Months Of Cessation Research Articles

Targeted treatment in inflammatory myofibroblastic tumors in children.

10046 Background: Inflammatory myofibroblastic tumors (IMTs) and epithelioid inflammatory myofibroblastic sarcoma (EIMS)-a variant of IMT, are rare mesenchymal neoplasms in children. Surgical resection has been the mainstay of treatment, however it may cause morbidities due to the size, location, invasiveness of the tumor. With the identification of targetable molecular alterations, targeted treatment has begun to be used in inoperable/relapsed/refractory cases. Methods: Files of children with IMT diagnosed and treated between 1990-2023 were retrospectively evaluated for demographic, clinical, molecular characteristics, treatment and outcome. Results: The mean age of 8 patients (5 male, 3 female) at diagnosis was 9 years (8 months-17 years). Six had IMT and two EMS. Tumor localization was intestine, retroperitoneum, lower extremity in two patients each; liver and back in one each. None had metastatic at diagnosis. Three of the six patients (one EMS) who underwent only surgical resection had negative surgical margins (one after re-resection) and are under follow-up with no evidence of disease (NED). Molecular analysis was performed in six patients. ALK was positive in the tumor tissue of five patients. One patient with an inoperable local recurrence received chemotherapy, had a life-threatening infection and resistant hypercalcemia. The molecular analysis by next-generation sequencing revealed a YWHAE-ROS fusion and she was treated by ceritinib, after which a significant (>90%) tumor shrinkage occurred and hypercalcemia resolved. She is currently in remission and continuing treatment. The patient with a positive surgical margin experienced local and metastatic (lung, liver) recurrences during follow-up and was treated with chemotherapy containing vincristine, actinomycin-D, and cyclophosphamide, the patient died due to progressive disease. In a patient with an unresectable tumor and ALK positivity, crizotinib treatment was initiated. After a treatment duration of seven months with crizotinib, the tumor completely regressed and treatment was stopped. On follow-up, local recurrence was detected after two months of cessation of crizotinib, crizotinib was restarted, considering the infiltrative appearance of the tumor and possible morbidities if operated. Two months after readministering crizotinib, complete response was achieved once again. The patient is continuing treatment with crizotinib. Thus, 7/8 patients are alive with NED for a median of 99 (9-174) months. Conclusions: Inflammatory myofibroblastic tumor and epithelioid inflammatory myofibroblastic sarcoma are rare in children. Surgery is the mainstay of treatment. The effectiveness of chemotherapy is yet unclear despite its use in inoperable cases. Molecular analysis of tumor tissue is highly recommended as targets such as ALK rearrangements or ROS fusions may enable the use of targeted treatments with fewer side effects.

Abstract 5304: ABL407, a LILRB4x4-1BB bispecific antibody with a wild type Fc, exhibits potent antitumor activity by modulating immune system in multiple ways involving T cells, myeloids, and regulatory T cells

Abstract Tumor-associated myeloid cells such as myeloid-derived suppressor cells (MDSC) accumulate in the tumor microenvironment (TME) and suppress anti-tumor immune responses in a broad range of cancers. LILRB4 (Leukocyte Immunoglobulin-Like Receptor Subfamily B Member 4), an emerging myeloid target, is specifically expressed in tumor-associated myeloid cells and suppresses the immune response, thus promoting cancer progression and metastasis. ABL407 is a First-in-Class bispecific antibody designed to simultaneously target LILRB4 and 4-1BB, enabling LILRB4 expression-dependent 4-1BB activation. By antagonizing LILRB4 signaling, ABL407 inhibited LILRB4 mediated immunosuppression, restoring T cell activity. In addition, ABL407 inhibited fibronectin, a potential LILRB4 ligand, -mediated suppression of myeloid cells. To evaluate the efficacy of ABL407, we established EL4 murine tumor model overexpressing LILRB4 (EL4/LILRB4) in h4-1BB transgenic mice and hLILRB1/4-h4-1BB triple transgenic mice. We observed LILRB4 was overexpressed in M-MDSC in the blood and liver-metastasized tumors. A significant decrease of M-MDSC population and tumor growth inhibition was observed in mice treated with anti-LILRB4 antibody and ABL407. ABL407 treatment resulted in a proportion increment of T cells. However, the percentage of Treg cells and M-MDSC in the liver and blood was reduced by ABL407 treatment in hLILRB1/4-h4-1BB triple transgenic mice. Mice with complete remission (CR) were further protected from the rechallenge of previously exposed tumor after 3 months of cessation of ABL407 treatment, implicating that immunological memory might be generated. In conclusion, our findings suggest that ABL407, LILRB4x4-1BB bispecific antibody, may be a promising strategy for the treatment of cancer. It can be applied as a "LILRB4 antagonist" as well as a "LILRB4-dependent 4-1BB agonist" across a broad spectrum of cancers. Citation Format: Minkyu Seon, Yangsoon Lee, Hyunseong Youn, Yelim Park, Sora Kim, Kyungjin Park, Jonghwa Won. ABL407, a LILRB4x4-1BB bispecific antibody with a wild type Fc, exhibits potent antitumor activity by modulating immune system in multiple ways involving T cells, myeloids, and regulatory T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5304.

