min) and was performed by an experienced intensivist (FST), whenever possible. Apart from the CPP intervention, all other relevant physiological variables were kept stable. Also, the same CPP challenge was performed for the following days, always initiating on a CPP around 60–70 mmHg and testing two additional steps. A maximum of 5 days of testing was considered (i.e., either brain oxygenation was normalized and the catheter removed or increased ICP or persistent brain hypoxia would prevent further testing); CPP “responders” were defined as those patients with a relative increase in PbtO2 from baseline values > 20%.\n\nData Collection\n\nFor all patients, demographics, comorbid diseases, reasons for ICU admission as well as ICU length of stay and hospital mortality were collected. The severity of disease scores [i.e., Glasgow Coma Scale on admission, World Federation of Neurological Surgeons (WFNS) score in SAH patients; Marshall (13) and modified Fisher scores (14, 15) for cerebral CT-scan in TBI or SAH patients, respectively; and location and volume of ICH] were collected. The use of different therapies (i.e., mechanical ventilation, sedative, analgesic, vasopressor, inotrope, antiepileptic, barbituric, and/or osmotic drugs), as well as different interventions (i.e., ICP monitoring, hypothermia, hypocapnia, and decompressive craniotomy) was collected. Intracranial hypertension was defined by the observation of at least one ICP value above 20 mmHg for at least 5 min at any time. Brain tissue hypoxia was defined by a PbtO2 below 20 mmHg.\n\nNeurological outcome at hospital discharge was assessed using the Glasgow Outcome Scale (GOS) (15); favorable neurological outcome (FO) was considered as a GOS 4–5, while unfavorable outcome (UO) as GOS 1–3.\n\nStudy Outcomes\n\nThe primary outcome of the study was to evaluate which level of CPP corresponds to a PbtO2 ≥ 20 mmHg. Secondary outcomes included: (a) proportion and characteristics of PbtO2 responders; (b) comparison of PbtO2 changes according to the presence of baseline tissue hypoxia; (c) comparison of PbtO2 changes over time; (d) association of PbtO2 changes with NPi, mFV, and/or PI changes; (e) differences in PbtO2 changes during CPP challenges according to neurological outcome.\n\nStatistical Analysis\n\nData were analyzed using R statistical software version 4.0.3 (R Foundation for Statistical Computing), Prism (GraphPad Software Inc.), and IBM SPSS Statistics for Macintosh 27 (Armonk, NY, USA). Categorical variables were expressed as count (percentage) and continuous variables as mean ± standard deviation (SD) or median (25th−75th percentiles). The Kolmogorov-Smirnov test was used, and histograms and normal-quantile plots were examined to verify the normality of distribution of continuous variables. Differences between groups were assessed using the chi-square test or Fisher's exact test for categorical variables and Student's t-test, or Mann–Whitney U-test for continuous variables, as appropriate. Mixed model procedure with restricted maximum likelihood (REML) estimation and “unstructured” covariance structure was used to examine the differences in PbtO2 changes during CPP challenge over different days of assessment. All tests are two tailed and the statistical significance was set at the 5% level.\n\nResults\n\nStudy Population\n\nOver a total of 162 patients, 109 were excluded (i.e., n = 49, not on vasopressors during the PbtO2 monitoring period; n = 29, refractory intracranial hypertension; n = 31, measurements not performed) and 53 were eventually included into the final analysis. No significant differences were observed between included and excluded patients (Supplementary Table 1), except for a shorter ICU length of stay and higher mortality for the excluded group. Characteristics of the study population are shown in Table 1; the most frequent brain injury was SAH (n = 29, 55%). Hospital mortality occurred in 18 (34%) of patients, while 33 (62%) presented with UO.\n\nTable 1 Characteristics of study population, according to neurological outcome (UO, unfavorable; FO, favorable).\n\n\tOverall (n = 53)\tUO (n = 33)\tFO (n = 20)\tp-value\t\nDemographics\t\nAge, years\t50 (40–58)\t51 (44–58)\t47 (38–57)\t0.45\t\nMale gender, n (%)\t31 (58)\t19 (58)\t12 (60)\t1.00\t\nComorbidities\t\nHypertension, n (%)\t14 (26)\t10 (30)\t4 (20)\t0.53\t\nHeart disease, n (%)\t2 (4)\t0\t2 (10)\t0.14\t\nAlcohol, n (%)\t12 (23)\t7 (21)\t5 (25)\t0.75\t\nSmoking, n (%)\t12 (23)\t6 (18)\t6 (30)\t0.34\t\nDiabetes, n (%)\t7 (13)\t5 (15)\t2 (10)\t0.70\t\nPrevious neurological disease, n (%)\t2 (4)\t1 (3)\t1 (5)\t1.00\t\nCKD, n (%)\t0\t0\t0\t\t\nCOPD, n (%)\t4 (8)\t3 (9)\t1 (5)\t1.00\t\nImmunosuppression, n (%)\t0\t0\t0\t–\t\nCancer, n (%)\t3 (6)\t3 (9)\t0\t0.28\t\nLiver cirrhosis, n (%)\t1 (2)\t1 (3)\t0\t1.00\t\nOn admission\t\nGlasgow coma scale\t7 (3–10)\t5 (3–9)\t7 (5–13)\t0.14\t\nType of disease, n (%)\t\t\t\t0.25\t\nTBI\t20 (38)\t10 (30)\t10 (50)\t\t\nSAH\t29 (55)\t21 (64)\t8 (40)\t\t\nICH\t4 (8)\t2 (6)\t2 (10)\t\t\nDuring ICU stay\t\nVasopressors, n (%)\t53 (100)\t33 (100)\t20 (100)\t–\t\nMechanical ventilation, n (%)\t53 (100)\t33 (100)\t20 (100)\t–\t\nRRT, n (%)\t1 (2)\t1 (3)\t0\t1.00\t\nOsmotic therapy, n (%)\t45 (85)\t29 (88)\t16 (80)\t0.46\t\nDecompressive craniectomy, n (%)\t10 (19)\t5 (15)\t5 (25)\t0.48\t\nHypothermia, n (%)\t10 (19)\t9 (27)\t1 (5)\t0.07\t\nAnti-epileptics, n (%)\t48 (91)\t29 (88)\t19 (95)\t0.64\t\nBarbiturates, n (%)\t21 (40)\t16 (48)\t5 (25)\t0.15\t\nIntracranial hypertension, n (%)\t36 (68)\t26 (79)\t10 (50)\t0.04\t\nSeizures, n (%)\t9 (17)\t5 (15)\t4 (20)\t0.72\t\nOn the first day of assessment\t\nBody temperature, °C\t37 (36.8–37.3)\t37 (36.8–37.3)\t36.9 (36.7–37.3)\t0.72\t\nPaCO2, mmHg\t37 (36–39)\t37 (36–39)\t37 (36–38)\t0.95\t\nPaO2, mmHg\t102 (98–110)\t100 (98–108)\t104 (99–111)\t0.38\t\nLactate, mmol/L\t1 (0.8–1.2)\t1 (0.8–1.2)\t1.0 (0.8–1.1)\t0.25\t\nHemoglobin, g/dl\t11.3 (10.8–12.2)\t11.2 (10.8–12.1)\t11.4 (10.9–12.2)\t0.88\t\nFVm MCA, cm/sec\t55.3 (48.5–65)\t51.7 (47.5–67.3)\t58.0 (54.7–63.2)\t0.46\t\nPulsatility Index\t0.90 (0.73–1.05)\t0.93 (0.73–1.08)\t0.85 (0.73–1.04)\t0.77\t\nMean NPi\t4.6 (4.03–4.66)\t4.3 (3.2–4.7)\t4.6 (4.3–4.6)\t0.82\t\niPbtO2, mmHg\t20 (17–23)\t19 (16–23)\t21 (18–24)\t0.34\t\nBrain hypoxia, n (%)\t26 (49)\t18 (55)\t8 (40)\t0.40\t\nOutcomes\t\nICU stay, days\t21 (11–26)\t17 (11–25)\t24 (14–28)\t0.15\t\nHospital mortality, n (%)\t18 (34)\t18 (55)\t0\t<0.01\t\nCKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; TBI, traumatic brain injury; SAH, subarachnoid hemorrhage; ICH, intracerebral hemorrhage; RRT, renal replacement therapy; PaCO2, partial arterial CO2 pressure; PaO2, partial arterial oxygen pressure; mFV-MCA, mean MCA flow velocity; NPI, neurological pupil index; iPbtO2, brain tissue oxygenation at baseline; ICU, intensive care unit.\n\nCPP Challenge and PbtO2\n\nOn the first day of assessment, baseline PbtO2 and CPP were 20 (16–21) mmHg and 73 (70–76) mmHg, respectively; brain hypoxia at baseline was observed in 26 (49%) of patients (Tables 1, 2). CPP was progressively increased to 83 (80–86) mmHg and 92 (90–96) mmHg, which resulted into a significant PbtO2 increase [to 22 (19–22) mmHg and 24 (20–24) mmHg, respectively; p < 0.001; Table 2]. During CPP increase, ICP also significantly decreased from baseline values. Median CPP value corresponding to PbtO2 values ≥ 20 mmHg on day 1 was 79 (74–87) mmHg, with 2 (4%) patients who never achieved such target; similar CPP values corresponding to PbtO2 values >20 mmHg were observed in traumatic (n = 38) and non-traumatic brain injury [79 (75–86) mmHg vs. 77 (72–88) mmHg; p = 0.52]. CPP challenges were repeated in 34 patients on day 2, 23 on day 3, 11 on day 4, and 7 on day 5; reasons for not performing CPP challenges the following days were mainly increased ICP (n = 4), the need for CPP > 90 mmHg to keep stable cerebral oxygenation (n = 5), or absence of operator and discontinuation of vasopressor therapy in others. Two patients on day 1 and 1 patient on day 3 never achieved the PbtO2 target. Similar values of CPP corresponding to PbtO2 values ≥ 20 mmHg were observed in the following days [80 (73–87) mmHg on day 2; 79 (72–92) mmHg on day 3; 80 (72–89) mmHg on day 4; 80 (68–92) mmHg on day 5; Figure 1]. No significant complications (i.e., increase in ICP, arrhythmias) during CPP challenge were reported.\n\nTable 2 Changes in study variables on the first day of assessment, according to different steps of mean arterial pressure (MAP) and neurological outcome (UO, unfavorable; FO, favorable).\n\n\t\tStep 1\tStep 2\tStep 3\tp-value\t\nAll (n = 53)\tMAP, mmHg\t83 (82–89)\t95 (91–99)\t105 (100–109)\t<0.01\t\n\tICP, mmHg\t12 (8–14)\t12 (9–15)\t11 (9–15)\t<0.01\t\n\tCPP, mmHg\t73 (70–76)\t83 (80–86)\t92 (90–96)\t<0.01\t\n\tPbtO2, mmHg\t20 (17–23)\t22 (20–24)\t24 (22–26)\t<0.01\t\nUO (n = 33)\tMAP, mmHg\t83 (81–87)\t93 (91–96)\t103 (100–110)\t<0.01\t\n\tICP, mmHg\t10 (6–14)\t11 (7–14)\t11 (9–15)\t<0.01\t\n\tCPP, mmHg\t73 (70–75)\t82 (79–85)\t91 (89–96)\t<0.01\t\n\tPbtO2, mmHg\t19 (16–23)\t22 (19–24)\t24 (22–26)\t<0.01\t\nFO (n = 20)\tMAP, mmHg\t86 (82–90)\t97 (94–100)\t107 (102–110)\t<0.01\t\n\tICP, mmHg\t13 (10–17)\t12 (10–17)\t13 (10–17)\t0.42\t\n\tCPP, mmHg\t74 (70–77)\t85 (81–88)\t93 (91–96)\t<0.01\t\n\tPbtO2, mmHg\t21 (18–24)\t22 (21–25)\t24 (23–28)\t<0.01\t\nUO, unfavorable outcome; FO, favorable outcome; MAP, mean arterial pressure; ICP, intracranial pressure; CPP, cerebral perfusion pressure; PbtO2, brain tissue oxygenation.\n\nFigure 1 Cerebral perfusion pressure corresponding to a PbtO2 > 20 mmHg (CPPOX).\n\nSecondary Outcomes\n\nA total of 25 (47%) were PbtO2 responders during the CPP challenge on day 1. PbtO2 responders had similar characteristics to non-responders, including the presence of TBI, with the exception a lower PbtO2 at baseline (Table 3). Changes in PbtO2 on the first day of assessment were significantly higher over time in responders than in non-responders (Table 4; Figure 2).\n\nTable 3 Characteristics of population according to PbtO2 responder or non-responder to CPP challenge.\n\n\tResponder (n = 25)\tNon responder(n = 28)\tp-value\t\nDemographics\t\nAge, years\t52 (41–59)\t50 (40–57)\t0.57\t\nMale gender, n (%)\t11 (44)\t20 (71)\t0.06\t\nComorbidities\t\nHypertension, n (%)\t9 (36)\t5 (18)\t0.21\t\nHeart disease, n (%)\t0\t2 (7)\t0.49\t\nAlcohol, n (%)\t6 (24)\t6 (21)\t1.00\t\nSmoking, n (%)\t8 (32)\t4 (14)\t0.19\t\nDiabetes, n (%)\t2 (8)\t5 (18)\t0.43\t\nPrevious neurological disease, n (%)\t0\t2 (7)\t0.49\t\nCKD, n (%)\t0\t0\t–\t\nCOPD, n (%)\t1 (4)\t3 (11)\t0.61\t\nImmunosuppression, n (%)\t0\t0\t–\t\nCancer, n (%)\t1 (4)\t2 (7)\t1.00\t\nLiver Cirrhosis, n (%)\t1 (4)\t0\t0.47\t\nOn admission\t\nGlasgow coma scale\t6 (3–9)\t7 (3–11)\t0.59\t\nType of disease, n (%)\t\t\t0.65\t\nTBI\t10 (40)\t10 (36)\t\t\nSAH\t14 (56)\t15 (54)\t\t\nICH\t1 (4)\t3 (10)\t\t\nMED\t0\t0\t\t\nDuring ICU stay\t\nVasopressors, n (%)\t25 (100)\t28 (100)\t–\t\nMechanical ventilation, n (%)\t25 (100)\t28 (100)\t–\t\nRRT, n (%)\t1 (4)\t0\t0.47\t\nOsmotic therapy, n (%)\t21 (84)\t24 (86)\t1.00\t\nDecompressive craniectomy, n (%)\t7 (28)\t3 (11)\t0.16\t\nHypothermia, n (%)\t4 (16)\t6 (21)\t0.73\t\nAnti-epileptics, n (%)\t24 (96)\t24 (86)\t0.36\t\nBarbiturates, n (%)\t12 (48)\t9 (32)\t0.27\t\nIntracranial hypertension, n (%)\t19 (76)\t17 (61)\t0.26\t\nSeizures, n (%)\t4 (16)\t5 (18)\t1.00\t\nOn the first day of assessment\t\nBody temperature, °C\t37.0 (36.8–37.3)\t36.9 (36.7–37.4)\t0.69\t\nPaCO2, mmHg\t38 (35–39)\t37 (36–38)\t0.51\t\nPaO2, mmHg\t102 (98–110)\t100 (98–111)\t0.79\t\nLactate, mmol/L\t1.1 (0.8–1.2)\t1.0 (0.7–1.1)\t0.12\t\nHemoglobin, g/dl\t11.3 (10.8–12.2)\t11.2 (10.7–12.2)\t0.63\t\nmFV, cm/sec\t56.0 (49.7–71.0)\t55.3 (47.3–62.7)\t0.13\t\nPulsatility Index\t0.91 (0.69–1.13)\t0.92 (0.80–1.05)\t0.41\t\nMean NPi\t4.6 (4.3–4.7)\t4.1 (3.2–4.6)\t0.30\t\niPbtO2, mmHg\t17 (16–19)\t22 (20–26)\t<0.01\t\nBrain hypoxia, n (%)\t20 (80)\t6 (21)\t<0.01\t\nOutcomes\t\nICU stay, days\t15 (12–24)\t23 (11–33)\t0.18\t\nHospital mortality, n (%)\t11 (44)\t7 (25)\t0.16\t\nGOS 3 months\t3 (1–4)\t3 (1–4)\t0.37\t\nUO\t16 (64)\t17 (61)\t1.00\t\nCKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; TBI, traumatic brain injury; SAH, subarachnoid hemorrhage; ICH, intracerebral hemorrhage; RRT, renal replacement therapy; PaCO2, partial arterial CO2 pressure; PaO2, partial arterial oxygen pressure; mFV-MCA, mean MCA flow velocity; NPI, neurological pupil index; iPbtO2, brain tissue oxygenation at baseline; ICU, intensive care unit; GOS, Glasgow Outcome Scale.\n\nTable 4 Changes in study variables on the first day of assessment, according to response to CPP challenge and baseline tissue hypoxia.\n\n\t\tStep 1\tStep 2\tStep 3\tp-value\t\nResponders(n = 25)\tMAP, mmHg\t83 (80–89)\t95 (90–98)\t103 (100–108)\t<0.01\t\n\tICP, mmHg\t11 (9–17)\t11 (10–15)\t11 (9–15)\t0.26\t\n\tCPP, mmHg\t72 (70–74)\t82 (80–85)\t91 (89–95)\t<0.01\t\n\tPbtO2, mmHg\t17 (16–19)\t21 (18–22)\t24 (22–26)\t<0.01\t\nNo responders (n = 28)\tMAP, mmHg\t83 (82–88)\t96 (92–99)\t107 (101–110)\t<0.01\t\n\tICP, mmHg\t12 (6–14)\t12,5 (9–15)\t12 (10–15)\t0.01\t\n\tCPP, mmHg\t74 (72–76)\t84 (80–87)\t94 (90–97)\t<0.01\t\n\tPbtO2, mmHg\t22 (20–26)\t23 (22–26)\t24 (22–27)\t<0.01\t\nNormal PbtO2(n = 27)\tMAP, mmHg\t83 (82–88)\t95 (92–100)\t105 (100–110)\t<0.01\t\n\tICP, mmHg\t12 (6–14)\t12 (9–14)\t11 (9–14)\t0.43\t\n\tCPP, mmHg\t74 (71–76)\t85 (81–88)\t94 (91–97)\t<0.01\t\n\tPbtO2, mmHg\t23 (21–26)\t24 (23–28)\t26 (24–29)\t<0.01\t\nTissue hypoxia(n = 26)\tMAP, mmHg\t86 (82–89)\t95 (91–98)\t106 (100–110)\t<0.01\t\n\tICP, mmHg\t11 (9–17)\t11 (10–17)\t12 (9–18)\t<0.01\t\n\tCPP, mmHg\t72 (70–74)\t82 (79–85)\t91 (88–96)\t<0.01\t\n\tPbtO2, mmHg\t17 (16–18)\t20 (18–22)\t22 (21–24)\t<0.01\t\nMAP, mean arterial pressure; ICP, intracranial pressure; CPP, cerebral perfusion pressure; PbtO2, Brain tissue oxygenation.