History Of Drug Exposure Research Articles

Examining molecular landscape and drug sensitivity profiles of patient-derived xenografts from resected brain metastases.

28 Background: Brain metastases (BrMet) remain an unmet need. Preclinical models of BrMet are rare but can be a valuable tool to interrogate pathology and develop novel therapeutic approaches. We previously published molecular profiles and drug sensitivity screening using novel BrMet patient-derived xenograft (PDX) models established from resected BrMet from patients with breast cancer. We further expanded our study to include BrMet from other solid tumors. Methods: We ascertained the genomic profiles of thirteen novel non-breast BrMet PDX models from patients undergoing clinically indicated surgical resection of BrMet. We then conducted drug sensitivity screening on ex vivo organoids with a panel of over 350 drugs to interrogate drug responses. We also collected information on molecular alterations and clinical treatment history from matched source patient material to correlate molecular alterations between tissue and matched PDXs when available, as well as with drug response in PDXs. Results: The PDXs included tumors that commonly (lung and melanoma) and less commonly (ovarian and sarcoma) metastasize to the brain. We observed potentially targetable DNA alterations in the DNA damaging repair pathway ( ATM, BRCA, CHEK2) and ERBB2. Using the drug sensitivity score 3 (DSS3), we assessed the sensitivity of the drugs tested. While the panel did not include the recently approved anti-HER2 targeted drugs, lapatinib (anti-HER2 TKI), and PARP inhibitors, e.g. olaparib and niraparib, were inactive against these PDXs. The three most active drugs among the BrMet PDXs were romidepsin, bortezomib, and triptolide, similar to what we observed previously for breast BrMet PDXs. When available, we correlated the DSS3 from the PDX testing with the drug exposure history and potentially actionable alterations reported in the matched source patient clinical samples. Interestingly, one case with CDKN2A/1B homozygous deletion had differential sensitivity against CDK inhibitors (highly active to dinaciclib but inactive to abemaciclib and palbociclib). Conclusions: We observed prevalent gene alterations associated with homologous recombination deficiency and HER2 among these non-breast BrMet PDX models, opening an opportunity for novel cross cancer approaches as these alterations are also reportedly linked to BrMet from breast cancer, these mechanisms may contribute to the propensity for BrMet. We also found that there are common drugs that are active across BrMet from different solid tumor types. To further explore the shared molecular features of BrMet across various solid tumors, we have established additional PDX models (near 100) from multiple solid tumors and plan to report on the molecular features.

Evaluation of otorhinolaryngologic, audiologic, and genetic findings in children with cystic fibrosis: A tertiary care experience.

To evaluate otorhinolaryngologic findings and the relationship between aminoglycoside (AG) exposure and hearing loss in paediatric patients with cystic fibrosis (cwCF). We also aimed to investigate the genetic predisposition to AG ototoxicity by screening for m.1555A>G mutations. CwCF who underwent otorhinolaryngologic and audiologic examinations were retrospectively included. Clinical characteristics, ear-nose-throat related symptoms, and a history of ototoxic drug exposure were recorded. m.1555A>G mutations were retrospectively screened among patients with audiologic evaluations. Two hundred thirty-four cwCF were included in this study with a median age of 10.7 (range, 6.8-14.2) years. Nasal obstruction (14.1%) was the most common symptom. Fifty-two (22.2%) patients had chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP). There was a positive correlation between CRSwNP and the symptom of nasal obstruction (r:.234, p < .001), snoring (r:.179, p = .006), and sleeping with mouth open (r:.138, p = .034). One hundred forty-nine (63.6%) patients had audiologic evaluations; 14 (9.4%) had hearing impairment. No statistical significance existed between ototoxicity and IV AG exposure (p = .90). Six (42.8%) of 14 patients did not receive ototoxic drugs. One hundred nineteen (50.8%) patients were screened for m.1555A>G mutations, and none were detected. Almost a quarter of the study population had CRSwNP. Neither the relationship between AGs exposure and hearing loss nor the genetic predisposition to AG ototoxicity could be shown in cwCF.