Abstract 5303: A novel TIGIT and 4-1BB bispecific antibody, ABL112, exhibits potent in vitro and in vivo antitumor activity through dual immune modulation

Abstract T cell immunoreceptor with Ig and ITIM domains (TIGIT) is an immune checkpoint molecule responsible for delivering inhibitory signals that suppress immune activation. Due to its inhibitory role in the immune response, TIGIT has emerged as a potential therapeutic target for various malignancies, with several clinical trials exploring the use of anti-TIGIT blocking antibodies with anti-PD-(L)1 therapies. Recent reports have indicated elevated expression of 4-1BB within intra-tumoral Tregs. Therefore, we hypothesized that a dual targeting approach involving both TIGIT and 4-1BB could effectively enhance intra-tumoral immunity. ABL112, a First-in-Class bispecific antibody targeting TIGIT and 4-1BB, demonstrated the induction of T cell activation by blocking the TIGIT signaling and TIGIT dependent 4-1BB clustering. By having intact Fc, ABL112 bound to FcγRI and its crosslinking with 4-1BB also induced 4-1BB activation. ABL112 selectively depleted Treg cells but not other T cells in vitro, potentially through antibody-dependent cell-mediated cytotoxicity. ABL112 demonstrated superior efficacy in tumor regression compared to anti-TIGIT monoclonal antibody across various mouse tumor models. Additionally, combining ABL112 with pembrolizumab significantly inhibited tumor growth better than combining anti-TIGIT monoclonal antibody with pembrolizumab. According to immune cell depletion assay, ABL112-mediated tumor suppressive activity was predominantly driven by CD8+ T cells, with a partial tumor reduction by CD4+ T cell or NK cell depletion. Mice with complete remission (CR) were further protected from the tumor re-challenge after 3 months of cessation of ABL112 treatment, and the proportion of tumor-specific memory T cells in the blood increased, suggesting long-term immunological memory has been established. In conclusion, ABL112 exhibited potent in vitro and in vivo anti-tumor activity through multiple mode of action including TIGIT inhibition and 4-1BB activation. These results strongly suggest that ABL112 is an innovative and promising therapeutic option with the combination of anti-PD-(L)1 therapies for cancer patients. Citation Format: Wonjun Son, Yangsoon Lee, Yelim Park, Jonghwa Won. A novel TIGIT and 4-1BB bispecific antibody, ABL112, exhibits potent in vitro and in vivo antitumor activity through dual immune modulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5303.