\n\nFigure 2 PbtO2 changes during the CPP challenge in responders and non-responders (left panel), in baseline normal PbtO2 values or tissue hypoxia (middle panel) or according to the neurological outcome (UO, unfavorable; FO, favorable – right panel).\n\nAmong patients with baseline tissue hypoxia on the first day of assessment (Supplementary Table 2), changes in PbtO2 were significantly higher in those with tissue hypoxia when compared to others (Table 4; Figure 2). Similar changes in PbtO2 between days 1, 2, and 3 were observed (Wald chi-square 6.42; p = 0.59; Figure 3); data on day 4 and 5 were not included into this analysis because of the high number of missing challenges.\n\nFigure 3 PbtO2 changes during the CPP challenge over the first 3 days of assessment.\n\nA total of 19 (56%), 10 (42%), 4 (36%), and 3 (43%) were PbtO2 responders during the CPP challenge on days 2, 3, 4, and 5, respectively. A total of 18 (53%), 12 (50%), 4 (36%), and 3 (43%) had baseline brain tissue hypoxia at baseline on days 2, 3, 4, and 5, respectively.\n\nA total of 123 paired assessment of PbtO2 with mFV and PI changes and 59 of PbtO2 with NPi changes were available over the first 5 days of assessment. No correlation of PbtO2 changes were observed with changes in mFV or PI (correlation index of −0.043 and −0.031, with p-values of 0.57 and 0.68, respectively), while a weak correlation between PbtO2 and NPi changes was observed (correlation index of 0.181, p = 0.017).\n\nDifferences between patients with UO and FO are shown in Table 1. Before the CPP challenge, baseline characteristics were similar between groups on day 1. Also, changes in PbtO2 over time on day 1 were not statistically significant between groups (Table 2; Figure 2).\n\nDiscussion\n\nIn this study, including a heterogeneous population of brain injured patients, increasing CPP resulted in a significant increase of the brain oxygenation in most of patients. The “optimal” CPP, i.e., the CPP value corresponding to the absence of tissue hypoxia, was higher than in recommended targets (i.e., around 80 mmHg). Half of patients showed a significant increase in PbtO2 during the CPP challenge, in particular, if they had lower PbtO2 values at baseline. The effects of CPP on PbtO2 changes were similar in the following days of assessment. Non-invasive neuromonitoring could not adequately predict PbtO2 changes during CPP increase.\n\nThe improvement in PbtO2 values during CPP increase using vasopressors has also been reported in previous studies. Johnston et al. reported a significant increase in brain oxygenation when CPP was increased from 70 to 90 mmHg (8); these changes were also associated with an increase in cerebral blood flow and a decrease in oxygen extraction fraction (OER). However, as CPP challenge resulted in a greater proportional increase in PbtO2 than OER, the authors concluded that this intervention could potentially increase the oxygen gradient between the vascular and tissue compartments. In another study, increasing CPP also resulted into a significant increase in PbtO2 (9). Our study included a larger population of patients, included other diseases than TBI, and tested two different CPP targets above the baseline values. Importantly, this CPP challenge should be performed only in those patients with low PbtO2 values at the baseline, in the absence of intracranial hypertension or hypoxemia. Increasing CPP in patients with normal PbtO2 at baseline would result in less significant oxygen improvement and no theoretical effect on tissue metabolism. In one study, Stocchetti et al. also reported that PbtO2 regularly improved after 22 CPP challenges, in particular when low oxygen values were present at the baseline (16). Baseline PbtO2 below 20 mm Hg was often associated with CPP values within normal ranges. Interestingly, increasing CPP with other drugs than norepinephrine, such as dopamine, might result in less predictable CPP increase and less significant PbtO2 increase (17, 18). Moreover, PbtO2 would change in response to CPP challenge if placed into “at-risk” areas, as in our study, while effects might be minimal if the catheter is inserted into normal-appearing parenchyma (17).\n\nIt has been suggested that cerebral hemodynamics after an acute brain injury could be assessed using non-invasive monitoring, such as cerebral blood flow velocities or cerebral autoregulation indices. As such, because PbtO2 is dependent on CPP below the lower limit of autoregulation (i.e., the value of CPP corresponding to the direct dependency of cerebral blood flow from the systemic driving pressure) (19), recommended CPP targets can still result in tissue hypoxia in the absence of elevated ICP, as autoregulation might be impaired or the lower limit shifted toward higher CPP thresholds in brain injured patients (20). Individualized CPP values based on optimal autoregulation status has also been suggested in TBI patients (20); however, targeting “safe” CPP values based on the plateau curve of autoregulation could not correspond to adequate brain oxygenation in some patients (21). In one study (19), PbtO2 was pressure dependent when autoregulation was impaired, while it remained within stable values if autoregulation was intact. However, tissue hypoxia could occur even within normal autoregulation indices (19), thus suggesting that only the presence of PbtO2 monitoring could help to optimize CPP and avoid tissue hypoxia. As such, it is not surprising that changes in PbtO2 during the CPP challenge would not correlate with changes in mFV or PI, two parameters derived from the analysis of cerebral blood flow velocities that are commonly used to estimate cerebral hypoperfusion in the presence of intracranial hypertension (22). In SAH patients, no correlation was observed between PbtO2 measurements and, simultaneously, TCD recording (23). In another study including TBI patients, episode of cerebral hypoxia had all mFV <40 cm/s; however, no correlation was observed between PbtO2 and mFV in the whole cohort (24). Unfortunately, we did not specifically assess cerebral autoregulation in our study and could not provide additional data to the relationship between autoregulatory status and brain oxygenation. Similarly, NPi assessment using automated pupillometry could reflect elevated ICP (25); however, as tissue hypoxia may occur even within normal ICP values, the lack of sufficient correlation between PbtO2 and NPi changes was expected.\n\nThis study has several limitations to acknowledge. First, the small sample size and monocentric and retrospective design might introduce significant selection biases and limit the generalizability of our findings, although characteristics of included and excluded patients were similar. Second, although we suggested the need for higher than recommended CPP targets, MAP transducer was zeroed at the atrium level, while some centers would place the zero-reference point next to cerebral anatomical structures, i.e., the foramen of Monro, which would result in 10–15 mmHg lower CPP, depending on the elevation of the head of the bed (usually 15–30°) (26). Third, many patients had baseline ICP, CPP, and PbtO2 within normal values at baseline, which might not entirely justify a daily “CPP challenge.” However, the duration of CPP challenge was short, being supervised by an experienced intensivist, and was clinically relevant, as conducted in a well-designed approach, and informative for daily patient management. Interestingly, in those patients with normal PbtO2 levels at baseline, lower than recommended CPP targets might have been theoretically used, still maintaining adequate oxygen levels. However, lower CPP values would be outside of routine management in brain injured patients and future studies should prospectively evaluate the safety of such approach. Fourth, the procedure was considered as safe (i.e., no complications were recorded); however, we did not assess changes in cerebral metabolism (i.e., glucose or lactate/pyruvate ratio), which might have also been influenced by changes in brain hemodynamics. Fifth, CPP augmentation was not compared with other interventions able to increase PbtO2 in brain injured patients (i.e., increase in FiO2 and arterial hyperoxia) (27). As such, whether increased CPP rather than, as an example, increased FiO2 would result in similar effects on brain oxygenation or would have a different safety profile in brain injured patients remains unknown. Sixth, we only assessed short-terms effects of increasing CPP, while persistently high CPP values might be associated with an increased risk of acute respiratory failure, at least in TBI patients, and would not result in better neurological outcome than standard targets (28). Seventh, we defined tissue hypoxia as a PbtO2 <20 mmHg; ischemic thresholds for PbtO2 have been tested using the association of this value with patients' outcome; a recent study identified a threshold of 19 mmHg which adequately separated patients with unfavorable and favorable neurological outcome after TBI (29). However, the ischemic threshold might vary among different brain disease and within patients and the presence of concomitant metabolism monitoring (i.e., microdialysis) might be helpful to identify ischemic levels of PbtO2 when they would be associated with low cerebral glucose levels and increased lactate/pyruvate ratio. Eighth, the cerebrovascular pathophysiology among the different types of acute brain injury is different; in particular, SAH patients can develop delayed cerebral ischemia between 4 and 15 days after the injury, whereas cerebral hyperemia and intracranial hypertension may be more common in TBI patients. As such, our findings are also relevant to the very early phase after the injury and in the absence of uncontrolled intracranial hypertension. Finally, we provided different descriptive analyses without multivariable assessment, as the number of events was limited; however, multiple statistical comparisons exposes to the inflation of false positive tests within dependent datasets.\n\nConclusions\n\nIn this heterogeneous population of acute brain injured patients, PbtO2 monitoring suggested the need for higher than recommended CPP targets to avoid tissue hypoxia. A higher response in brain oxygenation to the CPP challenge was observed in those patients with low PbtO2 values at baseline. The effects of CPP increase over brain oxygenation are consistent over time.\n\nData Availability Statement\n\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by Ethical Committee of the Erasme Hospital. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.\n\nAuthor Contributions\n\nFST, SS, and MK conceived the study protocol. AQ and FST performed the transcranial Doppler. MK, EG, and LP collected the data. HN, LP, and MK analyzed the data. FST, MK, JC, and OD drafted the present manuscript. SS, EG, LP, and AQ critically revised the manuscript. All authors read and approved the final manuscript.\n\nConflict of Interest\n\nFST is the Scientific Advisor for Neuroptics Inc. and received lecture fees from Integra LifeSciences. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nPublisher's Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fneur.2021.732830/full#supplementary-material\n\nClick here for additional data file.\n==== Refs\nReferences\n\n1. Helbok R Schiefecker AJ Beer R Dietmann A Antunes AP Sohm F . Early brain injury after aneurysmal subarachnoid hemorrhage: a multimodal neuromonitoring study. Crit Care. (2015) 19 :75. 10.1186/s13054-015-0809-9 25887441\n2. Maldonado JR . Acute brain failure: pathophysiology, diagnosis, management, and sequelae of delirium. Crit Care Clin. (2017) 33 :461–519. 10.1016/j.ccc.2017.03.013 28601132\n3. Carney N Totten AM O'Reilly C Ullman JS Hawryluk GWJ Bell MJ . Guidelines for the management of severe traumatic brain injury, fourth edition. Neurosurgery. (2017) 80 :6–15. 10.1227/NEU.0000000000001432 27654000\n4. Le Roux P Menon DK Citerio G Vespa P Bader MK Brophy GM . Consensus summary statement of the International multidisciplinary consensus conference on multimodality monitoring in neurocritical care : a statement for healthcare professionals from the neurocritical care society and the European Society of Intensive Care Medicine. Intensive Care Med. (2014) 40 :1189–209. 10.1007/s00134-014-3369-6 25138226\n5. Eriksson EA Barletta JF Figueroa BE Bonnell BW Vanderkolk WE McAllen KJ . Cerebral perfusion pressure and intracranial pressure are not surrogates for brain tissue oxygenation in traumatic brain injury. Clin Neurophysiol. (2012) 123 :1255–60. 10.1016/j.clinph.2011.08.035 22104471\n6. Fiore M Bogossian E Creteur J Oddo M Taccone FS . Role of brain tissue oxygenation (PbtO2) in the management of subarachnoid haemorrhage: a scoping review protocol. BMJ Open. (2020) 10 :e035521. 10.1136/bmjopen-2019-035521 32933956\n7. Kirkman MA Smith M . Brain oxygenation monitoring. Anesthesiol Clin. (2016) 34 :537–56. 