Endocrine Symptoms Research Articles

Ovarian Sertoli-Leydig cell tumors: an analysis of 13 cases

To report the clinical, ultrasound and histopathological characteristics, clinical management, and prognosis of 13 patients with Sertoli-Leydig cell tumors (SLCTs) of ovary. 13 patients with pathologically confirmed ovarian SLCTs at International Peace Maternity and Child Health Hospital from 2010 and 2019 were included in this study. The clinical, ultrasound and histopathological characteristics, clinical management, and prognosis of 13 patients were retrospectively analyzed. The age ranged 25-68years. Of the 8 (62%) patients presenting endocrine symptoms, 4 had post-menopausal hemorrhage, 4 had menstrual irregularity, 2 had androgenic manifestations, 1 had hirsutism, and 1 showed acne with thyroid nodules. 1 patient had elevated cancer antigen 125 (CA125), and 2 had elevated testosterone (T). The other 5 patients showed no symptoms of whom masses were detected incidentally by physical examination. All tumors were at stage I and confined to unilateral ovary. 11 tumors were solid or mixed solid-cystic masses with clear boundaries on ultrasound, and 1 tumor was a cystic mass. 7 tumors were intermediately differentiated and 6 were poorly differentiated, among which 1 case had heterologous elements (poorly differentiated) and 8 had a retiform pattern. Grade 2 endometrial cancer occurred in 2 cases (1 intermediately differentiated and 1 poorly differentiated). One case had multinodular goiter (intermediately differentiated). The patients were classified into endocrine function group (8/13) and no endocrine function (5/13). The proportion of retiform pattern of the group with endocrine function was significantly higher than that of no endocrine function group (p < 0.05). However, the mean age, diameter of tumors, and the proportions of poor differentiation and rupture showed no significant difference. All patients were treated with surgical excision. Three cases underwent surgery twice after the pathological results came out. For the final surgery, 1 patient underwent cystectomy, 3 underwent unilateral salpingo-oophorectomy, and 9 underwent total hysterectomy and bilateral salpingo-oophorectomy. 7 had received postoperative chemotherapy. All of 13 patients exhibited disease-free survival (DFS) with the longest follow-up time being 9years. The clinical characteristics and imaging findings may provide information for the diagnosis of SLCTs. Higher percentage of retiform pattern was found in endocrine function group. Concurrence of Grade 2 endometrial carcinoma with SCLTs was reported. The prognosis of SLCTs is good. Conservative surgery is acceptable for young patients wishing to preserve fertility.

48,XXYY syndrome presenting with long-term infertility and newly observed neck deformities: a case report

BackgroundLong-term infertility can be attributed to many factors, with the genetic factor being the most overlooked due to its many nonspecific morphological or endocrine signs. We present a rare case of a patient with progressive testicular failure associated with 48,XXYY syndrome.Case presentationA 39-year-old Arab man presented to our fertility clinic for fertility treatment. He was diagnosed with primary infertility, which had been present for 20 years at the time of presentation. Our patient had nonspecific morphological features of an abnormally wide neck with front slouching neck posture, clinodactyly of the third finger, and had moderate hypoandrogenemic features. A semen analysis revealed azoospermia. Genetic tests for azoospermia, including sex-determining region Y (SRY) detection and chromosome Y microdeletion, revealed no deletion present on the Y chromosome. Karyotyping was used and our patient was diagnosed with 48,XXYY syndrome.ConclusionGenetic testing (karyotyping and so on) played a key role in the diagnosis of our patient with long-term primary infertility secondary to 48,XXYY syndrome, and should play a vital role in all cases of long-term infertility, especially when presentation is accompanied by endocrine, skeletal, or morphological symptoms, signifying an underlying genetic factor.

MON-326 Non Functioning Pituitary Adenomas (NFPA): Sex Related Differences in Presentation, Clinical Features and Outcomes