Current status and progress of detection methods for common clinical toxicants

With the progress of science and technology and the development of society, more and more chemical substances have been discovered and countless chemicals have been artificially synthesized, and the risk of exposure to some toxic chemicals by human beings has been greatly increased, resulting in the increasing incidence of acute poisoning, which has seriously endangered the public's physical health and life safety. As the poisoned patients are unconscious or refuse treatment when they are admitted to the hospital, it is difficult to understand the drug exposure history by asking the medical history, so the toxicity detection has become the key to the clinical diagnosis and treatment, and this paper briefly introduces some common toxicity detection methods in the clinic in the hope that it will bring help to the clinical doctors.

A Case Report on Dyschromatosis Universalis Hereditaria with Palmar Involvement

Dyschromatosis universalis hereditaria (DUH) is a rare genetic disorder characterized by hyper- and hypopigmented macules forming a reticulate pattern on the skin. This report presents an unusual case of a 14-year-old male patient with DUH involving the palms, a relatively uncommon manifestation of the condition. The patient presented with hyperpigmented lesions on the palms, which had developed over the previous eight years. Family history revealed similar pigmentary changes, suggesting a hereditary pattern. Clinical examination revealed no history of chemical or drug exposure, photosensitivity, or photophobia. Systemic evaluation was unremarkable, except for a low cortisol level of 1.12 mcg/dl (normal range: 6.2 to 19.4 mcg/dl) on the ACTH stimulation test. Skin biopsy from the left palm revealed diffuse hypermelanosis confined to the basal cell layer and occasionally extending to the lower third of the epidermis. Additionally, increased collagenization was observed in the deep dermis. Based on these findings, a diagnosis of DUH was established. The patient was initiated on long-term hydrocortisone therapy for cortisol hormone replacement. This case highlights the rare occurrence of palmar involvement in DUH and underscores the importance of thorough clinical evaluation and histopathological examination in establishing an accurate diagnosis. DUH is an uncommon genodermatosis, and reports of palmar involvement are scarce in the literature. This case contributes to the existing knowledge about the varied clinical presentations of DUH and emphasizes the need for increased awareness among clinicians

Development of Method for Determining Topiramate in Various Biological Matrices (Plasma, Saliva, Hair) and Its Application in Clinical Practice

The aim of this work was to develop and validate of method for the determination of topiramate (TPM) by a high-performance liquid chromatographic method coupled to triple-quadrupole mass spectrometry (LC-MS/MS) in MRM mode in the human plasma, saliva, and hair, and implementation of this method for the determination of TPM in patients with epilepsy. Saliva may as an alternative matrix for monitoring drug level, and hair drug content may be a reliable biomarker of the history of drug exposure, allowing to assess patient long-term compliance. Chromatographic separation was achieved in 3 min on a Kinetex analytical column (5 μm C18 100 Å, 100×2.1 mm) using an isocratic elution of acetonitrile and 10 mM ammonium acetate at a ratio of 80:20 (v/v) and a flow rate of 0.2 mL/min. Detection of TPM and internal standard (IS) (TPM-d12) was performed in negative ion mode (ESI−). The following transitions were used m/z 338 → 77.90; 338 → 95.90 for TPM and 350.3 → 78.20 for IS. The method showed to be selective, accurate, precise, and linear for TPM over the concentration ranges of 0.20-30 μg/mL (plasma, saliva), and 5.0-500.0 ng/mL (hair). The simple and robust LC-MS/MS method was successfully applied for the determination of TPM in patients with epilepsy.

