Endocrine Side Effects Research Articles

Reirradiation for recurrent craniopharyngioma

PurposeReirradiation is rarely administered to patients with recurrent craniopharyngioma owing to concerns regarding visual and endocrine side effects. The purpose of this case series was to evaluate our institutional experience of patients with craniopharyngioma treated with 2 courses of fractionated radiation therapy. Methods and MaterialsA retrospective study was performed of all patients with craniopharyngioma treated with 2 courses of fractionated radiation therapy at a single institution. Electronic medical records and radiation therapy records were reviewed. ResultsWe identified 4 eligible patients with recurrent craniopharyngioma. With a median follow-up of 33 months after reirradiation, 3 patients attained disease control; 1 patient developed progressive disease, 27 months after reirradiation. In 3 evaluable patients, vision remained stable or improved after reirradiation; one patient had no light perception before reirradiation. None of the patients experienced additional endocrine toxicities after reirradiation, apart from one patient who had low serum thyroid stimulating hormone before reirradiation and later developed hypothyroidism after treatment. ConclusionsReirradiation may represent a safe and effective therapeutic option for selected patients with recurrent, refractory craniopharyngioma and without other salvage treatment options. Larger studies with longer-term follow up are warranted to better understand outcomes in these patients.

Risperidone plasma concentrations are associated with side effects and effectiveness in children and adolescents with autism spectrum disorder.

AimRisperidone is the most commonly prescribed antipsychotic drug to children and adolescents worldwide, but it is associated with serious side effects, including weight gain. This study assessed the relationship of risperidone and 9‐hydroxyrisperidone trough concentrations, maximum concentrations and 24‐hour area under the curves (AUCs) with body mass index (BMI) z‐scores in children and adolescents with autism spectrum disorder (ASD) and behavioural problems. Secondary outcomes were metabolic, endocrine, extrapyramidal and cardiac side effects and effectiveness.MethodsForty‐two children and adolescents (32 males) aged 6‐18 years were included in a 24‐week prospective observational trial. Drug plasma concentrations, side effects and effectiveness were measured at several time points during follow‐up. Relevant pharmacokinetic covariates, including medication adherence and CYP2D6, CYP3A4, CYP3A5 and P‐glycoprotein (ABCB1) genotypes, were measured. Nonlinear mixed‐effects modelling (NONMEM®) was used for a population pharmacokinetic analysis with 205 risperidone and 205 9‐hydroxyrisperidone concentrations. Subsequently, model‐based trough concentrations, maximum concentrations and 24‐hour AUCs were analysed to predict outcomes using generalized and linear mixed‐effects models.ResultsA risperidone two‐compartment model combined with a 9‐hydroxyrisperidone one‐compartment model best described the measured concentrations. Of all the pharmacokinetic parameters, higher risperidone sum trough concentrations best predicted higher BMI z‐scores during follow‐up (P < .001). Higher sum trough concentrations also predicted more sedation (P < .05), higher prolactin levels (P < .001) and more effectiveness measured with Aberrant Behavior Checklist irritability score (P < .01).ConclusionOur results indicate a therapeutic window exists, which suggests that therapeutic drug monitoring of risperidone might increase safety and effectiveness in children and adolescents with ASD and behavioural problems.

Severe Ketoacidosis as the First Clinical Manifestation of Type 1 Diabetes Mellitus Secondary to Immune Checkpoint Inhibitors

Introduction Immunotherapy represents one of the fundamental points on the oncological treatments. The increasingly frequent use of these treatments has allowed us to observe various side effects in up to 10 to 20% of patients and endocrine side effects are one of the most commonly described. We report a case of diabetic ketoacidosis in a 46-year-old male patient as debut of type-1 diabetes mellitus secondary to treatment with nivolumab. Case Report The patient who went to the emergency department due to abdominal pain associated with vomiting 48 hours previously. Diagnosed 4 years ago of clear cell renal carcinoma stage IV, due to pulmonary metastatic involvement, the patient was under treatment with nivolumab. Urgent blood and urine tests were performed in the urgency evaluation; the patient was diagnosis of severe diabetic ketoacidosis. Pancreatic endocrine complications are observed in 0.5 to 5% of the patients with immunotherapy. Among the adverse effects described are alterations in baseline fasting glycaemia and the possible development of type-1 diabetes. These molecules increase the activity of T-cells, amplify the cellular immune activity with the consequent increased immune response, which can lead to a destruction of the pancreatic β-cells. Strict endocrine control is necessary during immunotherapy treatment; however, there are no clear indications for the monitoring of pancreatic reserve levels or glycemic control. For these reasons, we propose the need for closer and regular monitoring of C-peptide and HbA1c (glycosylated hemoglobin) to prevent the development of the diabetes and their complications.