INTRODUCTION: NFPA are characterized as tumors without a typical hormonal hypersecretion syndrome. They are frequently diagnosed in the sixth decade, by visual field defects, hypopituitarism or incidentally. PATIENTS AND METHODS: retrospective and observational study that included 103 patients with NFPA (60 females) who were seen between 1999 and 2019 in our hospital. We compared and analyzed patients characteristics by sex: reason for consultation, hormonal status at diagnosis, invasiveness of the tumor through MRI, treatments and outcomeRESULTS: out of 103 patients, 58,2% were women (W). Men (M) were significantly older than women (56 vs. 45 yold. p=0,002). The presence of a macroadenoma was similar in both sexes (93%W vs. 94,7% M), however tumor invasiveness was more frequent in men (50% vs. 24,6%). Most men consulted for incidental finding (47,4% vs. 29,8%); most women consulted for symptoms related to the tumor(70% vs 52%): hypogonadism 31,6% W, 13% M; galactorrhea 17% W; visual field defects 21,7% W, 23,7%M, pituitary apoplexy 11,6% M. At baseline hormonal assessment hyperprolactinemia was more frequent (50,9% vs 42%) and higher in women (mean PRL levels 75 ng/ml vs. 37 ng/ml). Hypogonadism was more frequent in men (54% vs 42%) as well as hypopituitarism (15% vs. 10,5%). Surgery was the most used therapy in both sexes (69% M vs. 73%W) but males required more frequently second surgery and radiotherapy than females (15% vs. 5% and 10% vs. 5% respectively). Gonadotropin secreting adenoma was diagnosed in 62% of men and 37,5% by tumor immunohistochemistry, in the 45% of women who presented negative immunostaining the presence of a gonadotrophic lineage is not ruled out, median Ki-67 labeling was low in both sexes (2%). After surgery 66% of men and 37% of women showed tumor remnant > 1cm (p=0,001), tumor regrowth was seen in 38,4% men and 10,4% women (p=0,03). Hypogonadism was greater in men than in women (56% vs 39%). Ninety two percent of men and 60,9% of women developed some degree of pituitary deficiency after surgery (P<0,001). Men showed a higher degree of complete hypopituitarism compared to women (pretreatment 15% vs 10,5%, post treatment 32% vs 13%). CONCLUSION: NFPA in men are usually diagnosed incidentally at an older age, are more invasive at presentation with a higher incidence of pituitary dysfunction. Moreover, they presented with greater rate of tumor regrowth and hypopituitarism after surgery. NFPA in women are diagnosed earlier due to endocrine symptoms, had lower degree of invasiveness with better outcomes after treatment. Sex related differences in NFPA may be associated with the delay in diagnosis, although a more aggressive biology cannot be discarded.

Leveraging Prior Knowledge to Recover Characteristic Immune Regulatory Motifs in Gulf War Illness.

Potentially linked to the basic physiology of stress response, Gulf War Illness (GWI) is a debilitating condition presenting with complex immune, endocrine and neurological symptoms. Here we interrogate the immune response to physiological stress by measuring 16 blood-borne immune markers at 8 time points before, during and after maximum exercise challenge in n = 12 GWI veterans and n = 11 healthy veteran controls deployed to the same theater. Immune markers were combined into functional sets and the dynamics of their joint expression described as classical rate equations. These empirical networks were further informed structurally by projection onto prior knowledge networks mined from the literature. Of the 49 literature-informed immune signaling interactions, 21 were found active in the combined exercise response data. However, only 4 signals were common to both subject groups while 7 were uniquely active in GWI and 10 uniquely active in healthy veterans. Feedforward mediation of IL-23 and IL-17 by IL-6 and IL-10 emerged as distinguishing control elements that were characteristically active in GWI versus healthy subjects. Simulated restructuring of the regulatory circuitry in GWI as a result of applying an IL-6 receptor antagonist in combination with either a Th1 (IL-2, IFNγ, and TNFα) or IL-23 receptor antagonist predicted a partial rescue of immune response elements previously associated with illness severity. Overall, results suggest that pharmacologically altering the topology of the immune response circuitry identified as active in GWI can inform on strategies that while not curative, may nonetheless deliver a reduction in symptom burden. A lasting and more complete remission in GWI may therefore require manipulation of a broader physiology, namely one that includes endocrine oversight of immune function.

Delayed behavioral and genomic responses to acute combined stress in zebrafish, potentially relevant to PTSD and other stress-related disorders: Focus on neuroglia, neuroinflammation, apoptosis and epigenetic modulation

Stress is a common trigger of stress-related illnesses, such as anxiety, phobias, depression and post-traumatic stress disorder (PTSD). Various animal models successfully reproduce core behaviors of these clinical conditions. Here, we develop a novel zebrafish model of stress (potentially relevant to human stress-related disorders), based on delayed persistent behavioral, endocrine and genomic responses to an acute severe ‘combined’ stressor. Specifically, one week after adult zebrafish were exposed to a complex combined 90-min stress, we assessed their behaviors in the novel tank and the light-dark box tests, as well as whole-body cortisol and brain gene expression, focusing on genomic biomarkers of microglia, astrocytes, neuroinflammation, apoptosis and epigenetic modulation. Overall, stressed fish displayed persistent anxiety-like behavior, elevated whole-body cortisol, as well as upregulated brain mRNA expression of genes encoding the glucocorticoid receptor, neurotrophin BDNF and its receptors (TrkB and P75), CD11b (a general microglial biomarker), COX-2 (an M1-microglial biomarker), CD206 (an M2-microglial biomarker), GFAP (a general astrocytal biomarker), C3 (an A1-astrocytal biomarker), S100α10 (an A2-astrocytal biomarker), as well as pro-inflammatory cytokines IL-6, IL-1β, IFN-γ and TNF-α. Stress exposure also persistently upregulated the brain expression of several key apoptotic (Bax, Caspase-3, Bcl-2) and epigenetic genes (DNMT3a, DNMT3b, HAT1, HDAC4) in these fish. Collectively, the present model not only successfully recapitulates lasting behavioral and endocrine symptoms of clinical stress-related disorders, but also implicates changes in neuroglia, neuroinflammation, apoptosis and epigenetic modulation in long-term effects of stress pathogenesis in vivo.