Abstract 2941: ROR1 targeted 4-1BB costimulatory bispecific antibody, ABL102, exhibits potent in vitro and vivo antitumor activity and superior safety profile

Abstract ROR1, a member of the ROR (Receptor Tyrosine Kinase-Like Orphan Receptor)-family, is overexpressed in the process of embryo and fetal development, and controls cell polarity, cell migration and neurite growth. The expression is gradually reduced as development progresses, and it is hardly expressed in adults, but the overexpression of ROR1 is observed in various blood and solid cancer cells, so it is classified as an oncofetal gene. ABL102, a First-in-Class bispecific antibody targeting ROR1 and 4-1BB, elicits superior T cell activation by tumor specific T cell engagement through ROR1 dependent 4-1BB clustering. Our data showed that tumor target dependents binding of ROR1 and costimulatory 4-1BB by ABL102 induced 4-1BB activation in cell-based 4-1BB bioassay. ABL102 lead to IFN-γ secretion and tumor cell killing with a ROR1 dependent manner in co-culture assay with tumor cells and human PBMC. In h4-1BB knock-in mouse model bearing hROR1-expressing tumors, ABL102 potently inhibited tumor progression with a high rate of complete remission (CR). Mice with CR were further protected from the rechallenge of previously exposed tumors after 3 months of cessation of ABL102 treatment, implicating that immunological memory might be generated. In 4-week pilot toxicity study using cynomolgus monkeys, no ABL102-related toxicity was observed up to 100mg/kg, including mortality, body weight, hematology, liver toxicity, clinical chemistry and pathology, indicating a favorable safety profile. In conclusion, ABL102 exhibited potent in vitro and vivo anti-tumor activity and it was well tolerated and safe in the NHP toxicity study. These results strongly suggest that ABL102 is promising therapeutics for ROR1 positive cancer patients. Citation Format: Yangsoon Lee, Kyeong-Su Park, Wonjun Son, Sora Kim, Hyunseong Youn, Jiseon Yoo, Hanbyul Lee, Jonghwa Won. ROR1 targeted 4-1BB costimulatory bispecific antibody, ABL102, exhibits potent in vitro and vivo antitumor activity and superior safety profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2941.

Incidence, predictors and re-treatment outcomes of recurrent myopic choroidal neo-vascularization.

To evaluate incidence, predictors, and re-treatment outcome of recurrent myopic choroidal neovascularization (m-CNV). Retrospective consecutive observational series. From year 2014 to 2019, 167 eyes of 167 patients of treatment naïve m-CNV were enrolled. 59 and 108 eyes were treated with intra-vitreal ranibizumab and bevacizumab mono-therapy, respectively. Recurrence was defined as re-appearance of CNV activity, confirmed on optical coherence tomography (OCT) after at least 3 months of cessation of anti-VEGF therapy. Incidence of recurrence, predictors and re-treatment outcomes were studied. Overall, mean age and spherical equivalence (SE) was 47.95 ± 14.72 years and -12.19 ± 4.93 D respectively. Males constituted 50.9%. 44 eyes (26.4%) had a recurrence during a mean follow up of 16.5 ± 12.86 months. Kaplan-Meier survival analysis showed the risk of recurrence was 8, 26 and, 33.6% at 6, 12 and 18 months, respectively. Age (p = 0.511), gender (p = 0.218), SE (p = 0.092), anti-VEGF (p = 0.629) and baseline BCVA (p = 0.519) did not influence recurrence. Number of injections administered to control the disease in the first episode was the only significant predictor of recurrence (Cox Proportional Hazard Ratio 2.89-3.07, 95% Confidence Interval: 1.28-7.45; p = 0.005). At 12 months, eyes requiring one injection in first episode had a recurrence rate of 12% versus 45% in eyes requiring 3 or more injections in the first episode. A mean number of 1.9 additional injections per eye was needed during re-treatment. Final BCVA in the recurrence group was similar to that of non-recurrence group (0.53 ± 0.40 versus 0.55 ± 0.36 LogMAR; p = 0.755). Baseline BCVA (p = 0.0001) was the only predictor of final visual outcome irrespective of anti-VEGF drug (p = 0.38). Eyes requiring greater number of injections for disease control in first episode are "at risk" of early m-CNV recurrence. However, recurrence does not adversely affect visual outcome, if treated adequately.