T220. IMPACT OF SECOND-GENERATION ANTIPSYCHOTIC SIDE EFFECTS ON FUNCTIONING FROM A SCHIZOPHRENIA PATIENT PERSPECTIVE: GLOBAL PATIENT CENTERED SURVEY INCLUDING PATIENTS FROM ITALY

BackgroundSecond-generation antipsychotics (SGAs) used to treat patients with schizophrenia generally have lower risk of motor side effects (SEs) than first-generation antipsychotics, but they are associated with other well-known SEs. The goal of this study was to understand how specific SEs of SGAs impact daily functioning, emotional well-being, and overall quality of life of patients with schizophrenia from their own perspective.MethodsThis study was a cross-sectional, participant-reported web survey, conducted globally during 2017–2018. The survey captured participants’ socio-demographic information, and assessments using the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) instrument, and the Glasgow Antipsychotic Side-Effect Scale (GASS). Additionally, specific questions about functional and emotional impacts were developed for SEs recognized as being bothersome to patients,2 such as activating SEs (‘Feeling restless/unable to sit still’, ‘Shaky hands or arms’, and ‘Difficulty sleeping’) sedating SEs (‘Feeling sleepy during the day’, ‘Feeling drugged/like a zombie’) and metabolic or endocrine SEs (‘Weight gain’, ‘Problems enjoying sex’). Participants noted on a visual analog scale (VAS) the degree of impact on functioning, 0 indicating ‘no impact at all’ and 100 indicating the ‘largest degree of impact’. Participants with schizophrenia (≥18 years old) stable for at least one month, taking an SGA for 1–12 months, and self-reporting at least one SE were included.ResultsOf 6,556 respondents screened, 435 were included in the study – United States, n=180; Canada, n=99; Australia, n=28; and Europe, n=128 (Italy, n=90; Spain, n=22; Denmark, n=8; Norway, n=8). The majority of the participants were diagnosed within the last 5 years and nearly half were living with a spouse or partner. The employment rate (full time or part time) was 39.9% globally and 43.3% in Italy. Respondents in Italy were on ‘predominantly sedating’ (54.4%), and/or ‘similarly activating and sedating’ (43.3%) SGAs (as defined in Citrome, J Clin Psychopharmacol 2017). In Italy, Q-LES-Q-SF total score was (mean [standard deviation; SD]) 46.6 [9.1], out of a possible score range of 14–70 (globally, 44.3 [9.8]). Similar to other countries, participants from Italy showed lowest satisfaction scores for Q-LES-Q-SF items of ‘Sexual drive, interest and/or performance’, ‘Economic status’, and ‘Work’. In Italy, the most prevalent SEs reported on the GASS were ‘Feeling sleepy during the day’, ‘Difficulty sleeping’, and ‘Problems enjoying sex’, while globally patients reported ‘Feeling sleepy during the day’, ‘Difficulty sleeping’, and ‘Dry mouth’ as the most common SEs. More than half of the participants stated they had experienced gaining weight as an SE (52.4% globally and 62.2% in Italy). Globally, SEs perceived as bothersome by patients were reported to impact participants’ functioning and emotions. These SEs had at least a moderate to severe impact (defined by a VAS score ≥50) on all aspects of functioning (physical, psychological, social, and vocational). The most common emotions associated with SEs reported by participants were feeling ‘Frustrated’, ‘Dissatisfied’, and ‘Ashamed/embarrassed’. Generally, the results from the survey in Italy were comparable to those of the global survey.DiscussionFindings from this survey confirm that participants taking SGAs for the treatment of schizophrenia still have many SEs, including activating and sedating SEs, sexual SEs, and weight gain. These SEs have a considerable negative impact on participant’s daily functioning and quality of life satisfaction, including on work, and sexual drive, in addition to psychosocial effects.

Pre-operative hormone stimulation in hypospadias repair: A facilitator or a confounder