10.1016/j.anclin.2016.04.007 27521197\n8. Johnston AJ Steiner LA Coles JP Chatfield DA Fryer TD Smielewski P . Effect of cerebral perfusion pressure augmentation on regional oxygenation and metabolism after head injury. Crit Care Med. (2005) 33 :189–95. 10.1097/01.CCM.0000149837.09225.BD 15644668\n9. Rosenthal G Hemphill JC Sorani M Martin C Morabito D Obrist WD . Brain tissue oxygen tension is more indicative of oxygen diffusion than oxygen delivery and metabolism in patients with traumatic brain injury. Crit Care Med. (2008) 36 :1917–24. 10.1097/CCM.0b013e3181743d77 18496376\n10. Connolly ES Rabinstein AA Carhuapoma JR Derdeyn CP Dion J Higashida RT . Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/american Stroke Association. Stroke. (2012) 43 :1711–37. 10.1161/STR.0b013e3182587839 22556195\n11. Morgenstern LB Hemphill JC Anderson C Becker K Broderick JP Connolly ES . Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. (2010) 41 :2108–29. 10.1161/STR.0b013e3181ec611b 20651276\n12. Purkayastha S Sorond F . Transcranial Doppler ultrasound: technique and application. Semin Neurol. (2012) 32 :411–20. 10.1055/s-0032-1331812 23361485\n13. Marshall LF Marshall SB Klauber MR Van Berkum Clark M Eisenberg H Jane JA . The diagnosis of head injury requires a classification based on computed axial tomography. J Neurotrauma. (1992) 9 (Suppl. 1 ):S287–92.\n14. Rosen DS Macdonald RL . Subarachnoid hemorrhage grading scales: a systematic review. Neurocrit Care. (2005) 2 :110–8. 10.1385/NCC:2:2:110 16159052\n15. Jennett B Bond M . Assessment of outcome after severe brain damage. Lancet Lond Engl. (1975) 1 :480–4. 10.1016/S0140-6736(75)92830-5 46957\n16. Stocchetti N Chieregato A De Marchi M Croci M Benti R Grimoldi N . High cerebral perfusion pressure improves low values of local brain tissue O2 tension (PtiO2) in focal lesions. Acta Neurochir Suppl. (1998) 71 :162–5. 10.1007/978-3-7091-6475-4_47 9779173\n17. Kiening KL Härtl R Unterberg AW Schneider GH Bardt T Lanksch WR . Brain tissue pO2-monitoring in comatose patients: implications for therapy. Neurol Res. (1997) 19 :233–40. 10.1080/01616412.1997.11740805 9192372\n18. Steiner LA Johnston AJ Czosnyka M Chatfield DA Salvador R Coles JP . Direct comparison of cerebrovascular effects of norepinephrine and dopamine in head-injured patients. Crit Care Med. (2004) 32 :1049–54. 10.1097/01.CCM.0000120054.32845.A6 15071400\n19. Jaeger M Dengl M Meixensberger J Schuhmann MU . Effects of cerebrovascular pressure reactivity-guided optimization of cerebral perfusion pressure on brain tissue oxygenation after traumatic brain injury. Crit Care Med. (2010) 38 :1343–7. 10.1097/CCM.0b013e3181d45530 20154598\n20. Donnelly J Czosnyka M Adams H Robba C Steiner LA Cardim D . Individualizing thresholds of cerebral perfusion pressure using estimated limits of autoregulation. Crit Care Med. (2017) 45 :1464–71. 10.1097/CCM.0000000000002575 28816837\n21. Radolovich DK Czosnyka M Timofeev I Lavinio A Hutchinson P Gupta A . Reactivity of brain tissue oxygen to change in cerebral perfusion pressure in head injured patients. Neurocrit Care. (2009) 10 :274–9. 10.1007/s12028-009-9190-3 19184551\n22. Robba C Taccone FS . How I use transcranial Doppler. Crit Care Lond Engl. (2019) 23 :420. 10.1186/s13054-019-2700-6 31870405\n23. Craven CL Sae-Huang M Hoskote C Watkins LD Reddy U Toma AK . Relationship between brain tissue oxygen tension and transcranial Doppler ultrasonography. World Neurosurg. (2021) 149 :e942–6. 10.1016/j.wneu.2021.01.070 33513443\n24. Sokoloff C Williamson D Serri K Albert M Odier C Charbonney E . Clinical usefulness of transcranial doppler as a screening tool for early cerebral hypoxic episodes in patients with moderate and severe traumatic brain injury. Neurocrit Care. (2020) 32 :486–91. 10.1007/s12028-019-00763-y 31218643\n25. Robba C Pozzebon S Moro B Vincent JL Creteur J Taccone FS . Multimodal non-invasive assessment of intracranial hypertension: an observational study. Crit Care Lond Engl. (2020) 24 :379. 10.1186/s13054-020-03105-z 32591024\n26. Reinstrup P Unnerbäck M Marklund N Schalen W Arrocha JC Bloomfield EL . Best zero level for external ICP transducer. Acta Neurochir. (2019) 161 :635–42. 10.1007/s00701-019-03856-x 30848373\n27. Dellazizzo L Demers SP Charbonney E Williams V Serri K Albert M . Minimal PaO2 threshold after traumatic brain injury and clinical utility of a novel brain oxygenation ratio. J Neurosurg. (2018) 1–9. [Epub ahead of print].\n28. Contant CF Valadka AB Gopinath SP Hannay HJ Robertson CS . Adult respiratory distress syndrome: a complication of induced hypertension after severe head injury. J Neurosurg. (2001) 95 :560–8. 10.3171/jns.2001.95.4.0560 11596949\n29. Hirschi R Hawryluk GWJ Nielson JL Huie JR Zimmermann LL Saigal R . Analysis of high-frequency PbtO2 measures in traumatic brain injury: insights into the treatment threshold. J Neurosurg. (2018) 1–11. 10.3171/2018.4.JNS172604. [Epub ahead of print].\n\n",
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"journal": "Frontiers in neurology",
"keywords": "brain injury; brain oxygenation; individualized therapy; intracranial hemorrhage; optimal perfusion; subarachnoid hemorrhage; traumatic brain injury",
"medline_ta": "Front Neurol",
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"title": "Optimal Cerebral Perfusion Pressure Guided by Brain Oxygen Pressure Measurement.",
"title_normalized": "optimal cerebral perfusion pressure guided by brain oxygen pressure measurement"
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"abstract": "Hematopoietic stem cell transplantation (HSCT) can be lifesaving for some of the deadliest hematologic diseases. However, immunosuppression, polypharmacy and risk of infectious complications associated with HSCT can increase morbidity and mortality for recipients. Incidence of acute kidney injury (AKI) after HSCT can be as high as 70%, and concomitant infection can be a therapeutic challenge for oncologists, nephrologists and infectious disease specialists. We illustrate this challenge in the case of a 31-year-old man with acute lymphoblastic leukemia who underwent a double cord HSCT complicated by GvHD, systemic cryptococcal and BK virus infections and AKI. Kidney biopsy showed round to cup-shaped organisms with occasional budding, consistent with Cryptococcus and thrombotic microangiopathy. We discuss our findings and a literature review of disseminated cryptococcal infection with renal involvement after HSCT.",
"affiliations": "Department of Infectious Diseases, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Division of Renal Diseases and Hypertension, The University of Texas Medical School at Houston, Houston, TX, USA.;Department of Pathology and Laboratory Medicine, The University of Texas Medical School at Houston, Houston, TX, USA.;Division of Medical Oncology, Duke University Medical Center, Durham, NC, USA.;Department of Infectious Diseases, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Infectious Diseases, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Division of Renal Diseases and Hypertension, The University of Texas Medical School at Houston, Houston, TX, USA.;Department of Pathology and Laboratory Medicine, The University of Texas Medical School at Houston, Houston, TX, USA.;Division of Internal Medicine, Section of Nephrology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.",
"authors": "Oliver|N|N|;Luong|T|T|;Tchakarov|A|A|;Abdelrahim|M|M|;Mulanovich|V E|VE|;Kontoyiannis|D P|DP|;Jones|R|R|;Kebriaei|P|P|;Samuels|J|J|;Glass|W|W|;Abudayyeh|A|A|",
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"issue": "51(10)",
"journal": "Bone marrow transplantation",
"keywords": null,
"medline_ta": "Bone Marrow Transplant",
"mesh_terms": "D058186:Acute Kidney Injury; D000328:Adult; D003453:Cryptococcosis; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D057049:Thrombotic Microangiopathies; D014184:Transplantation, Homologous",
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"title": "Disseminated cryptococcal infection in allogeneic stem cell transplant patients: a rare cause of acute kidney injury.",
"title_normalized": "disseminated cryptococcal infection in allogeneic stem cell transplant patients a rare cause of acute kidney injury"
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"companynumb": "US-ROCHE-1866381",
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"abstract": "BACKGROUND\nThe incidence of cardiac thrombi in newborns has increased with the use of central venous catheters. Thrombolysis with recombinant tissue plasminogen activator (rTPA) has been used as an alternative to heparin in life threatening giant thrombus and embolization. The aim of this study is to describe the response and complications related to the use of rTPA in the management of life- threatening cardiac thrombi in newborns.\n\n\nMETHODS\nThe medical records of 8 newborn were reviewed in a retrospective study, of whom 7 were preterm with cardiac thrombi, and rTPA was used in all of them.\n\n\nRESULTS\nThe patients included 4 males with a mean weight of 1580 gr. The principal pathology was sepsis (7/8), all of them used venous central catheter. The superior vena cava was the most frequent location, with a mean time of installation before the diagnosis of 12 days. RN 7/8 thrombi were located in the right atrium with a size between 7 to 20 mm. Three patients received low molecular weight heparin prior to using rTPA. They received between 1 to 5 cycles with rTPA. In 4 patients complete resolution of the thrombus was achieved in a mean of 3.5 days. Four patients had intracranial haemorrhage grade I, without sequelae at follow-up. There were no deaths or embolism.\n\n\nCONCLUSIONS\nThis study is the first series of infants treated with rTPA in Chile, and where its use has quickly achieved complete resolution of the thrombus in 50% of cases, and partially in the others, thus reducing the secondary life-threatening risk of this disease.",
"affiliations": "Hospital Roberto del Río, Santiago, Chile; Departamento de Pediatría Norte, Facultad de Medicina, Universidad de Chile, Santiago, Chile; Clínica Alemana de Santiago, Santiago, Chile. Electronic address: pazenteno@yahoo.com.;Hospital Roberto del Río, Santiago, Chile; Departamento de Pediatría Norte, Facultad de Medicina, Universidad de Chile, Santiago, Chile; Clínica Santa María, Santiago, Chile.;Hospital Roberto del Río, Santiago, Chile.;Departamento de Pediatría Norte, Facultad de Medicina, Universidad de Chile, Santiago, Chile; Servicio de Neonatología, Hospital San José, Santiago, Chile.;Alumno de Medicina, Universidad de Chile, Santiago, Chile.;Alumno de Medicina, Universidad Finis Terrae, Santiago, Chile.",
"authors": "Álvarez Z|Patricia|P|;Verdugo L|Patricia|P|;Carvajal K|Luis|L|;Múhlhausen M|Germán|G|;Ríos A|Patricia|P|;Rodríguez V|Diego|D|",
"chemical_list": "D005343:Fibrinolytic Agents; D006493:Heparin; D010959:Tissue Plasminogen Activator",
"country": "Chile",
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"keywords": "Activador plasminógeno tisular recombinante; Intracardiac thrombi; Neonatal thrombolysis; Recombinant tissue plasminogen activator; Trombos cardiacos; Trombólisis neonatal",
"medline_ta": "Rev Chil Pediatr",
"mesh_terms": "D062905:Central Venous Catheters; D002677:Chile; D005260:Female; D005343:Fibrinolytic Agents; D005500:Follow-Up Studies; D006331:Heart Diseases; D006493:Heparin; D006801:Humans; D007231:Infant, Newborn; D020300:Intracranial Hemorrhages; D008297:Male; D012189:Retrospective Studies; D015912:Thrombolytic Therapy; D013927:Thrombosis; D013997:Time Factors; D010959:Tissue Plasminogen Activator; D016896:Treatment Outcome",
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"publication_types": "D016428:Journal Article",
"references": null,
"title": "Recombinant tissue plasminogen activator for the management of intracardiac thrombi in newborns.",
"title_normalized": "recombinant tissue plasminogen activator for the management of intracardiac thrombi in newborns"
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"companynumb": "CL-ROCHE-2061063",
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"abstract": "New triplet chemotherapy combinations are under investigation in advanced non small cell lung cancer (NSCLC). Carboplatin, plus paclitaxel, plus gemcitabine is among the most active and promising regimens. The use of more aggressive chemotherapy in order to improve results can increase toxicity. Amifostine (WR-2721) reduces toxicity of radiotherapy and chemotherapy and protects selectively a number of normal, but not neoplastic, tissue. Based on this background, we performed a phase II study on carboplatin, plus paclitaxel, plus gemcitabine with amifostine support in advanced NSCLC. Patients received chemotherapy at the following dosage: carboplatin AUC 5, i.v., at day 1; paclitaxel 175 mg/m2, i.v. by 3-hour infusion, at day 1; gemcitabine 1000 mg/m2, i.v. by 3-hour infusion, at days 1 and 8; every 3 weeks for a maximum of 6 cycles. Amifostine was administered at the dose of 740 mg/m2, i.v., at day 1 of each cycle. Seventeen patients entered the study. They were prevalently male, median age was 62 years, PS (ECOG) was 0 in 10 cases (58.8%), 1 in 6 (35.3%) and 2 in 1 (5.9%). Histology was epidermoid in 8 cases (47%) and adenocarcinoma in 9 (53%). We observed 8 (47.5%) objective responses with 2 (11.7%) complete responses. Median time to progression and median survival were 24 and 36 weeks, respectively. Treatment was well tolerated. The main toxicity was as follows: grade 3 neutropenia, grade 2 thrombocytopenia and grade 3 anemia in one (5.8%) case; grade 2 peripheral neurologic toxicity in 3 (17.6%) patients; grade 2 cardiac toxicity (atrial fibrillation) in one case; and grade 3 respiratory toxicity (dispnoea) in one patient. These data indicate that this combination has promising activity and tolerability. A randomized trial comparing carboplatin plus paclitaxel, plus gemcitabine versus carboplatin, plus paclitaxel, plus gemcitabine, plus amifostine in advanced NSCLC is warranted.",