Recurrence of metastatic Merkel carcinoma after cessation of avelumab in a patient previously with a complete response

AbstractBackgroundMerkel cell carcinoma (MCC) is a rare and aggressive cutaneous neuroendocrine malignancy. Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for patients with metastatic MCC (mMCC). In mMCC, the response duration after cessation of ICIs treatment for complete response (CR) is unknown.ObservationWe report a case of a woman in her 70s with metastatic MCC treated in first‐line with avelumab. The treatment was stopped after 2 years of CR. The patient relapsed after 11 months of cessation of treatment and rechallenge with avelumab at the same dosing regimen was decided. The first tumour assessment at 3 months after reintroduction revealed a CR.DiscussionIn contrast with observations made for patients who have discontinued ICIs in the metastatic melanoma setting, disease progression is observed after ICIs cessation in mMCC including for patients with low tumour burden and who achieve a CR.ConclusionThe case of our patient underlines this risk of relapse and suggests great caution before stopping ICIs in patients treated for mMCC, even when they are in CR.

Field changes on automated Humphrey’s field analyzer in tuberculosis following ethambutol therapy

This study was conducted to evaluate the visual field changes in tubercular patients on anti-tubercular therapy and to assess the reversibility of these changes after the discontinuation therapy. This study was conducted as a prospective analytical study at tertiary care centres in Bhopal and Jabalpur on all newly detected tuberculosis patients. Ocular history, relevant history was recorded and detailed ocular examination was done at the time of presentation, before initiating ATT. All the patients were followed up periodically till the cessation of treatment and three months thereafter. A total of 40 cases of newly diagnosed tuberculosis were registered with mean age of 38.4±13.99 years. We documented significant deterioration in visual acuity after 3 months of initiation of therapy. Once the ATT was stopped, the improvement in visual acuity was statistically significant 3 months after the cessation of ATT as compared to visual acuity 3 months after initiation of ATT (p<0.05). But residual visual impairment even after stoppage of ATT was observed. Color vison and visual field defects were observed in higher proportions of eyes following initiation of ethambutol which improved significantly after 3 months of cessation of ATT (p<0.05). Ethambutol, even in recommended dose according to DOTS, has been associated with ocular toxicity which manifests in the form of painless progressive loss of vision, color vision defects and visual field defects. Though these changes are usually reversible, few patients have irreversible damage. Thus, patients receiving ethambutol must be explained regarding these effects and followed up periodically.

학교 밖 청소년의 6개월 이내 재흡연 관련 요인

Objectives: The purpose of this study was to investigate the factors related to relapse within six months of cessation of smoking in out-of-school adolescents. Methods: The study included 45 adolescents who applied to the outreaching smoking cessation service provided by Daejeon Tobacco Control Center between July 2015 and March 2017 and maintained the abstinence for four weeks since registering for the service. The data on the participants were collected from the Integrated Information System for Smoking Cessation Services and analyzed using The Kaplan-Meier analysis and the Cox proportional hazard model. Results: Our results indicated that the rate of smoking relapse within six months was 75.6%. The variables related to this relapse were attempts to quit smoking in last one year and frequency of counseling. Adolescents who had previously tried to quit smoking were more likely to relapse than those who had never tried quitting (hazard ratio [HR]=4.24; 95% confidence interval [CI]=1.38-13.02). Additionally, if the number of counseling sessions to quit smoking was nine or more, the likelihood of relapse was reduced as compared to when the sessions were five or less. (HR=0.19; 95% CI=0.06-0.60 for ≥9 vs. ≤5 sessions). Conclusion: Our results indicate that it is necessary to offer continued and consistent counseling, focusing on their confidence in quitting, for out-of-school adolescents to discourage a relapse of smoking.