Preoperative hormone stimulation (PHS) is popular in hypospadias reconstructive surgery. While still controversial, it is performed to have a more developed gross anatomy of the glans and penis for improvement of the surgical condition and outcome. In this study we assessed morphometric and histologic effects of pre-operative testosterone therapy on the penis and prepuce in patients with hypospadias. 18 patients with hypospadias who received 3 monthly doses of 25mg testosterone injections were compared with 23 patients with hypospadias who were managed without pre-operative androgen therapy. Penile morphometry and hormone side effects were assessed in monthly pre-operative visits. Intra operative observations and preputial histopathology were also compared between the groups. Glans diameter enlarged significantly after the first dose of testosterone. (P<0.001) while morphologic changes were not significant by further injections. 72.2% showed one or more hormone related side effects that were mostly mild. Severe side effects such as thick pubic hair growth, frequent erections or considerable penis hyper-sensation were observed in 27.8%. Glans to corpus ratio was 0.2±0.75 in PHS group compare to 0.3±0.17 in control group. (P<0.001). Hemorrhage needing tourniquet placement was reported in 44.4% of the PHS patients compared to 26.1% among the control group. Histopathologic studies revealed increased vascularity and less inflammation of the prepuce in PHS group compared to controls. The glans and penis enlargement wasn't significant in 22.2% of patients who underwent PHS. We identified the first dose of testosterone as the most effective one. This finding supports the idea of close clinical monitoring to stop PHS when a significant response is observed and the expected goals are reached. Androgen side effects were not uncommon among our patients although they were mainly mild. Intraoperative assessments showed a decreased glans wing thickness to corporal body ratio in PHS group compared to controls. This finding caused more complex glanuloplasty while wrapping the glans wings over neo urethra and enlarged corporal bodies. We suggest limiting PHS to carefully selected cases considering the observed anatomical and histological changes and the side effects. Monthly monitoring during PHS is recommended to stop androgen therapy as soon as the minimum defined targets are reached. This may decrease the rate of androgen side effects while providing better surgical conditions.

Acupuncture and moxibustion combined with western medication for ninety cases of Bell's palsy at different stages: A randomized controlled trial

ObjectiveTo observe the differences in the clinical effect on Bell's palsy at the acute stage and the recover stage, as well as the differences in the clinical effect between the simple acupuncture-moxibustion therapy and the combined therapy of acupuncture-moxibustion and western medication, explore the optimal intervention time point and therapeutic regimen. MethodsAll of the patients were collected from the outpatients and the inpatients in the Specific Department of Acupuncture for Facial Paralysis in Hubei Chinese Medicine Hospital. A total of 128 patients with Bell's palsy were collected from February 2017 through to February 2018 and 90 patients of them were in compliance with the inclusion criteria. 90 cases were randomized into three groups, named group A (acupuncture and moxibustion at the acute stage), group B (acupuncture and moxibustion combined with western medication at the acute stage) and group C (acupuncture and moxibustion combined with western medication at the recovery stage), 30 cases in each one. In the group A, acupuncture and moxibustion were adopted at the acute stage of Bell's palsy. In the group B, at the acute stage, acupuncture and moxibustion were adopted in combination with the oral medication of hormone and vitamin. In the group C, at the recovery stage, acupuncture and moxibustion were adopted in combination with the oral medication of hormone and vitamin. The clinical healing time and the total effective rate were observed in the patients of the three groups and the occurrence of sequelae in facial paralysis was followed-up. Result① The clinical healing time in the Group B was slightly shorter than the Group A, but without statistical significance in comparison (P > 0.05). The clinical healing time in either the Group A or the Group B was shorter than Group C, indicating the statistical significance in comparison (both P < 0.05). ②The results of 3-month follow-up observation showed that there were 3 cases of sequelae in the group A, 2 cases in the Group B and 7 cases in the Group C. ③ After treatment, the total effective rate in either the Group A or the Group B was higher than the Group C, indicating the statistical significance in comparison (both P < 0.05). ConclusionThe simple use of acupuncture and moxibustion at the acute stage achieves the similar clinical effect on Bell's palsy as the treatment of acupuncture-moxibustion combined with western medication. The simple application of acupuncture and moxibustion prevents from the potential side effects of hormone to the largest extent and displays its dominate advantages in safety. Besides, the early intervention of acupuncture-moxibustion shortens the healing time and effectively improves the prognosis of Bell's palsy.