Surgical treatment of hypothalamic hamartomas.

Hypothalamic hamartomas are aberrant masses, composed of abnormally distributed neurons and glia. Along endocrine and cognitive symptoms, they may cause epileptic seizures, including the specific gelastic and dacrystic seizures. Surgery is the treatment of drug-resistant hamartoma epilepsy, with associated positive results on endocrine, psychiatric, and cognitive symptoms. Recently, alternatives to open microsurgical treatment have been proposed. We review these techniques and compare their efficacy and safety. Open resection or disconnection of the hamartoma, either through pterional, transcallosal, or transventricular approach, leads to good epileptological control, but its high complication rate, up to 30%, limits its indications. The purely cisternal peduncular forms remain the only indication of open, pterional approach, while other strategies have been developed to overcome the neurological, endocrine, behavioral, or cognitive complications. Laser and radiofrequency thermocoagulation-based disconnection through robot-guided stereo-endoscopy has been proposed as an alternative to open microsurgical resection and stereotactic destruction. The goal is to allow safe and complete disconnection of a possibly complex attachment zone, through a single intraparenchymal trajectory which allows multiple laser or radiofrequency probe trajectory inside the ventricle. The efficacy was high, with 78% of favorable outcome, and the overall complication rate was 8%. It was especially effective in patients with isolated gelastic seizures and pure intraventricular hamartomas. Stereotactic radiosurgery has proved as efficacious and safer than open microsurgery, with around 60% of seizure control and a very low complication rate. Multiple stereotactic thermocoagulation showed very interesting results with 71% of seizure freedom and 2% of permanent complications. Stereotactic laser interstitial thermotherapy (LiTT) seems as effective as open microsurgery (from 76 to 81% of seizure freedom) but causes up to 20% of permanent complications. This technique has however been highly improved by targeting only the epileptogenic onset zone in the hamartoma, as shown on preoperative functional MRI, leading to an improvement of epilepsy control by 45% (92% of seizure freedom) with no postoperative morbidity. All these results suggest that the impact of the surgical procedure does not depend on purely technical matters (laser vs radiofrequency thermocoagulation or stereotactic vs robot-guided stereo-endoscopy) but relies on the understanding of the epileptic network, including inside the hamartoma, the aim being to plan an effective disconnection or lesion of the epileptogenic part while sparing the adjacent functional structures.

Manifestaciones endocrinas de los tumores germinales del sistema nervioso central en niños

IntroductionCentral nervous system germ cell tumors need to be adequately diagnosed because their treatment is usually effective and they do not always require surgery. The study objectives are to describe the endocrine manifestations of these tumors and to compare the time of their onset to that of the occurrence of neurological and visual changes. Patients and methodsThe medical histories of patients under 14 years of age seen at a pediatric endocrinology unit between 2000 and 2018 were reviewed. Wilcoxon and Fisher statistical tests were performed. ResultsWe found 12patients (10 females) with an age at diagnosis of 9.4±1.7 years and a follow-up time of 5.5±3.0 years, 10with tumors in the sellar region, and each one with a pineal gland and a bifocal tumor. Clinical changes leading to diagnosis were neurological and/or visual in 9patients and hormonal in three. Seven patients diagnosed on the basis of neurological or visual symptoms had previously reported hormonal changes, giving us a total of 10 children at diagnosis (the most common diagnosis was central diabetes insipidus, found in 8). Endocrine symptoms had been present before diagnosis for 25.0±26.2 months, considerably longer than neuro-ophthalmological complaints (2.0±2.1 months, p=0.012). ConclusionsAlmost all intracranial germ cell tumors have associated endocrine manifestations at diagnosis, with central diabetes insipidus the most common. Hormonal symptoms usually appear long before neuro-ophthalmological manifestations. Adequate clinical and endocrinological assessment may allow for an earlier diagnosis of these tumors.

ДИСБАЛАНС НЕВРНОЙ И ЭНДОКРИННОЙ СИСТЕМЫ ПРИ РЕВМАТОИДНОМ АРТРИТЕ

With rheumatoid arthritis (RA), along with the main manifestations, there are a variety of neurological, neurotic and endocrine symptoms caused by immune effects. In addition, the chronic course of RA and the disability of patients leads to a violation of their usual way of life, a change in the circle of vital interests and the formation of neurotic disorders. Neurotic disorders are accompanied by a violation of the plasticity of the nervous system -its ability to regulate all structural and functional organizations and adaptation processes, which in turn leads to profound changes in immunological homeostasis, hormonal balance and all types of metabolism

Symptom interval and treatment burden for patients with malignant central nervous system germ cell tumours

ObjectivePatients with central nervous system germ cell tumours (CNS-GCTs) commonly initially present to primary care or general paediatricians. Prolonged symptom intervals (SI) are frequently seen in CNS-GCTs and have been...