"affiliations": "VI Divisione di Pneumologia, Ospedale Monaldi, Napoli, Italy.",
"authors": "Illiano|A|A|;Barletta|E|E|;De Marino|V|V|;Battiloro|C|C|;Barzelloni|M|M|;Scognamiglio|F|F|;Rossi|N|N|;Zampa|G|G|;De Bellis|M|M|;Gridelli|C|C|",
"chemical_list": "D011837:Radiation-Protective Agents; D003841:Deoxycytidine; C056507:gemcitabine; D016190:Carboplatin; D004999:Amifostine; D017239:Paclitaxel",
"country": "Greece",
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"issn_linking": "0250-7005",
"issue": "20(5C)",
"journal": "Anticancer research",
"keywords": null,
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"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D004999:Amifostine; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D002289:Carcinoma, Non-Small-Cell Lung; D002294:Carcinoma, Squamous Cell; D003841:Deoxycytidine; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D017239:Paclitaxel; D011837:Radiation-Protective Agents",
"nlm_unique_id": "8102988",
"other_id": null,
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"pmid": "11268491",
"pubdate": "2000",
"publication_types": "D016430:Clinical Trial; D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "New triplet chemotherapy combination with carboplatin, paclitaxel and gemcitabine plus amifostine support in advanced non small cell lung cancer: a phase II study.",
"title_normalized": "new triplet chemotherapy combination with carboplatin paclitaxel and gemcitabine plus amifostine support in advanced non small cell lung cancer a phase ii study"
} | [
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"companynumb": "IT-PFIZER INC-202101490276",
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{
"abstract": "Anti-synthetase syndrome (ASS) is an autoimmune disease characterized by autoantibodies against an aminoacyl transfer RNA synthetase with clinical features including interstitial lung disease, non-erosive arthritis, myositis, Raynaud's phenomenon, unexplained fever and/or mechanic's hands. Macrophage activation syndrome (MAS) is a potentially fatal hyper- inflammatory syndrome that can occur as a complication of systemic rheumatic diseases. However, the association of MAS and ASS has rarely been reported in the literature. Here, we report this association in a patient with overlap ASS and anti-CCP positive rheumatoid arthritis. First line management with steroids was complicated by diabetic ketoacidosis, hence requiring use of anti-IL1 therapy (anakinra) for disease control.",
"affiliations": "Rheumatology, Royal Berkshire NHS Foundation Trust, Reading RG1 5AN, UK.;Rheumatology, Royal Berkshire NHS Foundation Trust, Reading RG1 5AN, UK.;Rheumatology, Royal Berkshire NHS Foundation Trust, Reading RG1 5AN, UK.",
"authors": "Ahmad|Nadia|N|;Parmar|Aneel|A|;Kitchen|Joanne|J|",
"chemical_list": null,
"country": "England",
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"doi": "10.1093/omcr/omab045",
"fulltext": "\n==== Front\nOxf Med Case Reports\nOxf Med Case Reports\nomcr\nOxford Medical Case Reports\n2053-8855\nOxford University Press\n\n34158959\n10.1093/omcr/omab045\nomab045\nCase Report\nAcademicSubjects/MED00010\nomcrep/2300\nomcrep/1100\nA case of macrophage activation syndrome in a patient with anti-synthetase syndrome\nAhmad Nadia\nParmar Aneel\nKitchen Joanne\nRheumatology, Royal Berkshire NHS Foundation Trust, Reading RG1 5AN, UK\nCorrespondence address. Royal Berkshire NHS Foundation Trust, Rheumatology London Rd, Reading RG1 5AN, UK. Tel: 0118 322 7969; E-mail: nadiaahmad@live.co.uk\n6 2021\n18 6 2021\n18 6 2021\n2021 6 omab04526 11 2020\n22 3 2020\n11 4 2021\n© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com\n\nABSTRACT\n\nAnti-synthetase syndrome (ASS) is an autoimmune disease characterized by autoantibodies against an aminoacyl transfer RNA synthetase with clinical features including interstitial lung disease, non-erosive arthritis, myositis, Raynaud’s phenomenon, unexplained fever and/or mechanic’s hands. Macrophage activation syndrome (MAS) is a potentially fatal hyper- inflammatory syndrome that can occur as a complication of systemic rheumatic diseases. However, the association of MAS and ASS has rarely been reported in the literature. Here, we report this association in a patient with overlap ASS and anti-CCP positive rheumatoid arthritis. First line management with steroids was complicated by diabetic ketoacidosis, hence requiring use of anti-IL1 therapy (anakinra) for disease control.\n==== Body\nINTRODUCTION\n\nAnti-synthetase syndrome (ASS) is an autoimmune disease characterized by autoantibodies against an aminoacyl transfer RNA (tRNA) synthetase with clinical features that may include interstitial lung disease (ILD), non-erosive arthritis, myositis, Raynaud’s phenomenon, unexplained fever and/or mechanic’s hands [1]. Macrophage activation syndrome (MAS) can be a fatal complication of rheumatic disorders. It has rarely been reported in patients with ASS. Here, we describe this association in an adult patient.\n\nCASE REPORT\n\nWe present a case of 65-year-old Nepalese female with an overlap of ASS and anti-cyclic citrullinated peptide (CCP) antibody positive rheumatoid arthritis (RA) who developed MAS which was successfully treated with anakinra. She was diagnosed with ASS based on the presence of arthritis, ILD, anti-Jo1 and antiRo52 autoantibodies. She was maintained on 6-monthly Rituximab cycles (one 1gm infusion repeated 15 days after the first for each cycle), completed two cycles, last given 6 months prior to her presentation. In view of the coronavirus disease 2019 (COVID-19) pandemic the third cycle was withheld and Azathioprine was commenced which she took for 2 weeks. Two weeks prior to her admission Azathioprine was switched to an up titrating dose of Mycophenolate due to nonspecific symptoms of headache and dizziness attributed to possible medication intolerance. She was admitted with fever, abdominal pain and headaches. Clinical examination revealed pyrexia (38.3C), hypotension (109/70 mmHg), tachycardia (HR 94 bpm) and palmar maculopapular rash. Laboratory investigations showed pancytopenia, Hb 100 (115–165 g/L), WCC 2.40 (4–11 × 109/L), Platelets 61 (150–450 × 109/L), Neutrophils 1.75 (2–7 × 109/L), lymphocytes 0.50 (1– 4 × 10^9/L), Ferritin of >55 000 (15–300 ug/L), Triglycerides 4.3 (1.8 mmol/L), LDH 1200 (135–214 IU/L), Fibrinogen 2.8 g/l(normal), ALT 108 (<34 IU/L), CRP 141 (0–6 mg/L) and ESR 24 mm/hr.\n\nA septic screen for common bacterial and viral pathogens including parvovirus, Epstein-Barr virus, Cytomegalovirus, human immunodeficiency virus and hepatitis was negative. Multiple covid-19 swabs were negative. Computed tomography of chest, abdomen and pelvis showed no evidence of hepatosplenomegaly or an underlying malignancy. Lack of improvement with broad-spectrum antimicrobials, evolving pancytopenia, elevated ferritin and persistent fever with patient’s background history of autoimmune disease raised concerns about MAS. She fulfilled the 2014 HScore by Fardet et al. [2] with a score of 199 (cut off 169), (Fig 1). Treatment with IV methylprednisolone 15 mg/kg/day for 3 days was initiated followed by oral prednisolone, 60 mg along with ciclosporin 2 mg/kg/d. She had a history of type 2 diabetes, was on oral hypoglycaemic medications but developed hyperglycaemia and ketosis secondary to steroid and required Insulin therapy. Anakinra 100 mg once daily subcutaneously was added after Multidisciplinary team discussion to reduce steroid toxicity and facilitate a rapid steroid taper, whilst providing optimal disease control. Immediate clinical improvement was noted with normalization of fevers and gradual normalization of laboratory abnormalities including ferritin, cell counts (Fig 2) and inflammatory markers. We believe an underlying rheumatic immune disorder was the likely predisposing factor for the development of MAS in our patient, as she was not maintained on biologic/immunomodulatory therapy due to paused Rituximab in view of COVID-19 pandemic and possible intolerance to various agents.\n\nFigure 1 H score.\n\nFigure 2 Progression of serum ferritin and white cell count.\n\nDISCUSSION\n\nHaemophagocytic lymphohistiocytosis (HLH) is characterized by an unregulated inflammatory response with cytokine storm leading to multisystem organ failure and can be fatal if not recognized and treated promptly. HLH can be familial (primary) or acquired (secondary to infection, malignancy or active autoinflammation). Secondary HLH (sHLH) in association with rheumatologic autoimmune diseases including systemic lupus erythematosus, adult-onset Still disease, and systemic juvenile idiopathic arthritis is known as MAS [3]. However, it is rarely seen in patients with ASS and has been described only in case reports where most patients reportedly suffered from dermatomyositis. Anti- Jo-1, anti- Mi-2 and anti-MDA-5 autoantibodies have been found in cases of idiopathic inflammatory myositis complicated by MAS [4]. Early diagnosis is often challenging due to clinical manifestations mimicking sepsis, active autoimmune diseases and lack of widely accepted diagnostic criteria. Various tools have been developed which use clinical symptoms and laboratory abnormalities to risk-stratify patients but have limitations. The H-score by Fardet et al. [2] has been validated for the diagnosis of reactive HLH and subsequently showed good diagnostic accuracy in an observational study by Knaak et al. [5]. However, clinical judgement and awareness of the condition remains paramount in diagnosis. Timely diagnosis and treatment to reduce systemic inflammation is imperative to reduce high mortality. High-dose glucocorticoid monotherapy is usually the first line treatment with subsequent addition of immunomodulatory agents in refractory cases [6]. Over recent years, various biologics and immunotherapies have been used successfully for MAS treatment. This also includes Anakinra, a recombinant interleukin-1 (IL-1) receptor antagonist used in various autoinflammatory diseases. Although limited, there are now case reports and series showing favourable response to anakinra, both subcutaneously and intravenously in sHLH subtypes [7]. Its use is also appealing due to relatively short half-life that permits its discontinuation if an adverse effect occurs or concern for worsening infection arises.\n\nOur case was challenging as patient initially manifested joint symptoms with positive immunology for RA and later developed ILD with positive ASS immune profile in the absence of clinical myositis, typical skin rash and normal CK levels. Aminoacyl tRNA positivity has been described in patients who fulfilled RA diagnostic criteria in the literature and hence ASS is an important clinical condition in the differential diagnosis of early RA. It has been reported that development of myositis can take years after onset of arthritis and ILD, which are also not rarely seen before myositis and in some myositis never occurs [8]. The most common arthritis pattern seen in ASS is small joint symmetrical polyarthritis quite similar what seen in RA. AntiCCP and rheumatoid factor positivity can be observed in ASS and lead to false RA diagnosis [9]. On the other hand, established knowledge that ASS is seen in cases with classical RA is quite limited. Current literature regarding the use of anakinra in cases of adult MAS is limited, further information regarding its effectiveness and potential clinical benefits and risks is needed [10]. In this case, however, we had a successful response and outcome in resistant MAS associated with ASS using anakinra.\n\nCONFLICT OF INTEREST STATEMENT\n\nThe authors have declared no conflicts of interest.\n\nFUNDING\n\nNo specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript.\n\nETHICAL APPROVAL\n\nNot applicable.\n\nCONSENT\n\nAn informed consent for publication has been obtained, Identifying details ofthe.\n\nPatient have not been used in this case report.\n\nGUARANTOR\n\nDr Nadia Ahmad, nadiaahmad@live.co.uk\n\nRoyal Berkshire NHS Foundation Trust, Rheumatology.\n==== Refs\nREFERENCES\n\n1. Connors GR, Christopher-Stine L, Oddis CV, Danoff SK. Interstitial lung disease associated with the idiopathic inflammatory myopathies: what progress has been made in the past 35 years? Chest 2010;138 :1464–74.21138882\n2. Fardet, et al. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol 2014;66 :2613–20.24782338\n3. Tristano AG . Macrophage activation syndrome: a frequent but under-diagnosed complication associated with rheumatic diseases. Med Sci Monit 2008;14 :RA27–36.18301366\n4. Bazan-Socha S, Zolcinski M, Szostek M, et al. A fatal case of acquired hemophagocytic lymphohistiocytosis (macrophage activation syndrome) in the initial course of dermatomyositis with anti-Jo-1 antibody. Int J Rheum Dis 2017;20 :2171–74.24112831\n5. Knaak C, et al. Hemophagocytic lymphohistiocytosis in critically ill patients: diagnostic reliability of HLH-2004 criteria and HScore. Crit Care 2020;24 :244. doi: 10.1186/s13054-020-02941-3.32448380\n6. Schulert GS, Grom AA. Pathogenesis of macrophage activation syndrome and potential for cytokine-directed therapies. Annu Rev Med 2015;66 :145–59.25386930\n7. Halyabar O, Chang MH, Schoettler ML, Schwartz MA, Baris EH, Benson LA, et al. Calm in the midst of cytokine storm: a collaborative approach to the diagnosis and treatment of hemophagocytic lymphohistiocytosis and macrophage activation syndrome. Pediatr Rheumatol Online J 2019;17 :7.30764840\n8. Katzap E, Barilla-LaBarca ML, Marder G. Antisynthetase syndrome. Curr Rheumatol Rep 2011;13 :175–81.21455765\n9. Mumm GE, McKown KM, Bell CL. Antisynthetase syndrome presenting as rheumatoid-like polyarthritis. J Clin Rheumatol 2010;16 :307–12.20859229\n10. Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult patient. Blood 2015;125 :2908–14.25758828\n\n",