PDTM-12. ADGRB3 IS EPIGENETICALLY SILENCED IN WNT-MEDULLOBLASTOMA AND ITS REACTIVATION HAS THERAPEUTIC BENEFITS

Abstract Medulloblastoma (MB) are the most aggressive primary malignant brain tumors in children and are classified into four major molecular subgroups. WNT-MB is characterized by an activated WNT signature and has relatively better prognosis with treatment. However, young WNT-MB patients who survive after conventional treatment suffer from long-term irreversible neurocognitive and endocrine side effects leading to poor quality of life. ADGRB3 is a member of the ADGRB1-3 subfamily of adhesion GPCR transmembrane proteins, which are highly expressed in the cerebellum and hippocampal neurons. Our recent analysis of RNA-seq data from a published panel of MB tumor samples and RT-PCR experiments with tumor samples showed that ADGRB3 mRNA expression is selectively repressed in WNT-MB tumors compared to the other molecular subgroups and normal human cerebellum. We detected hypermethylation of the ADGRB3 promoter exclusively in WNT-MB samples. ChIP assays revealed enrichment of repressive methyl CpG binding MBD2 protein and trimethylated histone H3K9me3 in the ADGRB3 promoter region. We found that ATP dependent chromatin remodeler protein BRG-1 regulates ADGRB3 expression through epigenetic reprogramming at the gene promoter. Lentiviral reconstitution of ADGRB3 inhibited growth and WNT signaling in UW288-1, and PFSK-1 cells in culture. ADGRB3 reconstitution in UW288-1 MB cells causes a significant reduction in tumor growth and WNT target gene activation in orthotopic xenografts in nude mice. Furthermore, we found that ADGRB3 reactivation could be achieved using a blood brain barrier permeable MBD2 antagonist and an EZH2 inhibitor and this can significantly reduce cell growth and inhibit WNT signaling targets. Altogether, our findings define an epigenetic mechanism for ADGRB3 silencing in WNT-MB and demonstrated that reactivation of ADGRB3 can prevent WNT-MB tumor growth by suppressing WNT signaling. Our study supports translating epigenetic reactivation of ADGRB3 as a novel therapeutic intervention for children affected with WNT-MB.

Endocrine consequences of immune checkpoint inhibitors

Immune checkpoints inhibitors have fundamentally changed the management of oncologic patients. These treatments consist of monoclonal antibodies directed against CTLA-4 (cytotoxic T-lymphocyte antigen 4), PD-1 (programmed cell death protein-1) and PD-L1 (one of its ligands). By blocking these receptors or ligands, the antibodies reverse the immune tolerance induced by the cancerous cell on the T-lymphocyte and favour lymphocytic reactivation and anti-tumor activity. Immune tolerance to auto-antigens is maintained with the help of these checkpoints. Targeting them can lead to auto-immune side effects. These latter mostly impact the cutaneous and digestive system, but the endocrine glands are not spared. In this article, we provide monitoring and treatment algorithms for these endocrine immune side effects. An early diagnosis followed by the appropriate treatment would reduce their negative impact on the oncologic care.

Abstract 3477: ADGRB3 is epigenetically silenced in WNT-medulloblastoma and inhibits WNT signaling

Abstract Medulloblastoma (MB), is the most aggressive primary malignant brain tumor in children and are classified into four molecular subgroups. While some subtypes of MB show a favorable prognosis with treatment, still one third of patients succumb to this disease and the children who survive after therapy suffer from long-term neurocognitive and endocrine side effects of the conventional treatments. ADGRB3 (formerly called BAI3) is a member of the ADGRB1-3 subfamily of adhesion GPCR transmembrane proteins, which are highly expressed in the brain specially in cerebellum and hippocampal neurons. Our recent analysis of RNA-seq data from a published panel of medulloblastoma tumor samples and RT-PCR experiments with MB tumor samples showed that ADGRB3 mRNA expression was selectively repressed in WNT-MB tumor tissue compared to other three molecular subgroups and normal human cerebellar tissue. Using bisulfite sequencing and MS-PCR we have detected hypermethylation of the ADGRB3 promoter region exclusively in WNT-MB subgroup of MB tissues but not in the other three molecular subgroups and normal human cerebellar tissue. ChIP assays revealed enrichment of repressive methyl CpG binding protein MBD2 and the trimethylated histone H3K9me3 in the ADGRB3 promoter region of UW288-1 cells. Collectively, these indicates epigenetic silencing of ADGRB3 in WNT-MB via promoter hypermethylation and repressive histone modifications. We found that knockdown of ATP dependent chromatin remodeler protein Brg1 in MB cells can silence ADGRB3 expression through epigenetic reprogramming at the gene promoter. Lentiviral reconstitution of ADGRB3 in silent MB cells (UW288-1, PFSK-1) inhibited growth of these cells in culture and inhibited WNT signaling targets. ADGRB3 reconstituted UW288-1 MB cells when xenografted yielded significantly reduced tumor in immunocompromised mice compared to the parental cells. Pharmacological reactivation of ADGRB3 expression in silent WNT MB cells using our recently established MBD2 antagonist and an EZH2 inhibitor significantly reduced cell growth in vitro and inhibits some specific WNT signaling targets. We further identified a novel mechanism underlying ADGRB3 mediated regulation of WNT signaling by performing co-immunoprecipitation experiments. Altogether, our findings define an epigenetic mechanism for ADGRB3 silencing in WNT-MB and demonstrates a mechanism through which ADGRB3 restrains activation of WNT signaling involved in cerebellar transformation. Our findings highlight the potential of epigenetic reactivation of ADGRB3 as a less toxic therapeutic intervention for the children suffering from WNT-MB. Citation Format: Debanjan Bhattacharya, Dan Zhu, Satoru Osuka, Saroja Narra Devi, Erwin G. Van Meir. ADGRB3 is epigenetically silenced in WNT-medulloblastoma and inhibits WNT signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3477.