Abstract P2-12-11: Does goserelin have an effect on quality of life in women who have chemotherapy for early breast cancer? Results from the OPTION randomised trial

Abstract The OPTION trial examined whether or not premenopausal women with early breast cancer receiving chemotherapy benefited from ovarian function protection with goserelin. This trial showed some preservation of ovarian function and fertility in women aged 40 years or less*. Additionally the OPTION trial examined the immediate and late impact of treatments on patients’ Quality of Life (QoL) over a 5 year period. Patients and Methods: In the OPTION trial 227 pre-menopausal patients with early stage breast cancer were randomly assigned to chemotherapy with or without goserelin. Patients were stratified by age into ≤40 years and &amp;gt; 40 years of age. QoL was assessed with the Functional Assessment of Cancer Therapy - Breast (FACT-B) and Endocrine Symptom checklist(ES) at baseline (pre- treatment), 3, 6, 12, 18 and 24 months, then annually to 5 years. Results:-Two hundred and thirteen patients were available for analysis of QoL results. There was a temporary increase in endocrine symptoms of menopause in the goserelin group that was statistically higher than in the controls (P = 0.02) and was associated with a decrease in the main outcome measure of global QoL, TOI. This contrasted with a longer term outcome favouring the intervention in terms of QoL and fewer adverse endocrine symptoms, though these later findings were not statistically significant. Conclusions: Cytotoxic chemotherapy with or without goserelin causes a short term decrement in QoL for up to 6 months in otherwise well women.* Ann Onc 2017 28 1811-1816. Citation Format: Robert CF Leonard, Janine Mansi, Ann Yellowlees, Lesley Fallowfield, Valerie Jenkins. Does goserelin have an effect on quality of life in women who have chemotherapy for early breast cancer? Results from the OPTION randomised trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-12-11.

Abstract PD10-08: Baseline patient reported outcomes predict aromatase inhibitor adherence failure among women in enrolled in a randomized trial of text-messaging

Abstract Background: Non-adherence to aromatase inhibitors (AIs) for breast cancer is common and increases risk of recurrence. Few prospective studies have systematically evaluated reasons for adherence failure. S1105 randomized women to receive text message reminders or usual care, and no effect of the intervention was observed on the rates of adherence failure. We analyzed baseline characteristics to evaluate factors associated with non-adherence prospectively over 3-years.Methods: Patients enrolled in SWOG S1105 were required to have been on an AI for ≥30 days at enrollment. Patients were assessed for non-adherence of AIs every 3 months for 36 months, with non-adherence defined as urine AI metabolite assay results satisfying any of the following: &amp;lt;10 [units], undetectable, specimen submitted outside of the ± 21 day follow-up appointment window, or no submitted specimen. At baseline patients were asked about insurance, pill number dispensed (30 vs 90) and medication cost, and they completed patient reported outcomes (PROs) focused on pain and endocrine symptoms (BPI (Brief Pain Inventory), FACT-ES (Endocrine Symptoms)), quality of life (FACT-G), as well as their beliefs about medications (TSQM (Treatment Satisfaction Questionnaire for Medicine) and BMQ (Brief Medication Questionnaire)). PRO scales were split at the median creating high (&amp;gt;median) vs low (&amp;lt;=median) binary predictors. We examined the association of baseline factors with both adherence failure at 36 months with a logistic regression and time-to-adherence failure (TTAF) with a cox proportional hazard regression controlling for stratification factors. Results: In total, 724 patients were registered from 40 institutions between May, 2012 and September, 2013. The median age was 60.9 years, and 64.5% were on AI &amp;lt;12 months prior to registration. Observed adherence at 36 months was 55.4% (41.2% in-window, 14.2% out of window). Neither age nor race nor ethnicity was associated with long-term adherence. Of the 29 baseline factors we analyzed, 12 were associated with non-adherence at 36 months, including symptoms (FACT-ES total, OR=1.64, 95% CI:1.2, 2.22 p=.002; BPI Interference OR=1.68, 95% CI:1.23,2.28 p=.001; FACT G, OR=1.70, 95% CI:1.25, 2.31 p&amp;lt;.001), satisfaction with medications (TSQM global, OR=1.55, 95% CI:1.1,2.17 p=.01) and beliefs about medication (BMQ, OR=1.51, 95% CI:1.11, 2.05 p=.009). Nine of 29 baseline factors were associated with TTAF, including lack of private insurance (HR=1.20, 95% CI:1.01,1.41 p=.04) and 30 day vs. 90 day pill supply (HR=1.2, 95% CI:1.01,1.42 p=.04). Factors associated with self-reported adherence will be presented. Conclusions: Baseline endocrine symptoms, pain, medication satisfaction, beliefs and concerns about side effects are strongly associated with long-term AI adherence. Targeted behavioral and symptom management interventions to improve adherence should be focused on women at the highest risk of adherence failure. Citation Format: Dawn L Hershman, Joeseph M Unger, Anna Moseley, Grace C Hillyer, Kathryn B. Arnold, Julie R Gralow, N. Lynn Henry, Scott D Ramsey, Alfred I Neugut. Baseline patient reported outcomes predict aromatase inhibitor adherence failure among women in enrolled in a randomized trial of text-messaging [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD10-08.