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"title": "A case of macrophage activation syndrome in a patient with anti-synthetase syndrome.",
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"abstract": "A patient with relapsed/refractory B-cell acute lymphoblastic leukemia developed babesiosis before allogeneic hematopoietic cell transplantation while on atovaquone for Pneumocystis jirovecii pneumonia prophylaxis. Despite receiving a prolonged course of atovaquone and azithromycin until whole-blood Babesia microti DNA was no longer detected by polymerase chain reaction, her post-transplant course was complicated by relapsed babesiosis. We investigate the potential host and parasite characteristics causing relapsing/persistent infection.",
"affiliations": "Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.;Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.;Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.;Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.;Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.;Clinical Microbiology Laboratory, Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.;Tisch Cancer Institute, Division of Hematology/Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.;Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.;Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.",
"authors": "Rosenblatt|Joshua|J|https://orcid.org/0000-0003-4778-8264;Leung|Annie|A|;Baneman|Emily|E|https://orcid.org/0000-0002-8994-2023;Fuller|Risa|R|https://orcid.org/0000-0003-3263-166X;Taimur|Sarah|S|https://orcid.org/0000-0002-1776-7510;Paniz-Mondolfi|Alberto E|AE|https://orcid.org/0000-0003-1259-1736;Malone|Adriana K|AK|;Kirkman|Laura|L|https://orcid.org/0000-0003-4085-5540;Jacobs|Samantha E|SE|https://orcid.org/0000-0002-9770-886X",
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"fulltext": "\n==== Front\nOpen Forum Infect Dis\nOpen Forum Infect Dis\nofid\nOpen Forum Infectious Diseases\n2328-8957\nOxford University Press US\n\n10.1093/ofid/ofab323\nofab323\nID Teaching Cases\nAcademicSubjects/MED00290\nRelapsed Babesia microti Infection Following Allogeneic Hematopoietic Cell Transplantation in a Patient With B-cell Acute Lymphoblastic Leukemia: Case Report and Review of the Literature\nhttps://orcid.org/0000-0003-4778-8264\nRosenblatt Joshua 1\nLeung Annie 45\nhttps://orcid.org/0000-0002-8994-2023\nBaneman Emily 1\nhttps://orcid.org/0000-0003-3263-166X\nFuller Risa 1\nhttps://orcid.org/0000-0002-1776-7510\nTaimur Sarah 1\nhttps://orcid.org/0000-0003-1259-1736\nPaniz-Mondolfi Alberto E 2\nMalone Adriana K 3\nhttps://orcid.org/0000-0003-4085-5540\nKirkman Laura 45\nhttps://orcid.org/0000-0002-9770-886X\nJacobs Samantha E 1\n1 Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA\n2 Clinical Microbiology Laboratory, Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA\n3 Tisch Cancer Institute, Division of Hematology/Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA\n4 Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, New York, USA\n5 Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York, USA\nCorrespondence: Joshua Rosenblatt, MD, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1090, New York, NY 10029 (joshua.rosenblatt@mssm.edu).\n9 2021\n21 6 2021\n21 6 2021\n8 9 ofab32313 4 2021\n14 6 2021\n20 6 2021\n03 9 2021\n© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com\n\nAbstract\n\nA patient with relapsed/refractory B-cell acute lymphoblastic leukemia developed babesiosis before allogeneic hematopoietic cell transplantation while on atovaquone for Pneumocystis jirovecii pneumonia prophylaxis. Despite receiving a prolonged course of atovaquone and azithromycin until whole-blood Babesia microti DNA was no longer detected by polymerase chain reaction, her post-transplant course was complicated by relapsed babesiosis. We investigate the potential host and parasite characteristics causing relapsing/persistent infection.\n\nBabesia microti\nbabesiosis\nhematopoietic cell transplantation\nimmunocompromised host\ntick-borne pathogens\n==== Body\npmcCASE REPORT\n\nA 64-year-old female resident of Rockland County, New York, with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) awaiting hematopoietic cell transplantation (HCT) presented to the emergency department on 7/16/19 with fever and malaise for 1 day.\n\nShe had been previously diagnosed with CD20-positive Philadelphia chromosome-negative B-cell ALL in July 2018 and initiated treatment according to the dose-adjusted CALGB 10403 protocol [1]. Rituximab was incorporated into her regimen in the setting of CD20 positivity. Due to persistent minimal residual disease, she was transitioned to blinatumomab on 12/12/18 [2], then to salvage chemoimmunotherapy with inotuzumab plus mini–cyclophosphamide, vincristine, and dexamethasone (mini-CVD) on 4/9/19 [3]. She had been taking atovaquone 1500 mg daily for Pneumocystis prophylaxis since September 2018.\n\nOn hospital day 3, she was diagnosed with babesiosis after a Giemsa-stained thin blood smear revealed intra-erythrocytic and extracellular ring forms consistent with Babesia microti (2.5% parasitemia). The whole-blood B. microti polymerase chain reaction (PCR) and serum B. microti immunoglobulin M/immunoglobulin G (IgM/IgG; LabCorp Laboratories, Burlington, NC, USA) were positive and negative, respectively. The buffy coat smear was negative for Anasplasma/Ehrlichia. The source of infection was presumed tick-borne given the season and geography. Transfusion-transmitted infection was considered because the patient had received 2 red blood cell (RBC) transfusions in the preceding 5 weeks, but thought unlikely since the New York State blood supply is screened year-round for Babesia by nucleic acid amplification [4]. Figure 1 illustrates pertinent clinical and laboratory data (haptoglobin, percent parasitemia, and B. microti PCR positivity), as well as treatment regimens at the time of initial diagnosis and throughout the course of infection.\n\nFigure 1. Illustration of case patient’s clinical course, laboratory findings, and antibabesial therapies received from initial diagnosis to death. Abbreviations: aHUS, atypical hemolytic uremic syndrome; CMO, comfort measures only, HCT, hematopoietic cell transplantation; PCR, polymerase chain reaction.\n\nBecause of her overall clinical stability, she was started on first-line therapy for babesiosis with azithromycin 1 g per os (PO) daily and atovaquone 750 mg twice daily on 7/18/19. Had she presented with more severe illness, alternative therapy might have been considered upfront given that she had previously been on atovaquone. Due to persistent fevers, clindamycin 600 mg IV every 8 hours was added on 7/21/19. She was transfused 1 unit of packed RBCs on hospital days 5 and 9. Her fevers eventually resolved, and the markers of hemolysis began to improve.\n\nShe was discharged on 7/25/19 with atovaquone 750 mg twice daily, azithromycin 1 g PO daily, and atovaquone-proguanil 1 tablet daily with continued weekly monitoring of the parasite blood smear, B. microti PCR, and hemolysis labs [5–8, 13]. Although the haptoglobin normalized and the blood smear turned negative on 8/2/19, the B. microti PCR and IgM/IgG remained positive and negative, respectively. Atovaquone and azithromycin were continued, but atovaquone-proguanil was stopped. Allogeneic HCT, initially scheduled for mid-August, was delayed until the following month.\n\nShe was admitted on 9/20/19 for HCT. The reduced intensity conditioning regimen consisted of cyclophosphamide, fludarabine, and total body irradiation (200 cGy). She underwent haploidentical allogeneic HCT on 9/27/19 (71 days from diagnosis of babesiosis). Tacrolimus and mycophenolate mofetil were administered for prevention of graft-vs-host disease (GvHD). The immediate post-transplant course was complicated by delayed engraftment and neutropenic fever due to central line–associated Staphylococcus epidermidis and Escherichia coli bloodstream infection.\n\nWhile admitted for HCT, the B. microti PCR became undetectable on 10/5/19 (79 days from diagnosis). Atovaquone and azithromycin were discontinued on 10/13/19 following 2 consecutive negative PCRs and in the setting of elevated liver function tests that were thought to be medication-related. She continued weekly B. microti PCR surveillance. Neutrophil engraftment occurred on 10/28/19, and she was discharged on 11/4/19 on tacrolimus for GvHD prophylaxis and acyclovir, trimethoprim-sulfamethoxazole (TMP-SMX), and voriconazole for antimicrobial prophylaxis.\n\nShe was readmitted on 11/11/19 with acute kidney injury, ultimately determined to be prerenal in etiology, but TMP-SMX was changed back to atovaquone 1500 mg daily for possible drug-induced renal toxicity. The hospital course was further complicated by recurrent hemolysis. The blood parasite smear and B. microti PCR remained negative, so she was administered the first of 4 weekly doses of eculizumab 900 mg for presumed tacrolimus-associated thrombotic microangiopathy on 11/25/19. Due to difficulty achieving therapeutic levels of sirolimus, she was changed to ruxolitinib 10 mg twice daily and prednisone 35 mg (0.5 mg/kg) daily for GvHD prophylaxis. She was discharged home on 11/27/19.\n\nShe was readmitted 8 days later on 12/5/19 with sepsis secondary to E. coli bacteremia from spontaneous bacterial peritonitis in the setting of noncirrhotic portal hypertension and worsening cholestasis. She was diagnosed with severe sinusoidal obstruction syndrome, formerly known as hepatic veno-occlusive disease, via liver biopsy and started on defibrotide on 12/11/19 with rapid, albeit partial, improvement in her hyperbilirubinemia.\n\nDuring this hospitalization, the B. microti PCR turned positive on 12/6/19 (141 days from diagnosis), although no parasite forms were initially detected on blood smear. The B. microti IgM/IgG remained negative. She was continued on atovaquone, restarted on azithromycin 500 mg PO daily on 12/13/19, and later initiated on clindamycin 600 mg IV every 8 hours on 12/17/19 in the setting of fevers. While on this regimen, she developed high-grade parasitemia (10%–12%) on 12/31/19 (Supplementary Figure 1). Although the possibility of reinfection was explored, relapse was considered to be more likely given the clinical history. Despite our patient residing in an area endemic for Ixodes scapularis, there was a very limited window for possible reinfection. Following the first negative B. microti PCR on 10/5/2019, she was out of the hospital for only 13 days during November and December. Furthermore, there are considerably fewer cases this time of year [9].\n\nAtovaquone-proguanil 4 tablets daily, doxycycline 100 mg PO every 12 hours, and quinine 648 mg every 8 hours were added on 1/1/20, 1/2/20, and 1/3/20, respectively. RBC exchange transfusion was considered, but ultimately deferred due to concerns about hemodynamic instability from significant fluid shifts. Shortly thereafter, despite the percent parasitemia decreasing to 0.4%, she developed worsening shock with multi-organ failure. After she and her family chose to pursue comfort care measures, she died on 1/12/20.\n\nDISCUSSION\n\nA history of B-cell lymphoid malignancy with either asplenia and/or treatment with immunosuppressive medications (rituximab, an anti-CD20 monoclonal antibody, in particular) is associated with more severe acute Babesia infection and poorer outcomes following standard treatment regimens [10]. The 2020 Infectious Diseases Society of America clinical practice guidelines recommend treating these patients for a longer duration—at least 6 weeks, including 2 weeks after parasites are no longer seen on blood smear [11].\n\nDespite what is known about the clinical course and management of babesiosis in immunocompromised hosts, to our knowledge, there are only 3 other published case reports of babesial infections in HCT recipients (Table 1). These reports include a patient with refractory sickle cell anemia with transfusion-transmitted babesiosis in the immediate pretransplant period [12], a patient with chronic myelogenous leukemia who developed babesiosis 3 years post-transplant following treatment with rituximab and while on corticosteroids for chronic GvHD [13], and a patient with myelofibrosis who was diagnosed with babesiosis 14 months post-transplant after receiving tacrolimus, rituximab, and corticosteroids for GvHD [14]. Whereas the first patient responded to a 10-day course of therapy with atovaquone and azithromycin, the second patient had persistent parasitemia after 8 weeks on this regimen. It was not until he was transitioned to clindamycin and quinine, started on atovaquone-proguanil, and had azithromycin increased to 1000 mg daily that the parasitemia cleared. The third patient, meanwhile, was treated with doxycycline, clindamycin, and atovaquone for 6 weeks with rapid improvement in his hemolytic anemia.