Trends of Mycobacterium tuberculosis and Rifampicin resistance in Northwest Ethiopia: Xpert® MTB/RIF assay results from 2015 to 2021

BackgroundTuberculosis (TB) remains one of the leading causes of morbidity and mortality worldwide, particularly in countries with limited resources. The emergence of drug resistance in mycobacterium tuberculosis (MTB), particularly rifampicin (RIF) resistance, hindered TB control efforts. Continuous surveillance and regular monitoring of drug-resistant TB, including rifampicin resistance (RR), are required for effective TB intervention strategies and prevention and control measures.ObjectiveDetermine the trend of TB and RR-TB among presumptive TB patients in Northwest Ethiopia.MethodA retrospective study was conducted at the University of Gondar Comprehensive Specialized Hospital (UoG-CSH). The study included TB registration logbook data from all patients who visited the hospital and were tested for MTB using the Xpert® MTB/RIF assay between 2015 and 2021. The SPSS version 26 software was used to enter, clean, and analyze the laboratory-based data.ResultsA total of 18,787 patient results were included, with 93.8% (17,615/18787) of them being successful, meaning they were not invalid, error, or aborted. About 10.5% (1846/17615) of the 17,615 results were MTB-positive, with 7.42% (137/1846) RIF resistant. Age, anti-TB treatment history, and diagnosis year were associated with the presence of MTB and RR-MTB. Tuberculosis (TB) prevalence was higher in productive age groups, whereas RR-TB prevalence was higher in the elderly. Regarding diagnosis year, the prevalence of TB and RR-TB showed a declining trend as the year progressed. While MTB was detected in 12.8% (471/3669) of new and 22.2% (151/679) of re-treatment presumptive TB patients, RR-MTB was detected in 8.5% (40/471) of new and 18.5% (28/151) of re-treatment TB cases.ConclusionThe prevalence of TB and RR-TB in the study area showed a declining trend over the years. While TB was more prevalent in productive age groups (15 to 45 years), RR-TB was more prevalent in older populations (over 45 years), than others. Moreover, patients with a history of anti-TB drug exposure were more likely to be positive for DR-TB, highlighting the need to strengthen DOT programs for proper management of TB treatment.

Epigenetic memory of drug exposure history controls neural stem cell quiescence in the adult brain.

Epigenetic memory of drug exposure history controls neural stem cell quiescence in the adult brain.

The transcriptional response to acute cocaine is inverted in male mice with a history of cocaine self-administration and withdrawal throughout the mesocorticolimbic system

A large body of work has demonstrated that cocaine-induced changes in transcriptional regulation play a central role in the onset and maintenance of cocaine use disorder. An underappreciated aspect of this area of research, however, is that the pharmacodynamic properties of cocaine can change depending on an organism's previous drug-exposure history. In this study, we utilized RNA sequencing to characterize how the transcriptome-wide effects of acute cocaine exposure were altered by a history of cocaine self-administration and long-term withdrawal (30 days) in the ventral tegmental area (VTA), nucleus accumbens (NAc), and prefrontal cortex (PFC) in male mice. First, we found that the gene expression patterns induced by a single cocaine injection (10 mg/kg) were discordant between cocaine-naïve mice and mice in withdrawal from cocaine self-administration. Specifically, the same genes that were upregulated by acute cocaine in cocaine-naïve mice were downregulated by the same dose of cocaine in mice undergoing long-term withdrawal; the same pattern of opposite regulation was observed for the genes downregulated by initial acute cocaine exposure. When we analyzed this dataset further, we found that the gene expression patterns that were induced by long-term withdrawal from cocaine self-administration showed a high degree of overlap with the gene expression patterns of acute cocaine exposure - even though animals had not consumed cocaine in 30 days. Interestingly, cocaine re-exposure at this withdrawal time point reversed this expression pattern. Finally, we found that this pattern was similar across the VTA, PFC, NAc, and within each brain region the same genes were induced by acute cocaine, re-induced during long-term withdrawal, and reversed by cocaine re-exposure. Together, we identified a longitudinal pattern of gene regulation that is conserved across the VTA, PFC, and NAc, and characterized the genes constituting this pattern in each brain region.