The antipsychotic medication, risperidone, causes global immunosuppression in healthy mice.

Atypical antipsychotic medications such as risperidone are widely prescribed for diverse psychiatric indications including schizophrenia, bipolar disorder and depression. These medications have complex pharmacology and are associated with significant endocrine and metabolic side effects. This class of medications also carries FDA black box warnings due to increased risk of death in elderly patients. Clinical reports indicate that patients treated with these medications are more susceptible to infections; however, the underlying mechanisms/pharmacology are unclear. We have previously reported that risperidone and it’s active metabolite distributes to the bone marrow in clinically relevant concentrations in preclinical species, leading us to hypothesize that the hematopoietic system may be impacted by these medications. To test this hypothesis, using proteomic and cytokine array technology, we evaluated the expression of genes involved in inflammatory and immune function following short term (5 days) and longer term (4 weeks) treatment in healthy animals. We report that low-dose risperidone treatment results in global immunosuppression in mice, observed following 5 days of dosing and exacerbated with longer term drug treatment (4 weeks). These data are consistent with increased susceptibility to infection in patients administered these medications and have profound implications for the increasing off-label prescribing to vulnerable patient populations including children and the elderly.

Management of immune related adverse events induced by immune checkpoint inhibition

In recent years, immune checkpoint inhibitors (ICIs) were successfully introduced to cancer therapy and these drugs have already become essential for the treatment of various non-curable tumors. Compared to conventional chemotherapy or tyrosine kinase inhibitors, ICIs generally exhibit a favorable side effect profile further promoting their increasing prescription rate. However, increasing use of these substance made clear that ICI induced activation of the immune system may also lead to immune-related adverse events (irAEs). Common irAEs are dermatological, gastrointestinal, or endocrine side effects but further tissue types and organ systems may also be affected. A detailed knowledge of these potential side effects is important as early recognition is the key to successful treatment, reversibility of organ dysfunction and in some cases even prevention of fatal outcome. In more severe irAEs, immunosuppression may be necessary to cope with these side effects. To increase awareness of irAEs and support immediate and successful management, we provide a comprehensive review on most common irAEs of ICIs, their diagnosis, and treatment.

Determinant Factors Correlate with the Selection of Contraceptive Intra Uterine Device (IUD)

Background: The direction of national policies and strategies for the 2015-2016 period focused on improving family planning services by using Long Term Method to reduce risks to drop out. IUD is one of contraception with no hormonal side effect. IUD is a contraceptive device or small object inserted into the uterus that can be used for all women of reproductive age. Purpose: The purpose of this study to determine the economic factors, attitudes and support of husbands that affect the election of contraceptive IUD in the work area Puskesmas Mungkid, Magelang District. Methods : cross sectional design by using purposive sampling technique were applied. Univariate analysis to know the frequency distribution of each variable. Bivariate analysis using chi-square test for economic relations test, attitude, husband support with election planning. Multivariate analysis using logistic regression test to test the influence of economy, attitude and support of husband to IUD election. Results: Based on the results of the study, most respondents have less than the minimum wage of 71.7%, there are 53.3% of respondents have a negative attitude towards IUD, and 51.7% of respondents have husband support. of respondents who chose to use IUD as much as 16.7%. In the chi-square test, there is a relationship of attitude with the election of IUD (p value 0.004). Conclusion : Based on the result of the research, it is hoped that the mother can improve the mother's attitude toward IUD by improving the mother's knowledge through information.

Checkpoint Inhibitors.