The Reversion of DNA Methylation at Coronary Heart Disease Risk Loci in Response to Prevention Therapy

Coronary heart disease (CHD) is preventable, but the methods for assessing risk and monitoring response rely on imprecise lipid-based assessments. Recently, we have shown that an integrated genetic–epigenetic test that includes three methylation-sensitive digital PCR assays predicts 3-year risk for incident CHD better than lipid-based methods. However, whether methylation sites change in response to therapies that alter CHD risk is not known. Therefore, we assessed methylation at these three incident CHD-related sites in DNA from 39 subjects before and after three months of biochemically verified smoking cessation, then analyzed the relationship between change in methylation at each of the sites to the change in smoking intensity as assessed by cg05575921 methylation. We found that, in those who quit smoking, methylation change at one CHD risk marker (cg00300879) was significantly associated with change in cg05575921 methylation (p < 0.04). We conclude that changes in incident CHD-related methylation occur within three months of cessation of smoking, a major risk factor for CHD. This suggests that the effectiveness of treatment of other CHD risk factors, such as high cholesterol, may be similarly quantifiable using epigenetic approaches. Further studies to determine the relationship of changes of methylation status in response to treatment of other CHD risk factors are indicated.

CMV, EBV, JCV and BKV infection and outcome following kidney transplantation in children initiated on a corticosteroid-minimisation immunosuppressive regimen.

Modern immunosuppressive regimens in paediatric kidney transplant recipients have contributed to improved long-term allograft survival, but at the expense of an increased incidence of viral infections. Here, we describe, for the first time, the incidence, risk factors and clinical outcome of CMV, EBV, BKV and JCV viraemia in a cohort of paediatric allograft recipients treated with a corticosteroid-minimisation immunosuppressive regimen (CMR). We retrospectively analysed 98 children treated with a CMR (basiliximab induction, corticosteroids until day 4, long-term tacrolimus and mycophenolate mofetil), who received a kidney transplant in our centre between 2009 and 2019. Over the first 4 years post-transplant, the incidences of viraemia were as follows: CMV, 25.5%; EBV, 52.0%; JCV, 16.3%; BKV, 26.5%. Younger children at time of transplant were more likely to develop EBV and BKV viraemia. EBV viraemia was also associated with a regimen involving corticosteroids, but lacking MMF. Recipient CMV serology predicted the development of EBV, BKV and CMV viraemia. Fifty-six percent of CMV viraemia episodes in high-risk patients occurred whilst the graft recipients were still receiving anti-viral prophylaxis or within 3 months of cessation. There was no difference in graft function at latest follow-up between those with and without viraemia. Judicious monitoring of viraemia, coupled with timely clinical intervention, can result in similar long-term outcomes for graft recipients compared to controls. The high incidence of CMV viraemia observed within a short period of cessation of anti-viral prophylaxis supports an extension of the length of prophylactic treatment in high-risk allograft recipients.

Clinical Follow-up of Patients with Behçet Uveitis after Discontinuation of Infliximab Therapy

ABSTRACT Purpose To evaluate the clinical course of patients with Behçet uveitis after discontinuation of infliximab (IFX) therapy. Methods Medical records of eight patients who discontinued treatment between 2010 and 2018 were retrospectively analyzed. The main outcome measures were frequency of uveitis attacks per year, best-corrected visual acuity (BCVA), aqueous flare, foveal thickness and fluorescein angiography (FA) scores before initiation, during treatment and after 6, 12, and 24 months of cessation of the IFX therapy. Results The mean follow-up after withdrawal of infusions was 38.6 ± 20.4 (12–90) months. Frequency of uveitis attacks, BCVA, aqueous flare, foveal thickness and FA scores were improved significantly after treatment (p < .05). In terms of these parameters, there was no significant difference between the periods of during treatment and after 6, 12, and 24 months of cessation of the IFX therapy. Conclusion IFX therapy might be discontinued safely with an effective inflammation control in patients with Behçet uveitis.