The first genetically authenticated case of Leber hereditary optic neuropathy in Sri Lanka: a case report and review of the literature

IntroductionLeber hereditary optic neuropathy is a genetic disease of mitochondrial inheritance characterized by bilateral irreversible vision loss, predominantly affecting males. We report the first genetically authenticated Sri Lankan case of Leber hereditary optic neuropathy, illustrating its characteristic features of male predominance and variable penetrance.Case presentationA 15-year-old previously healthy Sri Lankan boy presented with painless progressive vision loss in his right eye, followed by vision loss in his left eye within 3 months. There was no history of drug or toxin exposure, or a family history of vision loss. His parents were nonconsanguineous. On examination, he could only perceive light. Funduscopy revealed bilateral optic atrophy. Routine hematological and biochemical blood tests, including inflammatory markers, were normal. Cranial magnetic resonance imaging was unremarkable. Optical coherence tomography, and the clinical presentation, suggested a diagnosis of Leber hereditary optic neuropathy, which was confirmed by detection of m.14484T > C pathogenic variant in the MT-ND6 gene through targeted genetic analysis for the three common pathogenic variants in mitochondrial deoxyribonucleic acid. He was homoplasmic for the variant, and his asymptomatic mother and two female siblings were also found to be harboring the variant with homoplasmy.ConclusionsThis case report is intended to increase awareness of Leber hereditary optic neuropathy, and highlights the need to consider this rare diagnosis in the appropriate clinical context. It also illustrates the phenomena of incomplete penetrance and male predominance, and suggests the possibility of an X-linked gene governing Leber hereditary optic neuropathy disease expression, which warrants further investigation.

Aetiology, clinical features, diagnostic studies, and outcomes of community-acquired pneumonia in kidney transplant recipients admitted to hospital: a multicentre retrospective French cohort study

ObjectivesTo assess the aetiology, clinical features, diagnostic studies and outcomes of community-acquired pneumonia (CAP) in a French cohort of hospitalized kidney transplant recipients. MethodsWe performed a retrospective, multicentre study in kidney transplant recipients admitted to ten French centres for CAP from January 2016 to December 2018. CAP discharge diagnoses were clinically and radiologically validated. We assessed a descriptive analysis of all confirmed CAP including medical ward and intensive care unit admissions. ResultsOne hundred sixty-five CAP episodes in 132 patients were included. Median time from transplantation to admission was 6.4 (interquartile range, 1.6–12.3) years, with corticosteroid exposure in 112/165 (67.9%) cases. Sputum culture was performed in 47/165 (28.5%) cases including 7/47 (14.9%) positive samples. Bronchoscopy was performed in 87/165 (52.7%) cases with pathogens identified in 39/87 (44.8%) cases. Microbiological studies led to identifying a respiratory pathogen in 64/165 (38.8%) CAP episodes including 11/64 (17.2%) polymicrobial cases. Among these 64 episodes, 75 microorganisms were identified; 46/75 (61.3%) were core respiratory pathogens and 29/75 (38.7%) were opportunistic or drug-resistant organisms including Pneumocystis jirovecii 9/75 (12%), Pseudomonas aeruginosa 5/75 (6.7%), multidrug-resistant Enterobacteriaceae 4/75 (5.3%), and Aspergillus 4/75 (5.3%). Patients required intensive care unit admission in 26/165 (15.8%) episodes, invasive ventilation in 20/165 (12.1%) cases, and 22/165 (13.3%) needed in-hospital dialysis. DiscussionCAP episodes occurred in kidney transplant recipients with a long history of immunosuppressive drug exposure. Diagnostic studies identified a microorganism in more than one-third of CAP episodes, including drug-resistant and opportunistic pathogens.

The Conditions and Quality of Postmortem Hair Sampling May Have a Subsequent Impact on the Interpretation of Toxicological Results in Hair.