Abstract PD10-07: Patient reported outcomes and early discontinuation of adjuvant endocrine therapy according to neighborhood poverty rate

Abstract Introduction: Early discontinuation (DC) of adjuvant endocrine therapy (AET) for hormone receptor positive breast cancer (BC) is associated with increased risk of recurrence and death. Symptoms and low socioeconomic status (SES) have both previously been associated with early AET DC. Prospective collection of patient-reported outcomes (PRO) is increasingly used in oncology practice, and can lead to improvements in quality of life and survival in advanced cancer. Compared to patients of high SES, those of low SES report higher symptom burden in multiple clinical settings. Whether PRO reporting during AET differs according to SES is unknown. Methods: We enrolled women initiating AET for stage 0-III BC in a prospective clinic-based cohort from March 2012 to Dec 2016. At baseline (BL), 3, 6, 12, and 24 months (mo), participants completed these PROs online: FACT-ES, MOS Sexual Problems, and NIH PROMIS measures for pain interference, fatigue, depression, anxiety, physical function and sleep disturbance. Neighborhood poverty (NP) rate, a surrogate for SES based on US Census estimates of the % of persons in a zip code below the federal poverty line, was categorized as 0-5% (low), &amp;gt;5-10% (moderate) and &amp;gt;10% (high). We assessed AET DC and cited reason for DC by chart review. Baseline characteristics were compared between NP groups using Fisher’s exact and t-tests. Changes in mean PRO scores from BL to follow-up (FU) time points for each NP group were estimated simultaneously from a linear mixed effects regression model with a random intercept for each patient. We evaluated differences in changes in mean scores for all 8 PRO measures over time according to NP group with an interaction test. Statistical significance of p &amp;lt; 0.05/8 = 0.006 was used, adjusting for multiple comparisons. Results: Among 320 women, mean age was 61 (range 26-90), 83% were White, 10% Black, 65% were post-menopausal and 84% had Stage I-II BC. NP categorization was: 97 (30.3%) low, 127 (39.7%) moderate and 96 (30%) high. Mean stage distribution, and proportions of participants who had mastectomy, chemotherapy and radiation did not differ by NP group. There were fewer post-menopausal women in the moderate/high NP groups (61%) compared to the low NP group (72%, p=0.04). The proportion of Black participants increased with NP group (low 5%, moderate 10%, high 16%, p=0.04). Overall, 180 (56%) were on an aromatase inhibitor (AI) and 140 (44%) were on tamoxifen. There was more AI use in the low NP group (64%) compared to the moderate/high NP groups (53%, p=0.08). At BL, there were no differences in mean score on any PRO by NP group. For all NP groups, endocrine symptoms worsened at all FU times (all p&amp;lt;0.05) and physical function improved at most FU times. Compared to BL, mean changes in pain interference over time differed by NP group (interaction p=0.005), with less pain interference at 6 and 12 mo in the moderate/high NP groups and no significant change in the low NP group. Mean changes in other PROs did not differ by NP group. At median FU of 41 mo (range 3-75), the proportion of participants who discontinued AET due to side effects/intolerance was similar across NP groups (low 12.6%, moderate 16%, high 17%, p=0.67). Discussion: We found that changes in PROs during AET were similar across SES based on NP rates with the exception of less reported pain interference over time in participants of lower SES. The lack of improvement in pain interference in participants of higher SES may be attributable to arthralgias due to more frequent AI use. Despite differences in pain interference, early DC of AET due to side effects/intolerance did not differ by SES in this cohort. Our findings suggest that PROs are generally similar among early BC patients of varied SES receiving AET and that factors other than symptoms may explain the previously reported association between early DC and low SES. Citation Format: Ramy Sedhom, Amanda Blackford, David Lim, Jennifer Ensminger, Claire Snyder, Vered Stearns, Karen Lisa Smith. Patient reported outcomes and early discontinuation of adjuvant endocrine therapy according to neighborhood poverty rate [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD10-07.