Impaired functional connectivity of sensorimotor network predicts recovery in drug-induced parkinsonism

ObjectiveIn a substantial portion of patients with drug-induced parkinsonism (DIP), parkinsonism may persist for long periods after discontinuation of offending drugs, suggesting subtle underlying neurodegeneration. We hypothesized that patients with DIP have impaired functional connectivity (FC) of brain networks, which may determine the reversibility of parkinsonism. MethodsIn this case-control study, we consecutively recruited 60 patients with DIP and 32 healthy controls. We used independent component analysis and dual regression of functional magnetic resonance imaging data to identify seven resting-state networks and compared FC of the networks between the DIP and control groups. Among regions where the two groups showed a significant difference in the FC with sensorimotor network, we compared the FC between patients who had completely recovered (n = 21) and those who had partially recovered (n = 39) within 3 months of cessation of the offending drugs. ResultsPatients with DIP had decreased FC between the sensorimotor network and widespread brain regions, when compared to healthy controls. FC in the prefrontal regions was negatively correlated with parkinsonian motor score. Patients who partially recovered had a significantly lower FC in the prefrontal and cerebellar regions than those who recovered completely, providing a useful predictor of recovery status. ConclusionsPatients with DIP had decreased FC of the sensorimotor network, which correlated with the severity of parkinsonism and predicted the recovery status after cessation of offending drugs. Impaired FC of the sensorimotor network can be used as a biomarker to evaluate the severity and prognosis of DIP.

P555 Frequent disease relapse after withdrawal of infliximab in IBD patients with sustained remission

Abstract Background In the UK, NICE guidance requires an annual review of TNF antagonists with the withdrawal of therapy in patients in confirmed remission. This study assesses the outcome of this practice in patients with Crohn’s disease (CD) and ulcerative colitis (UC) who received infliximab at a large referral centre. The primary outcome is relapse-free survival. Secondary objectives include evaluation of predictors of relapse, and response to subsequent therapy. Methods IBD patients who ceased infliximab due to remission at annual review were identified. Demographics and clinical characteristics were collected from electronic patient records. Disease activity from 3 months prior to cessation and throughout follow-up was recorded; active disease was defined as CRP&amp;gt;10, faecal calprotectin&amp;gt;50, endoscopic activity or radiological activity. Relapse was defined as the aforementioned markers of activity with clinician documentation of relapse. Immunomodulator use, active disease prior to cessation, age at diagnosis and ethnicity were analysed in patients who had completed 6, 12, 18 and 24 months of follow-up. Survival analysis and logistical regression were undertaken with SPSS®. In patients who relapsed, steroid use and future biologic use was evaluated. Analysis was undertaken for total IBD, CD and UC. Results 66 cases were identified (CD:UC = 40:26, F:M =28:38, Asian:Black:Caucasian:Multiracial/Unknown = 13:3:45:5). Median follow-up was 18.1 months (IQR 9.07–41.71). Failure free survival was: all IBD; 14.65 months (IQR 8.38–25.23), CD; 13.08 months (IQR 7.66–25.23) and UC; 14.65 months (IQR 5.91–22.47). Relapse rates of patients who completed follow-up at each time point are presented in Table 1: No predictors of disease relapse were identified at any time point. Thirty-seven patients experienced relapse, of whom 40.5% (15/37) were prescribed steroids, 86.5% (32/37) restarted a biologic and 67.7% (25/37) restarted infliximab. Of those who have completed infliximab induction, 56.5%(13/23) recaptured response to standard dose and a further 13.0% (3/23) required 10mg/kg. Alternative therapy was required in 30.4% (7/23). Conclusion Within 24 months of cessation 73.1% patients relapsed. The majority of these restarted a biologic. However, only 56.5% of patients who restarted infliximab responded to standard dose. With additional costs of newer biologics and morbidity of disease flare and steroid use, routine withdrawal of TNF antagonists should only occur after careful consideration.

A Case of Pulmonary Langerhans Cell Histiocytosis Diagnosed Using a Transbronchial Lung Biopsy After Two Months of Cessation of Smoking

A Case of Pulmonary Langerhans Cell Histiocytosis Diagnosed Using a Transbronchial Lung Biopsy After Two Months of Cessation of Smoking