In “postmortem” cases of high-energy trauma or extensively decomposed bodies, typical samples used for toxicological investigation (i.e., blood or urine) may not be available. In this context, alternative matrices (i.e., nails and hair) have proven to be valuable substitutes (1). Hair grows at around 1 cm per month (0.9–1.2 cm owing to inter- and intra-individual variations, nutrition, hormone status, etc. (2)). Consequently, segmental hair analysis provides a useful tool to determine drug exposure history. Analysis of fingernails and toenails can also be performed in “postmortem” cases alternatively and/or complementary to hair testing (3). Given the rate of nail growth speed (∼3 and 1.1 mm per month for fingernails and toenails, respectively (4)) and the incorporation of drugs along the entire length of the nails, it is routinely accepted that the windows of drug detection are 3–6 and 8–16 months in fingernail and toenail clippings, respectively (5). Nevertheless, segmental analyses cannot be performed on nails, and available data for the interpretation of nail results remain sparser than those for hair. The interpretation of results from nail or hair analyses can be complicated in cases of high-energy traumas or advanced stages of putrefaction owing to several pitfalls (e.g., external contamination by body fluids at the time of the death or by putrefaction fluids). In addition, sampling conditions can be challenging in such situations giving rise to poor-quality biological samples. The following case is intended to illustrate how a degraded quality of “postmortem” hair samples (performed by non-professionals, under poor conditions, i.e., not in an autopsy room) can have an impact on the interpretation of “postmortem” toxicological results in hair.

Local Adverse Drug Reactions in Ambulatory Asthma Patients Treated With Inhaled Corticosteroids: An Experience from a South Indian Teaching Hospital

Background:Inhaled corticosteroids (ICS) have an essential and established role in the treatment of asthma. Both systemic and local adverse effects may accompany the long-term use of ICS. Systemic adverse drug reactions (ADRs) of ICS are well established. However, there is a pau-city of information on local ADRs, especially in the Indian population.Objectives:This study aimed to determine the prevalence, severity, predictability, and preventabil-ity of local ADRs to ICS and their associated risk factors.Methods:Patients with asthma who need ICS were enrolled. Study patients were interviewed with open-ended questions to assess local ADRs to ICS at baseline and each follow-up visit, once a month for three months. Causality (Naranjo’s algorithm and WHO scale), severity (Hartwig SC scale), predictability (based on the frequency of occurrence of ADR and history of drug exposure), and preventability (Schumock and Thornton criteria) of local ADRs were assessed. Bivariate analy-sis and subsequently multivariate logistic regression were used to identify the risk factors for local ADRs to ICS.Results:A total of 243 patients (134 female) were included in the study. A total of 74 local ADRs were observed in 59 patients (a prevalence of 24.3%). The most common local ADRs included the feeling of thirst (14.8%), followed by cough during inhalation (8.6%) and taste disturbance (4.5%). All ADRs were predictable and mild in severity. Preventability assessment found 85.1% of local ADRs as ‘probably preventable’. Two out of five patients who had ADRs reduced or skipped doses because of the discomfort, despite their physician’s recommendation to continue their regular dose of ICS. Age &gt;41 years, use of MDI without spacer, and use of budesonide were identified as the risk factors for developing ADRs to ICS.Conclusion:Local ADRs to ICS were observed in approximately one in four patients with asthma. Two out of five patients who had ADRs reduced or skipped doses. Strategies to prevent local ADRs to ICS should focus on patients aged &gt;41 years, receiving budesonide, and using MDI without a spacer. We need to establish standards on the best practices for preventing ADRs, such as identify-ing the most suited device or ICS that is best tolerated by the individual patient and identifying the least ICS dose that maintains ideal asthma control.

Neonatal medium-sized vessel vasculitis: A rare case report

Vasculitis is a rare disorder during the neonatal period. We present a term male neonate of consanguineous parents and birthweight of 4 030 g who presented at 11 days of life with an evolving skin rash. There was no history of drug exposure in the neonate except for routine care. On day 7 of life, multiple erythematous plaques with necrotic or pustular centres appeared. There were no signs of mucosal involvement or sepsis and laboratory findings were normal. Skin biopsy revealed small and intermediate vessel vasculitis. At follow-up 2 weeks after discharge from the hospital, the skin lesions persisted, and at age 2 months, the patient presented with features of severe pneumonia and subsequently died. Vasculitis was reported as the cause of death on postmortem biopsy.

Maternal Methamphetamine Exposure Influences Behavioral Sensitization and Nucleus Accumbens DNA Methylation in Subsequent Generation.

