Citations

Objectives Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early‐onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD‐ and schizophrenia (SCZ)‐associated risk variants is associated with an earlier AAO in BD patients. Methods A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn‐Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18 years] vs adulthood [>18 years]) or considered as a continuous measure. The associations between BD‐ and SCZ‐PRSs and AAO were evaluated with regression models. Results BD‐ and SCZ‐PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment. Conclusions The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype.

Background: Catamenial epilepsy refers to cyclic seizure exacerbation in relation to the menstrual cycle. Three distinct patterns have been described: C1-perimenstrual, C2-periovulatory, and C3-inadequate luteal. There is experimental and clinical evidence that gonadal steroid hormones affect neuronal excitability with estrogens being mainly proconvulsant and progesterone anticonvulsant. If reproductive steroids have a role in seizure occurrence, they may also have a role in treatment. Objective: The objective of this study was to critically assess current evidence regarding the efficacy of progesterone as adjunctive therapy in women with intractable catamenial epilepsy. Methods: The objective was addressed through the development of a structured critically appraised topic. This included a clinical scenario with a clinical question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom line conclusions. Participants included consultant and resident neurologists, medical librarian, and content experts in the fields of epilepsy and gynecology. Results: A randomized, placebo-controlled clinical trial was selected for critical appraisal. This trial compared the efficacy of adjunctive cyclic natural progesterone therapy versus placebo for seizures in women with intractable partial epilepsy, stratified by catamenial and noncatamenial status. There was no significant difference in proportions of responders between progesterone and placebo in the catamenial and noncatamenial strata. Prespecified secondary analysis showed that the level of perimenstrual seizure exacerbation is a significant predictor of the responder rate for progesterone therapy. Conclusions: Cyclic natural progesterone is not superior to placebo in reducing seizure frequency in women with intractable partial epilepsy. Posthoc findings suggest that progesterone may benefit a subset of women with perimenstrually exacerbated seizures.

Abstract Introduction. Male breast cancer (male BC) is a rare disease for which disease management is extrapolated from females. IMBC, an international consortium, which previously reported on clinico-pathological aspects, now reports on molecular subgroups revealed by RNA sequencing and their relation to patient outcome. Methods. Tumor samples from the retrospective MALE BC registry diagnosed between 1990-2010 and with pathology and outcome data (relapse-free- (RFS) and overall survival (OS)) were included (n=699). To allow the discovery of prognostic features, we selected, stratified for known risk factors (TN stage, grade, age at diagnose and adjuvant endocrine treatment), from the cohort 152 cases with poor (RFS <= 4 yrs) and good outcome (RFS > 7yrs) evenly distributed. Here, we report RNA sequencing results of the first 73 cases, 38 with poor and 35 with good outcome. RNA sequencing reads were used to generate gene expression values and to report transcripts carrying driver mutations. Unsupervised clustering identified subgroups and within subgroups differentially expressed genes were identified. The reported prognostic male BC subgroups M1 and M2 (Johansson BCR 2012(14):R31) were also annotated. All identified subgroups were related to outcome using logistic regression (p-value using Wald test). Results. Unsupervised clustering revealed 2 main subgroups of which group 1 was enriched for expression of ER target genes, WNT3 and genes from amplicons known for female BC, e.g. 19p13 (CCNE1), 8q24 (MYC), and 11q13 (CCND1). The biology of the smaller group 2 was less defined but TGFβ2 expression was high as were various kallikreins (KLK) including interestingly KLK3 (prostate specific antigen). Other known amplified regions [(8p11 (FGFR1), 20q13 (ZNF217) and 12q15 (MDM2)] and mutated transcripts [PIK3CA (H1047R/L/Q; E542K, E545K, N345K; 16% of cases), TP53 and SF3B1 (K700E) (2% of cases)] were identified. Profound tumor infiltrate gene expression was present in 5% of cases and one third of cases expressed proliferation markers. Except for TP53, none of these latter characteristics were unevenly distributed among the 2 main subgroups. ER and AR were highly correlated, particularly in group 1. The two main groups could be further subdivided. Group 1 comprised 3 subgroups of which subgroup 1a expressed TFF1/3 and NAT1, well-known ER targets, while subgroups 1b and 1c expressed other ER targets,respectively BEX1 and PITX1. HOXC cluster expression differentiated subgroup 1b from 1a and 1c. None of these intrinsic subgroups were, however, related to RFS. The previously reported M2 subgroup, which largely segregated with subclusters 1a and 1b, was associated with a better RFS than the M1 subgroup (OR=2.9; 95%CI 1.1-7.5; p-value=0.03). Conclusions. 1) Intrinsic subtypes of male BC were revealed and their subgrouping is defined by ER associated subsets of genes. 2) The association of the reported M2 subgroup of male BC with longer RFS was validated; 3) Currently identified biological characteristics of male BC may improve future treatments. The full report on 152 cases including a comparison to female BC will be presented at the conference. This research was funded by Breast Cancer Research Foundation Citation Format: Martens JWM, Sieuwerts A, Ponchet C, Smid M, de Weerd V, Slaets L, Piper T, van Deurzen CHM, Schroder CP, Stangle C, Kloosterman W, van Leeuwen-Stok E, Nilsson C, Vermeij J, Peeters S, Goulioti T, Nowaczyk M, Aebi S, Rubio IT, Kelly C, Bayani J, Porter P, Murray M, Hudis C, Middleton L, Korde L, Ruddy K, Winer E, Bogler O, van den Weyngaert D, dal Lago L, Fraser J, Benstead K, van Asperen C, Linderholm B, Hedenfalk I, Tryfonidis K, Giordano S, Bartlett J, Cardoso F. Molecular subtyping of male breast cancer by the International male breast cancer program (IMBC): EORTC 10085/TBCRC 0-29/BIG 2-07/NABCG/BOOG 2009-04 [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD7-12.