Oxytocin receptor antagonist reverses the blunting effect of pair bonding on fear learning in monogamous prairie voles

Social relationships among spouses, family members, and friends are known to affect physical and mental health. In particular, long-lasting bonds between socio-sexual partners have profound effects on cognitive, social, emotional, and physical well-being. We have previously reported that pair bonding in monogamous prairie voles (Microtus ochrogaster) is prevented by a single prolonged stress (SPS) paradigm, which causes behavioral and endocrine symptoms resembling post-traumatic stress disorder (PTSD) patients in rats (Arai et al., 2016). Since fear memory function is crucial for anxiety-related disorders such as PTSD, we investigated the effects of pair bonding on fear learning in prairie voles. We applied an SPS paradigm to male prairie voles after the cohabitation with a male (cage-mate group) or female (pair-bonded group). The cage-mate group, but not the pair-bonded group, showed enhanced fear response in a contextual fear conditioning test following the SPS treatment. Immunohistochemical analyses revealed that cFos-positive cells in the central amygdala were increased in the pair-bonded group after the contextual fear conditioning test and that oxytocin immunoreactivity in the paraventricular nucleus of the hypothalamus was significantly higher in the pair-bonded group than the cage-mate group. This pair-bonding dependent blunting of fear memory response was confirmed by a passive avoidance test, another fear-based learning test. Interestingly, intracerebroventricular injection of an oxytocin receptor antagonist 30 min before the passive avoidance test blocked the blunting effect of pair bonding on fear learning. Thus, pair bonding between socio-sexual partners results in social buffering in the absence of the partner, blunting fear learning, which may be mediated by oxytocin signaling.

Biophysical classification of a CACNA1D de novo mutation as a high-risk mutation for a severe neurodevelopmental disorder

BackgroundThere is increasing evidence that de novo CACNA1D missense mutations inducing increased Cav1.3 L-type Ca2+-channel-function confer a high risk for neurodevelopmental disorders (autism spectrum disorder with and without neurological and endocrine symptoms). Electrophysiological studies demonstrating the presence or absence of typical gain-of-function gating changes could therefore serve as a tool to distinguish likely disease-causing from non-pathogenic de novo CACNA1D variants in affected individuals. We tested this hypothesis for mutation S652L, which has previously been reported in twins with a severe neurodevelopmental disorder in the Deciphering Developmental Disorder Study, but has not been classified as a novel disease mutation.MethodsFor functional characterization, wild-type and mutant Cav1.3 channel complexes were expressed in tsA-201 cells and tested for typical gain-of-function gating changes using the whole-cell patch-clamp technique.ResultsMutation S652L significantly shifted the voltage-dependence of activation and steady-state inactivation to more negative potentials (~ 13–17 mV) and increased window currents at subthreshold voltages. Moreover, it slowed tail currents and increased Ca2+-levels during action potential-like stimulations, characteristic for gain-of-function changes. To provide evidence that only gain-of-function variants confer high disease risk, we also studied missense variant S652W reported in apparently healthy individuals. S652W shifted activation and inactivation to more positive voltages, compatible with a loss-of-function phenotype. Mutation S652L increased the sensitivity of Cav1.3 for inhibition by the dihydropyridine L-type Ca2+-channel blocker isradipine by 3–4-fold.Conclusions and limitationsOur data provide evidence that gain-of-function CACNA1D mutations, such as S652L, but not loss-of-function mutations, such as S652W, cause high risk for neurodevelopmental disorders including autism. This adds CACNA1D to the list of novel disease genes identified in the Deciphering Developmental Disorder Study. Although our study does not provide insight into the cellular mechanisms of pathological Cav1.3 signaling in neurons, we provide a unifying mechanism of gain-of-function CACNA1D mutations as a predictor for disease risk, which may allow the establishment of a more reliable diagnosis of affected individuals. Moreover, the increased sensitivity of S652L to isradipine encourages a therapeutic trial in the two affected individuals. This can address the important question to which extent symptoms are responsive to therapy with Ca2+-channel blockers.

Primary intracranial germ cell tumors in children 36-year experience of a single center.

Intracranial germ cell tumors (ICGCTs) comprise approximately 0.4%-3% of all brain tumors. In this study, we aim to evaluate clinical characteristics, treatment and outcomes of patients with ICGCT. All patients with ICGCT diagnosed in Hacettepe University's Pediatric Oncology Department between January 1980 and January 2016 were evaluated, retrospectively. We identified 52 patients (male/female: 2.46) diagnosed with ICGT. Median age was 140 months. The median duration of symptoms was 3 months. Patients with endocrine symptoms were diagnosed later than others (P = 0.028). The primary site was pineal region in 20 patients, nonpineal region in 32 which included six bifocal involvements. Pineal location was more common in boys than girls (P = 0.02). Histopathological diagnosis was germinoma in 28 patients, nongerminomatous malignant germ cell tumors in 14 and immature teratoma in 4. The mean age for germinoma was higher than that of nongerminomatous tumors (P = 0.032). Patients treated with surgery and radiotherapy and chemotherapy. Median follow-up time was 52.5 months. Thirty-six patients were alive for 12-228 months. Relapsed/progressive disease was observed in 11 patients. Nongerminomatous tumors more frequently showed relapse/progression than germinoma (P = 0.06). Five-year overall and event-free survival rates for the whole group were 72.6% and 57.2%, respectively. Overall and event-free survival rates for germinoma were better than malignant nongerminomatous tumors. Although the ratio of ICGCTs to central nervous system tumors in our series was similar to western countries, some clinical features such as tumor location were similar to cases from East Asian countries. Although similar protocols were used survival rates lower than developed western and eastern developed countries.