The deleterious effects of methamphetamine (METH) exposure extend beyond abusers, and may potentially impact the vulnerability of their offspring in developing addictive behaviors. Epigenetic signatures have been implicated in addiction, yet the characteristics to identify prenatal METH abuse to offspring addiction risk remains elusive. Here, we used escalating doses of METH-exposed mouse model in F0 female mice before and during pregnancy to simulate the human pattern of drug abuse and generated METH-induced behavioral sensitization to investigate the addictive behavior in offspring mice. We then utilized whole genome-bisulfite sequencing (WGBS) to investigate the methylation signature of nucleus accumbens (NAc) in male METH-sensitized mice. Interestingly, male but not female offspring exhibited an enhanced response to METH-induced behavioral sensitization. Additionally, the METH-exposed group of male mice underwent a more comprehensive wave of epigenome remodeling over all genomic elements compared with unexposed groups due to drug exposure history. 104,219 DMCs (METH-SAL vs. SAL-SAL) induced by prenatal METH-exposure were positively correlated with that of postnatal METH-exposure (38,570, SAL-METH vs. SAL-SAL). Moreover, 4,983 DMCs induced by pre- and postnatal METH exposure (METH-METH vs. SAL-METH) were negatively correlated with that of postnatal METH exposure, and 371 commonly changed DMCs between the two comparison groups also showed a significantly negative correlation and 86 annotated genes functionally enriched in the pathways of neurodevelopment and addiction. Key annotated genes included Kirrel3, Lrpprc, and Peg3, implicated in neurodevelopmental processes, were down-regulated in METH-METH group mice compared with the SAL-METH group. Taken together, we render novel insights into the epigenetic correlation of drug exposure and provide evidence for epigenetic characteristics that link maternal METH exposure to the intensity of the same drug-induced behavioral sensitization in adult offspring.

Drug-induced autoimmune hepatitis: A minireview.

Drug-induced autoimmune hepatitis (DIAIH) is a specific phenotype of drug-induced liver injury that may lead to the devastating outcome of acute liver failure requiring liver transplantation. Drugs implicated in DIAIH include antimicrobials such as nitrofurantoin and minocycline, non-steroidal anti-inflammatory drugs, statins as well as anti-tumor necrosis agents. The clinical features of drug-induced liver injury are indistinguishable from idiopathic autoimmune hepatitis (AIH) as both may have positive AIH-related autoantibodies, elevated immunoglobulin G, as well as similar histopathological findings. In patients who show no clinical improvement, or there is progressive liver injury despite cessation of the suspected drug, a liver biopsy should be considered, whereby the presence of advance fibrosis on histology favors the diagnosis of idiopathic AIH. Empirical treatment with corticosteroids may be required in patients with non-resolving liver injury. A typical clinical scenario supportive of DIAIH includes a history of drug exposure with spontaneous resolution of liver injury after drug withdrawal and the absence of relapse after rapid steroid taper. In this article we report two cases of DIAIH secondary to Sorafenib and Atorvastatin along with a review of currently available literature. Early identification and treatment often lead to a favorable outcome in DIAIH.

The management of mirror foot polydactyly: A case report.

BackgroundMirror foot or mirror image duplication of the foot is an extreme form and very rare congenital anomaly. There are limited management recommendations, and most cases are treated before walking age. We present the clinical findings, surgical treatment, and results of a rare case of mirror foot polydactyly.Case presentationA five-month-old girl with bilateral mirror foot was referred to our orthopaedic department. She was born full-term by the caesarian section and there was no family history of similar skeletal abnormalities and no history of drug or radiation exposure during gestation. The child had eight toes on the right foot and seven toes on the left with fully developed metatarsal, proximal, middle, and distal phalanges. Radiographs confirmed the diagnosis of mirror foot with a full complement of normal lateral toes and three additional complete rays medial to the right foot and two additional complete rays medial to the left foot. The patient underwent ray resection and concurrent reconstruction of the medial arch of the foot. A medial longitudinal incision was used to excised the right medial three rays and left medial two rays. The target of this surgical intervention was for aesthetic or cosmetic reasons and enabling the patient to allow shoe wear.ConclusionMirror-foot abnormalities are distinctly uncommon entities and represent extreme forms of congenital duplication of the preaxial polydactyly spectrum. Treatment on age of five-month-old with medial longitudinal incision had a satisfying clinical and radiological results.