2259 Severely Jaundiced Body Builder: A Case of Acute Cholestatic Syndrome With Anabolic Androgenic Steroid Use

INTRODUCTION: Illicit use of anabolic androgenic steroids (AAS) has been growing among athletes and bodybuilders for cosmetic and performance purposes. We report a case of one of the possible hepatic complications of AAS, acute cholestatic syndrome (ACS), in a male with anabolic steroid abuse. CASE DESCRIPTION/METHODS: 27-year-old Polish man with no past medical history presented with jaundice, itching of the body, dark-colored urine, clay-colored stools for 5 weeks. No abdominal pain was reported. Patient reported taking for 4 months 4 types of AAS (testosterone, oxandrolone, methasterone and trenbolone) for body building, which he stopped taking 6 weeks prior to initial presentation due to fatigue. Vitals were normal, and on exam he appeared to be a muscular, jaundiced male with scratch marks on his skin. Abdominal exam revealed a non-tender, non-distended abdomen, with difficulty palpating the liver edge due to the muscularity. Laboratory tests were significant for total bilirubin of 34.8 mg/dL with direct of 23.5 mg/dL, AST 55 U/L, ALT 70 U/L, ALP 212 U/L, GGT 57 U/L, INR 1, creatinine 1.1 mg/dL. Liver ultrasound showed hepatomegaly with no biliary dilation and patent hepatic and portal veins. A liver biopsy was obtained showing portal neutrophil predominant inflammation with occasional eosinophils, mild portal fibrosis and cholestasis, suggestive of drug-induced hepatotoxicity. Liver function tests normalized after 4 months of cessation of AAS use, with resolution of his jaundice and pruritis. DISCUSSION: Body builders usually prefer polydrug use of AAS to maximize the desired effects and hypothetically reduce side effects at the same time. But contrary to their belief, the concomitant use of different illicit AAS may be a factor in their toxicity, making difficult to link an adverse effect with a specific substance. Acute cholesta tic syndrome, has been associated with use of the 17α – alkylated anabolic steroids ( i.e. oxandrolone, methasterone), thought related to an increase of reactive oxygen. This leads to prolonged direct toxic effects and intrahepatic cholestasis, though the pathophysiology remains unclear. ACS usually occurs 1-4 months after steroid initiation presenting with nausea, fatigue, pruritis; later, jaundice, dark urine, with significantly elevated total bilirubin and ALP but mild aminotransferase elevation can be seen. Management consists of stopping anabolic steroid use, supportive care and symptomatic treatment of pruritis.

Adrenal Insufficiency in Children with Juvenile Idiopathic Arthritis (JIA) Treated with Prednisolone

Background: Corticosteroids are options for the treatment of juvenile idiopathic arthritis (JIA) although with adverse effects. Adrenal insufficiency (AI) may happen after therapeutic glucocorticoid administration. Objectives: We designed a study to assess the adrenal insufficiency in children with JIA undergoing treatment with low-dose glucocorticosteroids for at least six months. Methods: This cross-sectional study was conducted at Imam Khomeini hospital and Children Medical Center hospital on 36 JIA patients after at least three months of cessation of low-dose, long-term corticosteroid therapy. Data regarding age, sex, age at diagnosis, the subtype of disease, and duration of treatment with corticosteroid were recorded. Fasting cortisol and cortisol after ACTH administration were measured. The AI diagnosis was made if the first level of cortisol was less than 3 µg/dL and the second level was less than 20 µg/dL. Results: The sample included 25 women (69.4%) with an overall mean age of 8.2 ± 3.4 years. The mean age at the time of diagnosis was 6.3 ± 3.2 years. The type of disease was oligoarticular in 32 (88.9%) cases and systemic in four (11.1%). Four cases had AI, all of whom were female with oligo-articular arthritis. In all the four cases, the adrenal function became normal three months after prednisolone cessation. The age at the time of study and the age at the time of disease diagnosis were significantly different between cases with and without AI. Conclusions: Adrenal insufficiency is not prevalent in children with JIA treated with low-dose glucocorticoids for a short time.

Effects of 3months of detraining on functional fitness and quality of life in older adults who regularly exercise.