Treatment with checkpoint inhibitors such as anti-programmed death-1 (anti-PD-1), anti-PD-ligand 1 (anti-PD-L1), and anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4) antibodies can prolong the survival of cancer patients, but it also induces autoimmune side effects in 86-96% of patients by activating the immune system. In 17-59% of patients, these are severe or even life-threatening. This review is based on pertinent articles retrieved by a search in PubMed and on an evaluation of a side-effect registry. Checkpoint-inhibitor-induced autoimmune side effects manifest themselves in all organ systems, most commonly as skin lesions (46-62%), autoimmune colitis (22-48%), autoimmune hepatitis (7-33%), and endocrinopathies (thyroiditis, hypophysitis, adrenalitis, diabetes mellitus; 12-34%). Rarer side effects include pneumonitis (3-8%), nephritis (1-7%), cardiac side effects including cardiomyositis (5%), and neurological side effects (1-5%). Severe (sometimes lethal) side effects arise in 17-21%, 20-28%, and 59% of patients undergoing anti-PD-1 and anti- CTLA-4 antibody treatment and the approved combination therapy, respectively. With proper monitoring, however, these side effects can be recognized early and, usually, treated with success. Endocrine side effects generally require long-term hormone substitution. Patients who have stopped taking checkpoint inhibitors because of side effects do not show a poorer response of their melanoma or shorter survival in comparison to patients who continue to take checkpoint inhibitors. The complex management of checkpoint-inhibitor-induced side effects should be coordinated in experienced centers. The creation of an interdisciplinary "tox team" with designated experts for organ-specific side effects has proven useful. Prospective registry studies based on structured documentation of side effects in routine clinical practice are currently lacking and urgently needed.

Psychosocial functioning and risk factors of children with juvenile idiopathic arthritis

Objective To investigate the psychosocial functioning and risk factors of children with juvenile idiopathic arthritis (JIA). Methods A total of 79 children with JIA were selected from the inpatients and outpatients in the department of clinical immunology, a top-grade hospital in Xi'an from February to December, 2017. Their demographic and disease data were collected by self-designed questionnaires. Disease remission was confirmed by using the JADAS-27 and pain intensity by visual analogue scale (VAS). The Children's Depression Inventory (CDI) and Multidimensional Anxiety Scale for Children (MASC) were rated by the children themselves. All data were analyzed with SPSS 17.0. Results A total of 316 effective questionnaires were collected, including 79 demographic questionnaires, disease questionnaires, CDI and MASC respectively. ⑴ The total scores of CDI were 15.22±9.56. The highest scores were found for the subscale of lack of happiness (4.57±3.63), while the lowest for the subscale of low self-esteem (1.75±1.57). The total scores of MASC were 39.15±21.12. The highest scores were found for the subscale of Injury avoidance (13.09±5.57) while the lowest for the subscale of separation anxiety (7.68±5.66). ⑵ Multiple stepwise linear regression analysis showed that pain, disease activity, hormonal side effects and fatigue were the main risk factors of the psychosocial functioning of the children with JIA. Conclusions The psychosocial functioning of children with JIA was not satisfied. It suggested that we should not only take the appropriate clinical treatment to control the disease but also take combined therapy such as psychological intervention as early as possible. Key words: Arthritis, juvenile rheumatoid; Psychology, social; Risk factors

Pneumonitis as a complication of immune system targeting drugs?-a meta-analysis of anti-PD/PD-L1 immunotherapy randomized clinical trials.

Anti-PD/PD-L1-targeted immunotherapy is associated with remarkably high rates of durable clinical responses in patients across a range of tumor types, although their high incidence of skin, gastrointestinal, and endocrine side effects with their use. The risk of pneumonitis associated with checkpoint inhibition therapy is not well described. A systematic review of the literature was conducted on randomized clinical trials (RCTs) comparing anti-PD/PD-L1 mono-immunotherapy (IMM) to chemotherapy (CTH) protocols in cancer patients. The primary endpoint was the pneumonitis rate in IMM compared to CTH. Secondary endpoints were (I) high-grade pneumonitis rate in IMM compared to CTH and (II) tumor response rate, progression-free survival (PFS), and overall survival (OS) between IMM and CTH. Random model and leave-one-out-analysis were performed. Thirteen RCTs studying 7,246 patients were included; 3,704 (51.12%) patients in the IMM arm and 3,542 (48.88%) patients in the chemotherapy arm. Seven non-small cell lung cancer (NSCLC) RCTs were included with 4,164 patients; 2,101 in the IMM arm and 2,063 patients in the CTH arm. Three RCTs were on melanoma patients (n=1,390). Nine RCTs compared mono-immunotherapy to CTH [docetaxel in 5 studies (38.5%), platinum-based in 2 studies (15.4%), dacarbazine in 1 study (7.7%) and everolimus in 1 study]. Both high-grade and all-grade pneumonitis were higher among patients in the IMM arm when compared to the CTH arm (OR =4.39, 95% CI: 1.65-11.69, P=0.003 and OR =2.46, 95% CI: 1.29-4.6, P=0.007). Tumor response rate was significantly better in the immunotherapy arm (OR =2.31, 95% CI: 1.62-3.29, P<0.001). PFS and OS were longer in patients who received IMM compared to patients in the CTH arm (HR =0.75, 95% CI: 0.65-0.85, P<0.001, and HR =0.71, 95% CI: 0.66-0.77, P<0.001). The incidence of high-grade and all-grade pneumonitis is higher in anti-PD-1 therapy but not in anti-PD-L1 therapy when compared to traditional CTH regimens for NSCLC and melanoma. High-grade adverse events were otherwise more common in the CTH arm. Tumor response rate, PFS, and OS are all substantially improved with IMM over CTH. These results can be used to guide therapy selection and set expectations for treatment effect in these patients.