The Ototoxic Potential of Cobalt From Metal-on-Metal Hip Implants: Objective Auditory and Vestibular Outcome.

During the past decade, the initial popularity of metal-on-metal (MoM) hip implants has shown a progressive decline due to increasingly reported implant failure and revision surgeries. Local as well as systemic toxic side effects have been associated with excessive metal ion release from implants, in which cobalt (Co) plays an important role. The rare condition of systemic cobaltism seems to manifest as a clinical syndrome with cardiac, endocrine, and neurological symptoms, including hearing loss, tinnitus, and imbalance. In most cases described in the literature, revision surgery and the subsequent drop in blood Co level led to (partial) alleviation of the symptoms, suggesting a causal relationship with Co exposure. Moreover, the ototoxic potential of Co has recently been demonstrated in animal experiments. Since its ototoxic potential in humans is merely based on anecdotal case reports, the current study aimed to prospectively and objectively examine the auditory and vestibular function in patients implanted with a MoM hip prosthesis. Twenty patients (15 males and 5 females, aged between 33 and 65 years) implanted with a primary MoM hip prosthesis were matched for age, gender, and noise exposure to 20 non-implanted control subjects. Each participant was subjected to an extensive auditory (conventional and high-frequency pure tone audiometry, transient evoked and distortion product otoacoustic emissions [TEOAEs and DPOAEs], auditory brainstem responses [ABR]) and vestibular test battery (cervical and ocular vestibular evoked myogenic potentials [cVEMPs and oVEMPs], rotatory test, caloric test, video head impulse test [vHIT]), supplemented with a blood sample collection to determine the plasma Co concentration. The median [interquartile range] plasma Co concentration was 1.40 [0.70, 6.30] µg/L in the MoM patient group and 0.19 [0.09, 0.34] µg/L in the control group. Within the auditory test battery, a clear trend was observed toward higher audiometric thresholds (11.2 to 16 kHz), lower DPOAE (between 4 and 8 kHz), and total TEOAE (1 to 4 kHz) amplitudes, and a higher interaural latency difference for wave V of the ABR in the patient versus control group (0.01 ≤ p < 0.05). Within the vestibular test battery, considerably longer cVEMP P1 latencies, higher oVEMP amplitudes (0.01 ≤ p < 0.05), and lower asymmetry ratio of the vHIT gain (p < 0.01) were found in the MoM patients. In the patient group, no suggestive association was observed between the plasma Co level and the auditory or vestibular outcome parameters. The auditory results seem to reflect signs of Co-induced damage to the hearing function in the high frequencies. This corresponds to previous findings on drug-induced ototoxicity and the recent animal experiments with Co, which identified the basal cochlear outer hair cells as primary targets and indicated that the cellular mechanisms underlying the toxicity might be similar. The vestibular outcomes of the current study are inconclusive and require further elaboration, especially with respect to animal studies. The lack of a clear dose-response relationship may question the clinical relevance of our results, but recent findings in MoM hip implant patients have confirmed that this relationship can be complicated by many patient-specific factors.

Genotype-Phenotype Relationships and Endocrine Findings in Prader-Willi Syndrome.