Morphologic Spectrum of Lymphadenopathy in Drug Reaction With Eosinophilia and Systemic Symptoms Syndrome.

Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DRESS) is a drug-induced, adverse T-cell-mediated hypersensitivity reaction that most often involves skin. The pathologic findings of DRESS-related lymphadenopathy have been described infrequently in the literature. To present a case series of DRESS-related lymphadenopathy with an emphasis on the morphologic spectrum. We describe detailed clinical and pathologic findings along with the literature review. We focus on the differential diagnosis between DRESS lymphadenopathy and angioimmunoblastic T-cell lymphoma (AITL). There were 4 men and 1 woman with a mean age of 41 years (range, 23-59 years). One patient (20%) died. Three lymph node biopsy specimens showed a pattern reminiscent of AITL (AITL-like pattern) and 2 cases showed necrotizing lymphadenitis (Kikuchi-like pattern), associated with vasculitis in 1 case. The AITL-like morphology of DRESS-related lymphadenopathy may be difficult to distinguish from genuine AITL. The clinical information is important for differential diagnosis, including history of drug exposure, age, and the rarity or absence of AITL-associated manifestations such as hemolytic anemia and hypergammaglobulinemia. Molecular analysis of the T-cell receptor genes is helpful, typically revealing a polyclonal pattern in DRESS-related lymphadenopathy. In the literature, 4 histologic patterns of DRESS lymphadenopathy have been described: reactive lymphoid hyperplasia, necrotizing lymphadenitis, Hodgkin lymphoma-like, and AITL-like. These patterns, particularly those that resemble lymphoma, highlight the importance of correct diagnosis to avoid unnecessary therapies.

S2668 Sorafenib-Induced Autoimmune Hepatitis: A Case Report,

Introduction: Drug-induced liver injury (DILI) with autoimmune hepatitis-like features (DIAIH) is a specific phenotype of DILI with clinical features indistinguishable from de-novo autoimmune hepatitis (AIH). We describe a case of DIAIH due to Sorafenib. Case Description/Methods: A 61-year-old man and teetotaller presented with 1-week history of jaundice and malaise. He was on Atorvastatin 40mg daily for 4 years for hyperlipidaemia. Sorafenib was recently initiated six weeks ago for recurrent sarcoma of the left thigh. Clinical examination was unremarkable apart from scleral icterus. Liver function test (LFT) showed severe hepatocellular (HC) injury (bilirubin 4.56 mg/dL, alkaline phosphatase 190 U/L, alanine transaminase 1004 U/L, aspartate transaminase 790 U/L peak INR 1.53). Viral hepatitis screening, AIH specific antibodies and abdominal imaging were unremarkable. Serum IgG was raised (18.6 g/L). Liver biopsy was supportive of DILI and AIH histological features were also noted (Fig.1a-f). Simplified AIH score was 6. Roussel Uclaf Causality Assessment Model (RUCAM) score was 9 for Sorafenib and 6 for Atorvastatin. Diagnosis of Sorafenib-induced AIH was made. His LFT improved spontaneously with normalization of LFT eight weeks after stopping Sorafenib. Discussion: Sorafenib often causes idiosyncratic DILI with mild elevation of transaminases. However, it rarely causes severe DILI and has no known association with DIAIH, unlike Atorvastatin and immune checkpoint inhibitors (e.g Nivolumab and Atezolizumab). To our knowledge, this is the first case report of DIAIH due to Sorafenib. In patients with severe DILI or DILI with probable AIH based on AIH scoring, liver biopsy should be considered for evaluation. However, differentiating DIAIH from de-novo AIH is often challenging as both present with HC injury, may have positive AIH specific antibodies, raised serum IgG and share similar histological findings. The key distinguishing features are the history of drug exposure within a time frame and no requirement for long term immunosuppressant. DIAIH may resolve spontaneously after stopping culprit drug. Corticosteroids should be initiated in cases without improvement upon drug cessation. In DIAIH requiring corticosteroids, relapse is rare after stopping corticosteroids and long-term immunosuppression is rarely needed. In conclusion, DIAIH should be considered in patients who present with severe HC DILI. Differentiating DIAIH from AIH is crucial as the former rarely requires long term immunosuppression.Figure 1.: Liver biopsy specimen [a] H&E 200X: A portal tract, zone 1, showing moderate chronic inflammation with interface damage and rare bile droplets. [b] H&E 200X: Lobulitis characterized by aggregates of plasma cells, swollen hepatocytes and rosetting within liver parenchyma zone 2. [c] H&E 200X: Centrilobular region zone 3 showing hepatocyte drop-out, aggregates of plasma cells, rosetting and bile pigment. Reticulin [d, 40X] and Sirius Red [e, 40X] special stains show collapse with mild early young fibrosis without elastic fibers demonstrated on Orcein [f, 40X], consistent with subacute injury. Overall, the appearances are supportive of subacute DILI in association with features suggestive of AIH (i.e. interface damage, plasma cell aggregates and resetting).