Bioidentical hormone therapy in menopause: relevance in dermatology

Hormone replacement therapy has been shown to be effective in alleviating menopausal symptoms. However, its use is controversial owing to potential health risks, such as thromboembolism and cancer. Bioidentical hormone therapy has recently become popular as an alternative to conventional hormone replacement therapy. These bioidentical hormones have a molecular structure identical to endogenous hormones found in a woman's body. A claimed advantage of bioidentical hormone therapy is the compounding practice in order to individualize therapy depending on patient's own hormone levels and symptoms. However, there is no scientific evidence to assess the validity of these claims. Bioidentical hormone therapy has also been used by dermatologists for its anti-aging effects on the skin, but little is known about efficacy and side effects of bioidentical hormones in this field. This review illustrates the main purpose of bioidentical hormone therapy for dermatological uses and its potential side effects, serving as a tool for dermatologists when facing these patients.

New therapeutic avenues for neurosteroids in psychiatric diseases

Discovered in the eighties by Pr Baulieu and colleagues, neurosteroids are a class of neuroactive brain-born steroids, which comprises the steroid hormones, their biosynthesis precursors and their metabolites. They can act through genomic as well as non-genomic pathways. Genomic pathways, only triggered by the neurosteroid hormones, are, in the brain, the same as those largely described in the periphery: the binding of these steroid hormones to nuclear receptors leads to transcription regulations. On the other hand, their precursors and metabolites, such as pregnenolone (PREG), dehydroepiandrosterone (DHEA), their respective sulfate esters, pregnenolone sulfate (PREG-S) and DHEA sulfate (DHEA-S) and allopregnanolone (ALLOP), are defined as neurosteroids, but no corresponding nuclear receptors have been identified so far. In fact, they trigger non-genomic pathways which consist in (i) inhibitory ionotropic receptors, (ii) excitatory ionotropic receptors and (iii) the microtubular system. Hence, inhibitory neurosteroids, whose mostly studied representative is ALLOP, positively modulate, or directly activate, the ionotropic GABA-A receptors. In contrast, excitatory neurosteroids, represented by PREG-S, DHEA-S and DHEA, inhibit the GABA-A receptors, and activate, directly or indirectly, through the sigma-1 receptors, the NMDA glutamate receptors. Neurosteroids of the third group, the microtubular neurosteroids, are able to bind microtubule associated proteins, in particular MAP2, to promote microtubule assembly, neurite outgrowth and in fine structural neuroplasticity. So far, PREG, DHEA and progesterone are the three identified microtubular neurosteroids. The pharmacological properties of neurosteroids have led to specific investigations for assessing their therapeutic potentialities in psychiatric diseases, using validated animal models. In some cases, clinical trials were also performed. These studies showed that ALLOP, the main inhibitory neurosteroid, displayed clear-cut anxiolytic-like and antidepressant-like efficacy in animals. It has been subsequently developed as Brexanolone and tested with success in phase III of clinical trials for the treatment of post-partum depression. Although showing pro-cognitive properties in animals, the sulfated neurosteroids, PREG-S and DHEA-S, were, in contrast, never tested in clinical trials, probably due to their poor stability and proconvulsivant side effects. Their respective non-sulfated forms, PREG and DHEA, showed antidepressant and antipsychotic efficacies in clinical trials, but these drugs never reached the phase III of clinical development because their therapeutic uses would have led to an overproduction of active metabolites responsible for intolerable side effects. The alternative strategy which has been selected consists of the development of non-metabolizable synthetic derivatives of these natural steroids, which keep the same neuroactive properties as their parent molecules, but are devoid of any hormonal side effects. An example of such innovative drugs is MAP4343, a synthetic derivative of PREG, which exhibits potent antidepressant-like efficacy in validated animal models. It is currently tested in depressed patients.

Endocrine and metabolic adverse effects of immune checkpoint inhibitors: an overview (what endocrinologists should know).