Little is known about the effects of detraining in older adults, particularly those who regularly exercise. To determine the consequences of 3months of cessation of a habitual supervised exercise on functional fitness and quality of life in aged adults and to explore the associations among those parameters. Thirty-eight women and 11 men (mean age 75.5 ± 5.7years) took part in a physical exercise program for 9 months, followed by a 3-month detraining period. Participants completed physical function tests and questionnaires regarding the quality of life and leisure-time physical activity at the end of the exercise program (baseline) and 3months later (detraining). After the detraining period, performance in the 8 Foot Up and Go test (p < 0.001) and the physical and mental components of the quality of life (p < 0.001) declined. Significant correlations were observed when comparing the 8 Foot Up and Go test (p < 0.05), Chair Stand test (p < 0.05), and the 6-min Walk test (p < 0.001) to the physical component of the quality of life after the detraining period. Three months of a detraining period in older people who habitually undertake supervised activities is enough to produce a decline in dynamic balance and also quality of life. To avoid the deleterious effect of periods of cessation of supervised exercise, as a suggestion, specifically designed exercises could be prescribed for an older population, with emphasis on balance exercises.

Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination

ObjectiveWe characterised the clinical course, treatment and outcomes in 59 patients with relapsing myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination.MethodsWe evaluated clinical phenotypes, annualised relapse rates (ARR) prior and on immunotherapy...

Metabolomic Fingerprinting in Various Body Fluids of a Diet-Controlled Clinical Smoking Cessation Study Using a Validated GC-TOF-MS Metabolomics Platform.

Untargeted GC-TOF-MS analysis proved to be a suitable analytical platform to determine alterations in the metabolic profile. Several metabolic pathways were found to be altered in a first clinical study comparing smokers against nonsmokers. Subsequently, we conducted a clinical diet-controlled study to investigate alterations in the metabolic profile during the course of 3 months of smoking cessation. Sixty male subjects were included in the study, and plasma, saliva, and urine samples were collected during four 24 h stationary visits: at baseline, while still smoking, after 1 week, after 1 month, and after 3 months of cessation. Additionally, subjects were monitored for their compliance by measurements of CO in exhaled breath and salivary cotinine throughout the study. GC-TOF-MS fingerprinting was applied to plasma, saliva, and urine samples derived from 39 compliant subjects. In total, 52 metabolites were found to be significantly altered including 26 in plasma, 20 in saliva, and 12 in urine, respectively. In agreement with a previous study comparing smokers and nonsmokers, the fatty acid and amino acid metabolism showed significant alterations upon 3 months of smoking cessation. Thus these results may indicate a partial recovery of metabolic pathway perturbations, even after a relatively short period of smoking cessation.

Gene and metabolite time-course response to cigarette smoking in mouse lung and plasma.

Prolonged cigarette smoking (CS) causes chronic obstructive pulmonary disease (COPD), a prevalent serious condition that may persist or progress after smoking cessation. To provide insight into how CS triggers COPD, we investigated temporal patterns of lung transcriptome expression and systemic metabolome changes induced by chronic CS exposure and smoking cessation. Whole lung RNA-seq data was analyzed at transcript and exon levels from C57Bl/6 mice exposed to CS for 1- or 7 days, for 3-, 6-, or 9 months, or for 6 months followed by 3 months of cessation using age-matched littermate controls. We identified previously unreported dysregulation of pyrimidine metabolism and phosphatidylinositol signaling pathways and confirmed alterations in glutathione metabolism and circadian gene pathways. Almost all dysregulated pathways demonstrated reversibility upon smoking cessation, except the lysosome pathway. Chronic CS exposure was significantly linked with alterations in pathways encoding for energy, phagocytosis, and DNA repair and triggered differential expression of genes or exons previously unreported to associate with CS or COPD, including Lox, involved in matrix remodeling, Gp2, linked to goblet cells, and Slc22a12 and Agpat3, involved in purine and glycerolipid metabolism, respectively. CS-induced lung metabolic pathways changes were validated using metabolomic profiles of matched plasma samples, indicating that dynamic metabolic gene regulation caused by CS is reflected in the plasma metabolome. Using advanced technologies, our study uncovered novel pathways and genes altered by chronic CS exposure, including those involved in pyrimidine metabolism, phosphatidylinositol signaling and lysosome function, highlighting their potential importance in the pathogenesis or diagnosis of CS-associated conditions.