Species Distribution of Candidemia and Their Susceptibility in a Single Japanese University Hospital: Prior Micafungin Use Affects the Appearance of Candida parapsilosis and Elevation of Micafungin MICs in Non-parapsilosis Candida Species.

Introduction: Micafungin is a recommended echinocandin antifungal agent for candidemia treatment and prophylaxis. However, overuse of echinocandin antifungals may cause resistance. There is currently no information available regarding the low susceptibility associated with using micafungin. This study investigated the effect of micafungin use on changes in the detected Candida species and low susceptibility. Methods: We conducted a retrospective survey and included records of Candida spp. detected in blood cultures from January 2010 to December 2018 in our hospital. Survey items included clinical outcomes at 30 days after positive cultures, patient characteristics, and drug prescription status. Patient background information included gender, previous hospitalization, stay in the intensive care unit, comorbidities, and history of surgery (within 90 days before candidemia onset) and drug exposure. Species detected and their minimum inhibitory concentrations (MICs) and amount of antifungal prescriptions by department were investigated. Risk factors for detecting C. parapsilosis and for low susceptibility to micafungin were evaluated using multivariate analysis. Results: A total of 153 Candida clinical blood isolates were collected and C. albicans was the most prevalent species, followed by C. parapsilosis and C. glabrata. In the analysis by department, antifungal use and non-albicans Candida species were most frequently detected in the hematology department. Multivariate analysis showed that prior micafungin use increased the risk of C. parapsilosis (odds ratio (OR) 4.22; 95% confidence interval (CI) 1.39–12.79; p = 0.011). MIC90 of micafungin on C. glabrata and C. parapsilosis was 1.0 μg/mL. Prior micafungin use was clarified as a risk factor resulting in MIC > 0.06 μg/mL for micafungin in non-parapsilosis Candida species (OR 13.2; 95% CI 3.23–54.2; p < 0.01). Conclusion: Prior micafungin use increased the risk of C. parapsilosis and the MIC > 0.06 μg/mL of micafungin in non-parapsilosis Candida species. Since there are only a few antifungal options, further antifungal stewardship considering azole antifungal agents use is required.

PHACE syndrome: A remarkable phakomatosis

A 1.5-month-old baby girl presented with an increasing infantile hemangioma (IH) involving most of her right hemiface, most predominantly her forehead and eyelid. The lesion measured 9.5 × 6 cm. She was born premature at 34 weeks due to maternal cervical insufficiency at a birth weight of 2.590 kg. There was no history of maternal drug exposure during gestation and her birth history was unremarkable. The girl did not have any apparent developmental delays or a family history of IH. Ophthalmologic examination excluded orbital abnormalities.