Immune checkpoint inhibitors (ICIs) are novel anticancer agents, recently introduced with the aim of boosting the immune response against tumors. ICIs are monoclonal autoantibodies that specifically target inhibitory receptors on T cells: cytotoxic T lymphocyte antigen 4 (CTLA4), programmed death 1 (PD-1) and its ligand (PD-1L). ICIs also generate peculiar dysimmune toxicities, called immune-related adverse events (irAEs), that can potentially affect any tissue, and some may be life-threatening if not promptly recognized. The endocrine and metabolic side effects of ICIs are reviewed here, with a particular focus on their clinical presentation and management. They are among the most frequent toxicities (around 10%) and include hypophysitis, thyroid disorders, adrenalitis, and diabetes mellitus. Treatment is based on the replacement of specific hormone deficits, accompanied by immunosuppression (with corticosteroids or other drugs), depending on irAEs grade, often without the need of ICI withdrawal, except in more severe forms. Prompt recognition of endocrine and metabolic irAEs and adequate treatment allow the patients to continue a therapy they are benefiting from. Endocrinologists, as an integral part of the multidisciplinary oncologic team, need to be familiar with the unique toxicity profile of these anticancer agents. Practical recommendations for their management are proposed.

Treatment of sudden deafness with type 2 diabetesmellitus by post-auricular subperiosteal injection of methylprednisolone

Objective:To investigate the therapeutic effect of post-auricular subperiosteal injection of methylprednisolone combined with ginkgo biloba injection and mouse nerve growth factor in sudden deafness with type 2 diabetesmellitus. To understand the effect of post-auricular subperiosteal injection of methylprednisolone on type 2 diabetesmellitus complicated with sudden deafness and its effect on blood-glucose level, and to explore a more effective and safe method for treating this special group of sudden deafness. Method: Total 84 patients suffered from type 2 diabetesmellitus with sudden deafness and treated in Shaanxi Provincial People's Hospital from March 2017 to June 2018 were randomly divided into experimental group(post-auricular subperiosteal injection of methylprednisolone+ginkgo biloba injection, mouse nerve growth factor)(n=48) and a control group(ginkgo biloba injection, mouse nerve growth factor)(n=36). Each group was divided into high frequency, low frequency and flat and total deafness group. Then to compare the clinical efficacy of the two groups and the difference of the fluctuation of blood glucose and HbA1c before treatment and 2 hours after treatment. Result:①The effective rate of treatment in the experimental group was 79.17%, higher than that in the control group(58.33%), P<0.05. The results indicated that the effect of post-auricular subperiosteal injection of methylprednisolone combined with ginkgo biloba injection and mouse nerve growth factor was effective in sudden deafness with type 2 diabetesmellitus. ②There was no significant difference in the fluctuation of blood glucose and HbA1c before treatment and 2 hours after treatment in the experimental group, and it indicated that this treatment can effectively avoid systemic side effects of steroid and ensure the safety of the treatment. Conclusion:Post-auricular subperiosteal injection of methylprednisolone combined with ginkgo biloba injection and mouse nerve growth factor is effective in patients with sudden deafness with type 2 diabetesmellitus, furthermore, blood glucose will not be affected by the using of steroid, and it will aviod systemic hormonal side effects.

Sexual Dysfunction: Hypoactive Sexual Desire Disorder

Healthy female sexual functioning is driven by sexual desire. Sexual desire, traditionally defined as sexual thoughts and fantasies, is a natural life force and an art form affecting all aspects of a woman’s interpersonal and professional life. Virtually, all diagnostic categories of female sexual dysfunction, including arousal disorder, anorgasmia, and sexual pain disorder are linked to, caused by, or aggravated by loss of sexual desire. Decreased sexual desire is a diagnosis (hypoactive sexual desire disorder, HSDD) with its own International Classification of Diseases code (F52.0).. Impact is often subtle. HSDD may express as seemingly unrelated emotional disturbances that degrade life quality in family relationships, in the workplace, or both. For some women, it is severely distracting. The diagnosis of HSDD is made when symptoms are sufficient to cause distress. In older women, HSDD is heavily impacted by menopause-associated withdrawal of reproductive hormones, particularly testosterone and estradiol. HSDD greatly improves with transdermal replacement of these steroids. Side effects of transdermal hormones are minimal but response can be gratifying. In premenopausal women, HSDD behaves more as a psychoendocrine disorder that is responsive in some patients to flibanserin, a nonhormonal 5-HT1A receptor agonist. Side effects of flibanserin are significant but manageable. This review contains 12 figures, 6 tables, and references. Key Words: estradiol, flibanserin, hypoactive sexual desire disorder, menopause, selective serotonin reuptake inhibitors, sexual desire, sexuality, testosterone, transdermal, women