Prader-Willi syndrome (PWS) is a complex imprinting disorder related to genomic errors that inactivate paternally-inherited genes on chromosome 15q11-q13 with severe implications on endocrine, cognitive and neurologic systems, metabolism, and behavior. The absence of expression of one or more genes at the PWS critical region contributes to different phenotypes. There are three molecular mechanisms of occurrence: paternal deletion of the 15q11-q13 region; maternal uniparental disomy 15; or imprinting defects. Although there is a clinical diagnostic consensus criteria, DNA methylation status must be confirmed through genetic testing. The endocrine system can be the most affected in PWS, and growth hormone replacement therapy provides improvement in growth, body composition, and behavioral and physical attributes. A key feature of the syndrome is the hypothalamic dysfunction that may be the basis of several endocrine symptoms. Clinical and molecular complexity in PWS enhances the importance of genetic diagnosis in therapeutic definition and genetic counseling. So far, no single gene mutation has been described to contribute to this genetic disorder or related to any exclusive symptoms. Here we proposed to review individually disrupted genes within the PWS critical region and their reported clinical phenotypes related to the syndrome. While genes such as MKRN3, MAGEL2, NDN, or SNORD115 do not address the full spectrum of PWS symptoms and are less likely to have causal implications in PWS major clinical signs, SNORD116 has emerged as a critical, and possibly, a determinant candidate in PWS, in the recent years. Besides that, the understanding of the biology of the PWS SNORD genes is fairly low at the present. These non-coding RNAs exhibit all the hallmarks of RNA methylation guides and can be incorporated into ribonucleoprotein complexes with possible hypothalamic and endocrine functions. Also, DNA conservation between SNORD sequences across placental mammals strongly suggests that they have a functional role as RNA entities on an evolutionary basis. The broad clinical spectrum observed in PWS and the absence of a clear genotype-phenotype specific correlation imply that the numerous genes involved in the syndrome have an additive deleterious effect on different phenotypes when deficiently expressed.

CN11 - The effect of e-mobile education on the quality of life in women with breast cancer

BackgroundThe aim of this study was to determine the effect of e-mobile education on the quality of life of women diagnosed with breast cancer who received endocrine hormone therapy. MethodsThe study was conducted as a randomized controlled study between January and July 2018 in the Medical Oncology Outpatient Clinic of a state hospital in the province of Turkey.A total of 64 patients were included in the study according to the inclusion criteria of randomization, split into treatment (n=31) and control group (n=33).Data were collected using Patient Introductory Information Form, FACT-ES Quality of Life Scale and NCCN Distress Thermometer.The data were collected twice during the first week of the study and 12th week at the end of the study by face-to-face and/or telephone interviews.Treatment group patients were received information via mobile application for three months during which they were contacted in every 15 days; e-mobile training was provided, including information about breast cancer definition, treatment process, symptoms experienced during endocrine hormone therapy, adequate nutrition, regular physical activity and coping with stress. ResultsThe mean total quality of life after e-mobile training to the treatment group was found to be significantly higher than the control group, and the mean distress score was lower than the control group (p<0.05).For quality of life subscales of patients in the e-mobile training and treatment group; the scores of physical well-being, emotional well-being and endocrine symptoms were found to be significantly higher than the control group (p<0.05).There was found no difference between the mean scores of social / family well-being subscale scores of the patients in the e-mobile training and treatment group and the control group.Treatment group reported that e-mobile training was “informative and useful a training” (87.1%). ConclusionsAs a result of the study, it has been concluded the quality of life of the patients increased when nurses use the e-mobile training and counseling in order to manage the disease process and symptoms of the women diagnosed with breast cancer and who are receiving endocrine hormone therapy with the help of the developing technologies and using the mobile technologies. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Comparison and Clinical Implementation of Quality of Life Tools in Patients with Small Bowel Neuroendocrine Tumors Treated with Lu-DOTA-TATE PRRT

Aim: This study assesses if clinically developed quality of life (QoL) tools are as effective in small bowel neuroendocrine tumors (NETs) as NET-specific research questionnaires. Methods: QoL in patients with small bowel NETs treated with Lu-DOTA-TATE was assessed with The European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, QLQ-GI.NET21 and Edmonton Symptom Assessment System Revised (ESAS-r) at baseline and after four treatments. Repeated measures ANOVA was performed. Results: Both EORTC and ESAS-r demonstrated maintained overall QoL. EORTC demonstrated statistically and clinically significant improvement in insomnia, diarrhea, gastrointestinal, endocrine symptoms and social function. ESAS-r demonstrated statistically and clinically significant improvement in overall total symptom distress score. Conclusion: ESAS-r is quick and easy to interpret. It is not as sensitive to individual symptoms but does track overall function. EORTC assessment is more complex, but better reflects QoL for NET specific symptoms.

Advances in the diagnosis and treatment of adrenocortical carcinoma

Adrenocortical carcinoma is a malignant endocrine tumor. There is no unified standard for diagnosis and treatment because of the low incidence. There are two peaks in the age of onset, which are 0 to 10 years and 40 to 50 years, and the incidence of children and women is higher. The percentage of 60 to 70 ACC patients show clinical symptoms due to the excess hormone, but there are still many patients with poor clinical symptoms. The common endocrine symptoms include polycythemia, masculinity or male breast development. The prognosis of ACC is poor, and the classification and staging of the tumor and hypercortisol are associated with the prognosis. Surgical resection is the first choice, but the recurrence rate of the tumor is high and the overall survival rate is low after operation. In this paper, the clinical characteristics, diagnosis, differential diagnosis, prognosis and treatment of ACC are summarized by reviewing the past researches. Key words: Therapeutic used; Review; Surgical procedures, operative; Adrenocortical carcinoma; Clinical features