\n\nTable 1. Description of Published Cases of Babesiosis in Hematopoietic Cell Transplant Recipients\n\n\tUnderlying Disease\tTransplant Type\tImmunosuppression at the Time of Initial Babesia Diagnosis\tTime From HCT to Diagnosis\tMode of Diagnosis\tInitial Treatment and Duration\tPersistent/Relapsing Infection\tSubsequent Treatment\tFinal Outcome (Clinical and Microbiological)\t\nPatient 1 [12]\tSickle cell anemia\tNonmyeloablative peripheral blood SCT\tUnknown\t~6 mo\tPositive blood parasite smear, Babesia IFA, and Babesia PCR\tAtovaquone 750 mg twice daily and azithromycin 600 mg daily for 10 d\tNo\tN/A\tSurvived\nNo further evidence of parasitemia by blood smear or Babesia PCR\t\nPatient 2 [13]\tCML\tAllogeneic SCT\tPrednisone 5–10 mg daily, MMF until 5 mo before diagnosis, and rituximab until 7 mo before diagnosis\t3 y\tPositive blood parasite smear\tAtovaquone 750 mg twice daily and azithromycin 500 mg daily for 8 wk\tYes\nPersistent parasitemia and worsening hemolysis\tClindamycin 600 mg Q8H, quinine 628 mg Q8H, azithromycin 1000 mg daily, and atovaquone-proguanil (500/100 mg for the first 7 d, followed by 250/100 mg) twice daily for 6 wk, then azithromycin and atovaquone-proguanil alone\tSurvived\nParasitemia became undetectable on 4-drug therapy; Babesia PCR turned negative the following month\t\nPatient 3 [14]\tMyelofibrosis\tHLA-matched unrelated donor allogeneic HCT\tCorticosteroids, tacrolimus, and rituximab\t14 mo\tPositive blood parasite smear and Babesia PCR\tDoxycycline, clindamycin, and atovaquone for 6 wk\tNo\tN/A\tSurvived\nParasitemia resolved within 2 wk\t\nPatient 4 (current case)\tB-cell ALL\tHLA-matched related donor allogeneic HCT\tRituximab until 9 mo before diagnosis\t2 mo before HCT\tPositive blood parasite smear and B. microti PCR\tAtovaquone 750 mg twice daily and azithromycin (1000 mg initially, then 500 mg) daily for nearly 3 mo\tYes\nRelapsed infection with recurrent parasitemia and hemolysis\tAtovaquone 750 mg twice daily, azithromycin 500 mg daily, clindamycin 600 mg Q8H, atovaquone-proguanil 4 tablets daily, doxycycline 100 mg Q12H, and quinine 648 mg Q8H\tExpired\t\nAbbreviations: ALL, acute lymphoblastic leukemia; CML, chronic myelogenous leukemia; GvHD, graft-vs-host disease; HCT, hematopoietic cell transplantation; IFA, indirect fluorescent assay; MMF, mycophenolate mofetil; PCR, polymerase chain reaction; SCT, stem cell transplantation.\n\nHerein we report the fourth such case of babesiosis in a patient following HCT and, to our knowledge, the first and only case of a patient who underwent HCT while on antibabesial therapy with a positive B. microti PCR and a negative B. microti IgG, with a post-transplant course complicated by relapsed babesiosis. Of note, none of the previous case reports in HCT recipients comment on the B. microti IgG status at the time of initial diagnosis or following treatment. Adding to the uniqueness of this particular case, our patient suffered a relapse following 2 months of B. microti PCR negativity. In our review of the literature, only 1 other case of relapsed babesiosis following a negative Babesia PCR result has been described [6]. The patient, who had a remote history of Hodgkin’s disease treated with splenectomy and chemoradiation, received 10 weeks of atovaquone and azithromycin until the Babesia PCR turned negative, but unfortunately developed relapsing infection 2 months later and ultimately died. Similar to our patient, she never had documented seroconversion during follow-up.\n\nOur patient had several risk factors for relapsing/persistent infection, the most important of which was likely her net state of immunosuppression. Before infection, she had been treated with rituximab for her leukemia. Although the last dose had been administered ~9 months before her initial Babesia diagnosis, the immunomodulatory effects of rituximab have the potential to last >18 months [7]. Even after clearing her blood smear, she was unable to mount an antibody response to the parasite, as evidenced by persistently negative B. microti serologies, suggesting ongoing humoral deficiency.\n\nAlthough the specific role of humoral immunity in achieving clinical cure remains unclear, it would appear that B cells, whether by producing antibodies and/or serving as antigen-presenting cells for T cells, are highly important, if not necessary, for sustained remission of babesiosis [7, 10]. Following a prolonged treatment course, our patient never seroconverted, possibly signifying incomplete parasite clearance despite a negative blood parasite smear and B. microti PCR.\n\nAside from chemotherapy for her ALL, our patient received multiple other immunosuppressive medications, including fludarabine (associated with profound and prolonged T lymphopenia) [15], eculizumab (associated with terminal complement deficiency) [16], and ruxolitinib (associated with impaired dendritic cell function and T-cell priming) [17]. Although none of these drugs have been implicated in relapsing/persistent babesiosis, their precise contribution (alone or in combination) remains unknown. Our patient also received an extended course of corticosteroids, which only further contributed to her degree of immunosuppression.\n\nBased on prior reports, we also considered whether atovaquone or azithromycin drug resistance contributed to our patient’s poor outcome. She was on atovaquone monotherapy during the initial incubation period and received nearly 3 months of dual therapy following diagnosis. This prolonged antimicrobial pressure, coupled with incomplete parasite clearance due to profound immunosuppression, might have led to decreased susceptibility to 1 or both of these agents.\n\nStemming from findings in hamsters, there has long been concern about the risk of acquiring atovaquone resistance in the setting of monotherapy [18]. Further investigation has identified Babesia variants associated with relapsing disease in humans, although we still do not fully understand the clinical implications of these mutations [19]. A recent case report demonstrated a possible molecular mechanism of acquired resistance in a patient with chronic lymphocytic leukemia who developed resistance to both atovaquone and azithromycin following an initial 6-week course of standard therapy [8]. In the case of both drugs, resistance was due to point mutations in the genes encoding their respective target proteins, with concomitant predicted changes in their binding sites.\n\nUsing the methods described in the Supplementary Data, PCR was performed using the primers listed in Supplementary Table 1 on genomic samples extracted from archived thin blood smears collected at the time of our patient’s babesiosis relapse. PCR analysis revealed a point mutation in the cytb gene, which encodes the target for atovaquone (Figure 2). This mutation (ATG to ACG) alters the amino acid at position 134 (M134T) in the highly conserved CYTb ubiquinol-binding pocket (QO domain). Mutations at this position have been previously described in cases of resistance to atovaquone in both babesiosis and malaria [20, 21]. Although there was insufficient specimen volume to amplify the cytb gene from the pretreatment sample, we suspect that this mutation arose de novo at some point during our patient’s extended treatment course. Despite extensive exposure to azithromycin, PCR on these same samples demonstrated a wild-type sequence for rpl4, the gene encoding the target for azithromycin.\n\nFigure 2. Possible molecular mechanism for atovaquone resistance. A, Comparison of wild-type and our case patient’s cytb genome sequence following relapse reveals a point mutation, highlighted in green. B. Comparison of wild-type and our case patient’s CYTb amino acid sequence following relapse reveals a missense mutation with an amino acid substitution at position 134, highlighted in red, corresponding to possible resistance.\n\nIn summary, the management of babesiosis in HCT patients in the peritransplant period remains a significant challenge. These patients are at significantly increased risk of persistent/relapsing infection due to profound and prolonged immunosuppression. Complicating matters are that reduction of immunosuppression increases the risk of GvHD, extended antibabesial therapy carries a risk of acquired drug resistance, and no standardized approach to monitoring these patients has been established.\n\nTaking all this into account, it may be most prudent to consider continuation of antibabesial therapy in highly immunocompromised hosts until it is possible to achieve some degree of immune reconstitution, either through reduction of iatrogenic immunosuppression or remission of the underlying immunosuppressive condition. Further studies are needed in this population to help define the most appropriate combination of medications, the optimal duration of therapy, and the best approach to monitoring. Given the rapidly expanding population of immunosuppressed hosts, in part due to novel therapeutics compromising humoral and cell-mediated immunity, this research would be especially timely.\n\nSupplementary Data\n\nSupplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.\n\nofab323_suppl_Supplementary_Materials Click here for additional data file.\n\nAcknowledgments\n\nFinancial support. None.\n\nPotential conflicts of interest. All authors: no reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.\n\nPatient consent. Consent was unable to be obtained from the patient before death. Ethical board approval was not believed to be indicated because this case report did not involve human subjects research.\n==== Refs\nReferences\n\n1. StockW, LugerSM, AdvaniAS, et al. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood 2019; 133 :1548–59.30658992\n2. GökbugetN, DombretH, BonifacioM, et al. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood 2018; 131 :1522–31. 29358182\n3. JabbourE, RavandiF, KebriaeiP, et al. Salvage chemoimmunotherapy with inotuzumab ozogamicin combined with mini–hyper-CVD for patients with relapsed or refractory philadelphia chromosome–negative acute lymphoblastic leukemia. JAMA Oncol 2018; 4 :230–234.28859185\n4. US Food and Drug Administration, Center for Biologics Evaluation and Research. Recommendations for reducing the risk of transfusion-transmitted babes. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/recommendations-reducing-risk-transfusion-transmitted-babesiosis. Accessed 28 May 2021.\n5. VyasJM, TelfordSR, RobbinsGK. Treatment of refractory Babesia microti infection with atovaquone-proguanil in an HIV-infected patient: case report. Clin Infect Dis 2007; 45 :1588–90.18190320\n6. WormserG, PrasadA, NeuhausE, et al. Emergence of resistance to azithromycin-atovaquone in immunocompromised patients with Babesia microti infection. Clin Infect Dis 2010; 50 :381–6.20047477\n7. RaffalliJ, WormserGP. Persistence of babesiosis for >2 years in a patient on rituximab for rheumatoid arthritis. Diagn Microbiol Infect Dis 2016; 85 :231–2.27036977\n8. SimonMS, WestbladeLF, DziedziechA, et al. Clinical and molecular evidence of atovaquone and azithromycin resistance in relapsed Babesia microti infection associated with rituximab and chronic lymphocytic leukemia. Clin Infect Dis 2017; 65 :1222–5.28541469\n9. Centers for Disease Control and Prevention. Babesiosis surveillance - United States, 2011–2015. 2019. Available at: https://www.cdc.gov/mmwr/volumes/68/ss/ss6806a1.htm. Accessed 26 May 2021.\n10. KrausePJ, GewurzBE, HillD, et al. Persistent and relapsing babesiosis in immunocompromised patients. Clin Infect Dis 2008; 46 :370–6.18181735\n11. KrausePJ, AuwaerterPG, BannuruRR, et al. Clinical practice guidelines by the Infectious Diseases Society of America (IDSA): 2020 guideline on diagnosis and management of babesiosis. Clin Infect Dis 2021; 72:e49–64 .\n12. CirinoCM, LeitmanSF, WilliamsE, et al. Transfusion-associated babesiosis with an atypical time course after nonmyeloablative transplantation for sickle cell disease. Ann Intern Med 2008; 148 :794–5.18490697\n13. LubinAS, SnydmanDR, MillerKB. Persistent babesiosis in a stem cell transplant recipient. Leuk Res 2011; 35 :e77–8.21185598\n14. BadeNA, YaredJA. Unexpected babesiosis in a patient with worsening anemia after allogeneic hematopoietic stem cell transplantation. Blood 2016; 128 :1019.28092881\n15. GamberaleR, GalmariniCM, Fernández-CalottiP, et al. In vitro susceptibility of CD4+ and CD8+ T cell subsets to fludarabine. Biochem Pharmacol 2003; 66 :2185–91.14609743\n16. BenamuE, MontoyaJG. Infections associated with the use of eculizumab: recommendations for prevention and prophylaxis. Curr Opin Infect Dis 2016; 29 :319–29.27257797\n17. LussanaF, CattaneoM, RambaldiA, SquizzatoA. Ruxolitinib-associated infections: a systematic review and meta-analysis. Am J Hematol 2018; 93 :339–47.29150886\n18. WittnerM, LedermanJ, TanowitzHB, et al. Atovaquone in the treatment of Babesia microti infections in hamsters. Am J Trop Med Hyg 1996; 55 : 219–22.8780464\n19. LemieuxJE, TranAD, FreimarkL, et al. A global map of genetic diversity in Babesia microti reveals strong population structure and identifies variants associated with clinical relapse. Nat Microbiol 2016; 1 :16079.27572973\n20. KorsinczkyM, ChenN, KoteckaB, et al. Mutations in Plasmodium falciparum cytochrome b that are associated with atovaquone resistance are located at a putative drug-binding site. Antimicrob Agents Chemother 2000; 44 :2100–8.10898682\n21. LawresLA, GargA, KumarV, et al. Radical cure of experimental babesiosis in immunodeficient mice using a combination of an endochin-like quinolone and atovaquone. J Exp Med 2016; 213 :1307–18.27270894\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2328-8957",
"issue": "8(9)",
"journal": "Open forum infectious diseases",
"keywords": "Babesia microti; babesiosis; hematopoietic cell transplantation; immunocompromised host; tick-borne pathogens",
"medline_ta": "Open Forum Infect Dis",
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"nlm_unique_id": "101637045",
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"pages": "ofab323",
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"pmid": "34514015",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports",
"references": "27572973;14609743;18490697;27270894;28541469;28092881;18190320;10898682;20047477;27036977;8780464;29150886;21185598;28859185;33252652;30658992;27257797;18181735;29358182",
"title": "Relapsed Babesia microti Infection Following Allogeneic Hematopoietic Cell Transplantation in a Patient With B-cell Acute Lymphoblastic Leukemia: Case Report and Review of the Literature.",
"title_normalized": "relapsed babesia microti infection following allogeneic hematopoietic cell transplantation in a patient with b cell acute lymphoblastic leukemia case report and review of the literature"
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"abstract": "Background. Methylphenidate (MPH) is widely used in treating children with attention-deficit-hyperactivity disorder. Hepatotoxicity is a rare phenomenon; only few cases are described with no liver failure. Case. We report on the case of a 12-year-old boy who received MPH for attention-deficit-hyperactivity disorder. Two months later the patient presented with signs and symptoms of hepatitis and MPH was discontinued, showing progressive worsening and developing liver failure and a liver transplantation was required. Other causes of liver failure were ruled out and the liver biopsy was suggestive of drug toxicity. Discussion. One rare adverse reaction of MPH is hepatotoxicity. The review of the literature shows few cases of liver injury attributed to MPH; all of them recovered after withdrawing the treatment. The probable mechanism of liver injury was MPH direct toxicity to hepatocytes. In order to establish the diagnosis of MPH-induced liver injury, we used CIOMS/RUCAM scale that led to an assessment of \"possible\" relationship. This report provides the first published case of acute MPH-induced liver failure with successful hepatic transplantation. Conclusions. It is important to know that hepatotoxicity can occur in patients with MPH treatment and monitoring the liver's function is highly recommended.",
"affiliations": "Department of Clinical Pharmacology, Hospital Universitario La Paz, IdiPaz, School of Medicina, Universidad Autónoma de Madrid, Paseo de la Castellana 261, 28046 Madrid, Spain.;Pediatric Hepatology Department, Hospital Universitario La Paz, IdiPaz, Paseo de la Castellana 261, 28046 Madrid, Spain.;Pathological Anatomy Department, Hospital Universitario La Paz, IdiPaz, Paseo de la Castellana 261, 28046 Madrid, Spain.;Department of Clinical Pharmacology, Hospital Universitario La Paz, IdiPaz, School of Medicina, Universidad Autónoma de Madrid, Paseo de la Castellana 261, 28046 Madrid, Spain.;Department of Clinical Pharmacology, Hospital Universitario La Paz, IdiPaz, School of Medicina, Universidad Autónoma de Madrid, Paseo de la Castellana 261, 28046 Madrid, Spain.;Pediatric Hepatology Department, Hospital Universitario La Paz, IdiPaz, Paseo de la Castellana 261, 28046 Madrid, Spain.;Department of Clinical Pharmacology, Hospital Universitario La Paz, IdiPaz, School of Medicina, Universidad Autónoma de Madrid, Paseo de la Castellana 261, 28046 Madrid, Spain.",
"authors": "Tong|Hoi Y|HY|;Díaz|Carmen|C|;Collantes|Elena|E|;Medrano|Nicolás|N|;Borobia|Alberto M|AM|;Jara|Paloma|P|;Ramírez|Elena|E|",
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"doi": "10.1155/2015/437298",
"fulltext": "\n==== Front\nCase Rep PediatrCase Rep PediatrCRIPECase Reports in Pediatrics2090-68032090-6811Hindawi Publishing Corporation 10.1155/2015/437298Case ReportLiver Transplant in a Patient under Methylphenidate Therapy: A Case Report and Review of the Literature Tong Hoi Y. \n1\nDíaz Carmen \n2\nCollantes Elena \n3\nMedrano Nicolás \n1\nBorobia Alberto M. \n1\nJara Paloma \n2\nRamírez Elena \n1\n\n*\n1Department of Clinical Pharmacology, Hospital Universitario La Paz, IdiPaz, School of Medicina, Universidad Autónoma de Madrid, Paseo de la Castellana 261, 28046 Madrid, Spain2Pediatric Hepatology Department, Hospital Universitario La Paz, IdiPaz, Paseo de la Castellana 261, 28046 Madrid, Spain3Pathological Anatomy Department, Hospital Universitario La Paz, IdiPaz, Paseo de la Castellana 261, 28046 Madrid, Spain*Elena Ramírez: elena.ramirez@inv.uam.esAcademic Editor: Seyed Mohsen Dehghani\n\n2015 22 1 2015 2015 43729813 10 2014 9 12 2014 Copyright © 2015 Hoi Y. Tong et al.2015This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nBackground. Methylphenidate (MPH) is widely used in treating children with attention-deficit-hyperactivity disorder. Hepatotoxicity is a rare phenomenon; only few cases are described with no liver failure. Case. We report on the case of a 12-year-old boy who received MPH for attention-deficit-hyperactivity disorder. Two months later the patient presented with signs and symptoms of hepatitis and MPH was discontinued, showing progressive worsening and developing liver failure and a liver transplantation was required. Other causes of liver failure were ruled out and the liver biopsy was suggestive of drug toxicity. Discussion. One rare adverse reaction of MPH is hepatotoxicity. The review of the literature shows few cases of liver injury attributed to MPH; all of them recovered after withdrawing the treatment. The probable mechanism of liver injury was MPH direct toxicity to hepatocytes. In order to establish the diagnosis of MPH-induced liver injury, we used CIOMS/RUCAM scale that led to an assessment of “possible” relationship. This report provides the first published case of acute MPH-induced liver failure with successful hepatic transplantation. Conclusions. It is important to know that hepatotoxicity can occur in patients with MPH treatment and monitoring the liver's function is highly recommended.\n==== Body\n1. Introduction\nMethylphenidate hydrochloride (MPH) is a chain substituted amphetamine derivative that primarily acts as norepinephrine-dopamine reuptake inhibitor. The Food and Drug Administration (FDA) first approved MPH on 1955; however, it was not until the 1990s when MPH saw a dramatic increase in its prescription. In the PATS study almost one-third of the children revealed some side effects, mainly weight loss and neurological effects [1]. A few scattered and sporadic cases of hepatotoxicity with MPH treatment have been reported and usually referred to transient elevation of liver enzymes. This report describes a case of irreversible methylphenidate-induced liver failure.\n\n2. Case Presentation\nA 12-year-old boy with no relevant medical history was treated with MPH at an appropriate dose of 30 mg daily for attention-deficit-hyperactivity disorder (ADHD), and no other treatment was received in the previous months. After two months of treatment, the patient presented with a 2-day history of generalized itching, malaise, fatigue, and anorexia and with no fever. At that time, MPH was discontinued. Initial aminotransferases (alanine aminotransferase, ALT; aspartate aminotransferase, AST), total bilirubin, and alkaline phosphatase were elevated, while hepatitis panel (HBsAg, anti-HBcore, anti-HAV, anti-HIV, CMV IgM, and syphilis) was negative, and the patient's health continued to worsen in the next two months and finally he developed signs of liver failure and was transferred to Spain for hepatic transplantation. When the patient arrived, his liver function continued to deteriorate, and laboratory test on the first day determined the following levels: ALT of 155 U/L, AST of 310 U/L, and total serum bilirubin of 28.7 mg/mL, coagulation disorders (prothrombin activity of 13% and international normalized ratio of 4.9). After two days, the patient developed encephalopathy, with hyperammonemia (178 µcg/dL), he was translated to intensive care unit (Table 1). Alternative diagnoses were ruled out through immunological test (antinuclear antibodies, ANA; smooth muscle antibody; LKM antibody) negatives. Alpha-fetoprotein was negative. Infectious origin through microbiological test revealed the following: Enterovirus was negative; Herpes simplex virus IgM, negative; CMV IgG, positive; CMV IgM, negative; Epstein-barr VCA IgM, negative; anti-EBNA IgG, positive; Parvovirus IgM, negative; Parvovirus IgG, positive; IgM, negative; Adenovirus, negative; the hepatitis panel (HBsAg, anti-HB core, anti-HVA, anti-HVC, and anti-HVE), negative; anti-HIV, negative; Toxoplasma IgG, positive; Toxoplasma IgM, negative; and Syphilis, negative. Serum ceruloplasmin was 15.4 mg/dL (normal ranges 20–60 mg/dL) and serum copper was 68 mcg/dL (normal ranges 50–150 mcg/dL). Abdominal ultrasound revealed a decreased hepatic size, the caudate lobe was prominent, and there were images of periportal fibrosis, the bile duct was of normal caliber. On the 4th hospitalization day in Spain, successful liver transplantation was performed. Liver biopsy reported parenchyma showing conserved architecture with bridging perivenular submassive necrosis; periportal hepatocytes showed pseudoacinar change and cholangiolar reaction. In the best preserved areas, the hepatocytes had intrahepatic and canalicular cholestasis. The portal tract had normal morphology with no evidence of inflammatory or thrombotic phenomenon. At any level acute or chronic inflammatory infiltrates, abscesses, or eosinophils were not observed (Figure 1). Patient gradually improved over the next weeks and the liver function showed a normalization trend, and MPH has not been restarted and for the next 2 years the patient has been well controlled with no further hepatic alteration events.\n\n3. Discussion\nADHD is a common neurobehavioral disorder and one of the most prevalent chronic health problems in childhood [1]. The current estimated prevalence of ADHD is 2–6% among preschool-age children and 3–7% for school-age children [2]. Recently, practice guidelines support the benefits of treatment with both behaviour therapy and MPH, which is the most commonly prescribed psychostimulant [3]. Common side effects of MPH include loss of appetite and anxiety, and the most worrying side effect was a small but significant impact on the cardiovascular system including increases in blood pressure and heart rate as well as sudden cardiac death [4, 5]. However, one known but rare adverse effect of MPH is hepatotoxicity. Only few case reports of liver injury attributed to MPH have been published, possibly due to the fact that most of the patients generally develop mild, asymptomatic, and reversible elevation of liver chemistries. The first case of hepatotoxicity due to MPH was described in 1972. In the case of a 67-year-old woman with MPH treatment, laboratory test showed elevated aminotransferases and alkaline phosphatase and MPH was discontinued and her liver's enzymes normalized [6].\n\nThe mechanism of hepatotoxicity associated with most drugs is idiosyncratic, which implies that drug-induced liver injury (DILI) develops in only a small proportion of subjects exposed to a drug in therapeutic doses, and must be consider the interaction between genetic and environmental risk factors making DILI unpredictable for most hepatotoxins. Thereby, we have found two case reports whose mechanism of hepatotoxicity of MPH could be idiosyncratic. They were patients with normal liver function previously. In one case after 5 weeks and in the other case after 3 months of onset of MPH therapy, elevated levels of aminotransferases and bilirubin were presented and alternative diagnostics were excluded. MPH was discontinued and liver's enzymes decreased [7, 8].\n\nAllergy idiosyncratic hepatotoxicity is another possible mechanism of DILI, characterized by the presence of fever, skin reactions, eosinophilia, and formation of autoantibodies [9]. The other two cases in the literature can support this possible causal mechanism of MPH-induced hepatotoxicity. First, for the case of a 19-year-old black woman who had been injected intravenously with MPH and was admitted for jaundice, fever, and pain in the right upper abdomen, laboratory data showed elevated liver enzymes; a liver biopsy was performed revealing portal inflammation with lymphocytes, plasma cells, and eosinophils. Autoantibodies were not reported. Patient gradually got better the next 2 weeks and was given injection of MPH intravenously for two days after recovery and liver enzymes again showed a significant increase, proving positive rechallenge effect which strengthens the link of hepatotoxicity due to MPH [10]. The other case was reported by Lewis et al. a 57-year-old Caucasian male with a history of orthotopic liver transplantation 4 years before because of chronic hepatitis C, had maintained stable treatment and the liver's enzymes had been normal after transplantation. On routine laboratory evaluation that discovered elevation of ALT, AST, and bilirubin, the only new medication that began 1 month earlier was MPH for depressive symptoms. Immunologic tests reported positive ANA, positive anti-SMA, negatives antimitochondrial antibody and anti-LKM, and elevated serum IgG immunoglobulins. A liver biopsy showed severe lobular and periportal necroinflammatory infiltrate with predominance of lymphocytes, plasma cells, and eosinophils, consistent with autoimmune hepatitis. MPH therapy was discontinued and liver's enzymes returned to previous levels [11].\n\nMPH is a drug whose toxicity is increased by adrenergic agonist drugs [12]. A study in mice proved that when MPH is given as a single dose of 75 to 100 mg/Kg, it produced hepatic necrosis in male mice and when coadministered with beta-2 adrenoreceptors drugs can produce important potentiation of the liver injury by the increase in the MPH concentration [13]. In the literature, the cardiovascular effects of the sympathomimetic amines (increase in the heart rate, blood pressure, and blood vessel contraction) [14] have been described as well as cases of ischemic events (myocardial infarction and stroke) and sudden death in children and adults taking ADHD stimulants [4, 15]. For this reason we cannot discard that the overall low flow of blood in the liver could be another mechanism of MPH-induced liver injury.\n\nIn our case, we think that the mechanism of liver injury was MPH direct toxicity to hepatocytes as an idiosyncratic reaction, and we cannot support that the liver failure was due to autoimmune hepatitis, because of the negative findings of immunological test (ANA, smooth muscle antibody, and LKM antibody) and the absence of inflammatory damage or infiltration by plasma cells, lymphocytes, or eosinophils in the explanted liver [16]. And we do not have data on ischemia hepatopathy. In order to establish the diagnosis of DILI [17] we used CIOMS/RUCAM scale [18] that led to the assessment of “possible” relationship.\n\nAll cases reported were mild and recovered after withdrawing MPH, but in contrast, the case of our patient was severe and he was referred for liver transplantation. Our review of possible MPH-induced liver injury indicates a spectrum of presumed hepatotoxicity ranging from mild elevation of aminotransferases with spontaneous recovery after withdrawal of MPH to severe fulminant hepatitis requiring liver transplantation.\n\nIn conclusion, drug-induced liver injury (DILI) represents a frequently adverse drug reaction. Drugs account for 20–40% of all instances of fulminate hepatic failure. Approximately 75% of the idiosyncratic drug reactions result in liver transplantation or death [19]. It is important to know that although rarely but subacute liver failure can occur in patients with MPH treatment and must be taken into account by clinicians. This is the first case report of liver transplantation due to MPH therapy. This case has been reported to the National Pharmacovigilance Agency of Spain (registered as number 3433).\n\nAbbreviations\nADHD:Attention-deficit-hyperactivity disorder\n\nALT:Alanine aminotransferase\n\nANA:Antinuclear antibody\n\nAnti-HBc:Hepatitis B core antibody\n\nAnti-HBs:Hepatitis B surface antibody\n\nAnti-SMA:Anti-smooth muscle antibody\n\nAnti-VHA:Hepatitis A antibody\n\nAnti-VHB:Hepatitis C antibody\n\nAnti-VHE:Hepatitis E antibody\n\nAST:Aspartate aminotransferase\n\nCMV:Cytomegalovirus\n\nDILI:Drug-induced liver injury\n\nFDA:U.S. Food and Drug Administration\n\nLKM:Liver-kidney microsome antibodies\n\nMPH:Methylphenidate hydrochloride.\n\nDisclosure\nThe authors have indicated they have no financial relationships relevant to this paper to disclose.\n\nConflict of Interests\nThe authors have no conflict of interests relevant to this paper to disclose.\n\nFigure 1 Liver biopsy.\n\nTable 1 Laboratory results of liver function.\n\n(a) Date\tEpisode\tALT\n(normal, <35)\nUI/L\tAST\n(normal, <45)\nUI/L\tTotal bilirubin\n(normal, 0–1.2) mg/dL\tAlkaline phosphatase\n(normal, 30–355)\nUI/L\tProthrombin activity\n(80–120)\n%\t\n18/12/10\tControl\t13\t21\t0.3\t56\t101\t\n26/02/11\tJaundice, Coluria, acholia\nMPH was discontinued\t423\t857\t4\t339\t71\t\n04/04/11\tWorsening coagulopathy\t182\t361\t12.2\t304\t36\t\n(b) Date\tEpisode\tALT\n(normal, 30–65)\nUI/L\tAST\n(normal, 15–37)\nUI/L\tGGT\n(normal, 5–85)\nUI/L\tTotal bilirubin\n(normal, 0.2–1.4) mg/dL\tAlkaline phosphatase\n(normal, 42–362)\nUI/L\tProthrombin activity\n(80–120)\n%\t\n04/05/11\tArrived to Hospital Universitario La Paz\t138\t310\t29\t28.7\t \t13\t\n05/05/11\tOnset of NAC\t141\t332\t21\t36.9\t275\t17\t\n06/05/11\tEncephalopathy medium-severe intensity with hyperammonemia\t122\t269\t29\t27\t \t27\t\n07/05/11\t \t119\t238\t29\t27.4\t \t19\t\n08/05/11\tHepatic transplantation\t110\t243\t30\t26.9\t \t21\t\n08/05/11\tAfter hepatic transplantation\t480\t792\t44\t10.8\t \t41\t\n09/05/11\t \t534\t996\t48\t6.9\t \t51\t\n10/05/11\t \t389\t373\t43\t3.9\t \t97\t\n11/05/11\t \t348\t213\t135\t5.4\t \t105\t\n12/05/11\t \t356\t185\t \t5.4\t \t94\t\n13/05/11\t \t310\t124\t494\t5.6\t \t102\t\n14/05/11\t \t259\t78\t511\t4.7\t \t108\t\n15/05/11\t \t269\t104\t737\t4.9\t \t109\t\n16/05/11\t \t260\t93\t703\t4.1\t \t118\t\n17/05/11\t \t377\t193\t1106\t4.7\t \t109\t\n18/05/11\t \t459\t194\t1099\t4.4\t \t113\t\n19/05/11\t \t478\t188\t1139\t3.9\t \t107\t\n20/05/11\tDischarge from ICU\t338\t86\t946\t3\t \t115\t\n21/05/11\t \t279\t64\t939\t2.7\t \t105\t\n22/05/11\t \t206\t39\t782\t2.4\t \t104\t\n23/05/11\t \t165\t30\t745\t2.3\t260\t99\t\n24/05/11\t \t127\t25\t629\t2\t \t95\t\n26/05/11\t \t111\t35\t604\t1.8\t \t103\t\n28/05/11\t \t93\t33\t522\t1.6\t \t97\t\n31/05/11\t \t75\t36\t417\t1.4\t \t108\t\n03/06/11\t \t82\t39\t351\t1.2\t192\t119\t\n07/06/11\tDischarge from the hospital\t61\t22\t305\t1.3\t189\t113\t\n10/06/11\t \t42\t25\t262\t2.13\t220\t105\t\n20/06/11\t \t23\t20\t152\t1.14\t188\t104\t\nNAC: N-acetylcysteine.\n==== Refs\n1 Greenhill L. Kollins S. Abikoff H. Efficacy and safety of immediate-release methylphenidate treatment for preschoolers with ADHD Journal of the American Academy of Child and Adolescent Psychiatry 2006 45 11 1284 1293 10.1097/01.chi.0000235077.32661.61 2-s2.0-33750523835 17023867 \n2 Greenhill L. L. Jensen P. S. Cooper J. R. Stimulant medication treatment of children with attention deficit hyperactivity disorder Attention Deficit Hyperactivity Disorder: State of Science. Best Practices 2002 Kingston, NJ, USA Civic Research Institute 9 27 \n3 Subcommittee on Attention-Deficit/Hyperactivity Disorder ADHD: clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/ hyperactivity disorder in children and adolescents Pediatrics 2011 128 5 1007 1022 10.1542/peds.2011-2654 2-s2.0-80355130491 22003063 \n4 Arcieri R. Germinario E. A. P. Bonati M. Cardiovascular measures in children and adolescents with attention-deficit/hyperactivity disorder who are new users of methylphenidate and atomoxetine Journal of Child and Adolescent Psychopharmacology 2012 22 6 423 431 10.1089/cap.2012.0014 2-s2.0-84871226888 23362511 \n5 Martinez-Raga J. Knecht C. Szerman N. Martinez M. I. Risk of serious cardiovascular problems with medications for attention-deficit hyperactivity disorder CNS Drugs 2013 27 1 15 30 10.1007/s40263-012-0019-9 2-s2.0-84873044659 23160939 \n6 Goodman C. R. Hepatotoxicity due to methylphenidate hydrochloride New York State Journal of Medicine 1972 72 18 2339 2340 2-s2.0-0015510746 4506888 \n7 Torres E. L. del Valle V. G. Pachkoria K. Cueto R. Lucena M. I. Hepatotoxicidad por metilfenidato en el tratamiento del trastorno por déficit de atención con hiperactividad Casos Farmacoterápicos 2005 3 4 269 270 \n8 Bernhard M. K. Hugle B. Merkenschlager A. Elevated liver enzymes under therapy with methylphenidate in a boy with T-cell leukemia Journal of Pediatric Neurology 2009 7 3 297 299 2-s2.0-67749095051 10.3233/JPN-2009-0303 \n9 Russmann S. Kullak-Ublick G. A. Grattagliano I. Current concepts of mechanisms in drug-induced hepatotoxicity Current Medicinal Chemistry 2009 16 23 3041 3053 10.2174/092986709788803097 2-s2.0-70349406480 19689281 \n10 Mehta H. Murray B. LoIudice T. A. Hepatic dysfunction due to intravenous abuse of methylphenidate hydrochloride Journal of Clinical Gastroenterology 1984 6 2 149 151 10.1097/00004836-198404000-00010 2-s2.0-0021136271 6715854 \n11 Lewis J. J. Iezzoni J. C. Berg C. L. Methylphenidate-induced autoimmune hepatitis Digestive Diseases and Sciences 2007 52 2 594 597 10.1007/s10620-006-9525-2 2-s2.0-33846796305 17219064 \n12 Robert S. M. DeMott R. P. James R. C. Adrenergic modulation of hepatotoxicity Drug Metabolism Reviews 1997 29 1-2 329 353 9187524 \n13 Roberts S. M. Harbison R. D. Roth L. James R. C. Methylphenidate-induced hepatotoxicity in mice and its potentiation by β -adrenergic agonist drugs Life Sciences 1994 55 4 269 281 2-s2.0-0028245406 10.1016/0024-3205(94)00729-2 7913199 \n14 Wilens T. E. Hammerness P. G. Biederman J. Blood pressure changes associated with medication treatment of adults with attention-deficit/hyperactivity disorder The Journal of Clinical Psychiatry 2005 66 2 253 259 10.4088/jcp.v66n0215 2-s2.0-20044387015 15705013 \n15 Nissen S. E. ADHD drugs and cardiovascular risk The New England Journal of Medicine 2006 354 14 1445 1448 10.1056/nejmp068049 2-s2.0-33645507718 16549404 \n16 Suzuki A. Brunt E. M. Kleiner D. E. The use of liver biopsy evaluation in discrimination of idiopathic autoimmune hepatitis versus drug-induced liver injury Hepatology 2011 54 3 931 939 10.1002/hep.24481 2-s2.0-80052023773 21674554 \n17 García-Cortés M. Lucena M. I. Andrade R. J. Camargo R. Alcántara R. Is the Naranjo probability scale accurate enough to ascertain causality in drug-induced hepatotoxicity? Annals of Pharmacotherapy 2004 38 9 1540 1541 10.1345/aph.1e007 2-s2.0-4143090284 15266043 \n18 Bénichou C. Criteria of drug-induced liver disorders. Report of an international consensus meeting Journal of Hepatology 1990 11 2 272 276 2254635 \n19 Mehta N. Ozick L. Gbadehan E. Drug-induced hepatotoxicity Medscape reference, January 2013, http://emedicine.medscape.com/article/169814-overview\n\n",
"fulltext_license": "CC BY",
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"issue": "2015()",
"journal": "Case reports in pediatrics",
"keywords": null,
"medline_ta": "Case Rep Pediatr",
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"nlm_unique_id": "101581030",
"other_id": null,
"pages": "437298",
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"pmid": "25688317",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
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"title": "Liver Transplant in a Patient under Methylphenidate Therapy: A Case Report and Review of the Literature.",
"title_normalized": "liver transplant in a patient under methylphenidate therapy a case report and review of the literature"
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"companynumb": "ES-MYLANLABS-2018M1066966",
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"occurcountry": "ES",
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"activesubstancename": "METHYLPHENIDATE"
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{
"abstract": "Emergency cerclage was performed on 27 years old patient with membrane prolapse in 21 weeks' gestation. Ultrasonographically guided amniocentesis was performed intraoperatively in order to decrease intraamniotic pressure. Aggressive prophylactic management (wide spectrum antibiotics and tocolysis-nifedipine) resulted in pregnancy prolongation up to 30 week of gestation. At that time healthy premature newborn (1520 g, Apgar score 7 in 1st minute) was delivered by caesarean section. The mother was discharged from the hospital on the 4th postoperative day, whereas the child after 5 weeks weighted 2130 g.",
"affiliations": "II Katedry i Kliniki Ginekologii Operacyjnej, Akademii Medycznej w Lublinie.",
"authors": "Rechberger|T|T|;Pietras|G|G|;Adamiak|A|A|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "Poland",
"delete": false,
"doi": null,
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"fulltext_license": null,
"issn_linking": "0017-0011",
"issue": "72(12)",
"journal": "Ginekologia polska",
"keywords": null,
"medline_ta": "Ginekol Pol",
"mesh_terms": "D000328:Adult; D000649:Amniocentesis; D000900:Anti-Bacterial Agents; D023802:Cerclage, Cervical; D002584:Cervix Uteri; D004638:Emergency Treatment; D005321:Extraembryonic Membranes; D005260:Female; D005322:Fetal Membranes, Premature Rupture; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D007752:Obstetric Labor, Premature; D011247:Pregnancy; D011256:Pregnancy Outcome; D011391:Prolapse; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "0374641",
"other_id": null,
"pages": "1112-5",
"pmc": null,
"pmid": "11883220",
"pubdate": "2001-12",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Emergency cerclage with concomitant amniocentesis as a method of treatment of membranes prolapse--case report.",
"title_normalized": "emergency cerclage with concomitant amniocentesis as a method of treatment of membranes prolapse case report"
} | [
{
"companynumb": "PHHY2014PL133759",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMOXICILLIN\\CLAVULANIC ACID"
},
"drugadditional": nul... |
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