Abstract Introduction: Male BC is a rare disease (dx) for which management is extrapolated from trials in female BC. Comprehensive prospective data about QoL in men with BC could inform treatment. The international Male BC Consortium conducted a prospective registry of male BC patients of all stages who newly presented to a participating center between October 2013 and February 2017. A QoL substudy was conducted as part of this registry at most participating sites. Methods: Informed consent for participation in the QoL substudy was requested from new enrollees. Those who consented were asked to complete a survey including the EORTC QLQ-C30 and BR23 (breast cancer specific module), adapted by replacing female-specific items with male-specific sexual activity/function items from the prostate module (PR25). Outcomes were scored according to standard EORTC QLQ procedures on a 0-100 scale (with higher scores on QoL/functioning scales representing better QoL and functioning, and higher scores on symptom scales representing worse symptoms). Forms were analyzed centrally by EORTC. In order to compare to female BC, we used reference data from 2782 mixed age (62% under age 60) women with BC (of whom 1,147 had recurrent or metastatic dx, and 464 had stage 1-2 dx) reported in the EORTC QLQ-C30 Reference Values manual (2008). Results: A total of 557 men were enrolled in EORTC10085, 445 at sites participating in the QoL substudy. Consent forms were received from 422/445 (95%) for the substudy. Baseline survey (required to be completed within 30 days of enrollment) compliance was 85% (359/422). Median age at diagnosis was 67 years. There were 111 men (45%) with node-positive M0/MX dx and 27 men (8%) with M1 dx. Their median global health status score at baseline was 75 (IQR 67-83), higher than that documented historically in female BC (67, with IQR 50-83, in both the 2782 women with mixed stage and the subgroup of 464 with stage 1-2 tumors). The participating men's median social functioning score was 100 (IQR 67-100), also higher than the 83.3 (IQR 67-100) reported in mixed stage female BC patients, though no different than the 100 (IQR 67-100) found in women with stage 1-2 dx. Men's most commonly reported symptoms included fatigue (median score 13.9, IQR 0-33), insomnia (median score 0, IQR 0-33), and pain (median score 0, IQR 0-33), for which women's median scores were 33 (IQR 11-44), 33 (IQR 0-33), and 17 (IQR 0-50) with mixed stage dx, and 22 (IQR 0-33), 33 (IQR 0-33), and 17 (IQR 0-33) with stage 1-2 dx. Men's median sexual activity score was 33.3 (IQR 0-50), with less sexual activity reported by older patients and men with M1 dx. In those who were sexually active, median sexual function score was 83 (IQR 75-92), with no difference by age or stage. Conclusions: QoL and symptom burden in male BC patients appears no worse (and possibly better) than that in female patients. Future analyses of 1- and 5-year surveys from this study will assess the impact of specific treatments on changes in symptoms and QoL over time. These data will be useful in future efforts to tailor treatments and target interventions for male BC. Funding: Breast Cancer Research Foundation, Dutch Pink Ribbon Foundation, Swedish BRO, and EBCC Council. Citation Format: Schroder C, Cardoso F, Dijkstra N, van Leeuwen-Stok E, Linderholm B, Morgenstern D, Van Poznak C, Wolff AC, Poncet C, Gomez HL, Aalders K, Bjelic-Radisic V, Werutsky G, Tryfonidis K, Coens C, Giordano SH, Ruddy KJ. Quality of life (QoL) in male breast cancer (BC): Prospective study of the EORTC10085/TBCRC029/BIG2-07/NABCG International male BC program [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-23-02.

Objective To assess the impact of parental migraine on adolescents (aged 13‐21 years) living within the parental home from the adolescent's perspective. Background Family members are affected by their parent's migraine. We surveyed adolescents on the social, academic, and emotional effects of their parent's migraine. Methods The Chronic Migraine Epidemiology and Outcomes (CaMEO) study was a longitudinal Web‐based study with cross‐sectional modules designed to assess migraine symptoms, severity, frequency, and disability; migraine‐related consulting practices, healthcare utilization, medication use, comorbid health conditions, and family related burden associated with migraine. The Family Burden Module (adolescent version; FBM‐A) from the CaMEO study assessed parents with migraine and adolescent household members (dyads). Adolescents ranged in age from 13‐21 years and were living at home with their parent. The initial FBM‐A survey included 52 items covering five domains, which was refined and reduced by confirmatory factor analysis to 36 items covering four domains. Depression (9‐item Patient Health Questionnaire) and anxiety (7‐item Generalized Anxiety Disorder scale) were assessed. Item responses were stratified by parent migraine status (episodic migraine [EM], <15 headache days/month; chronic migraine [CM], ≥15 headache days/month). Frequencies of activities/events missed because of parental headache were categorized as ≥1 time or ≥4 times/previous 30 days. Results The sample included 1,411 parent‐adolescent dyads (parent with EM, n = 1,243 [88.1%]; parent with CM, n = 168 [11.9%]). Burden due to a parent's migraine was reported in four domains based on 36 items including: Loss of Parental Support and Reverse Caregiving (5 items); Emotional Experience (13 items); Interference with School (4 items); and Missed Activities and Events (14 items). Across domains, perceived burden was greater for adolescents of parents with CM vs EM. Rates of moderate‐to‐severe anxiety symptoms were higher among adolescents of parents with CM (6.2 vs 11.3%, P = .01), while moderate‐to‐severe depression symptom rates were similar (5.5 vs 8.9%, P = .08). More adolescents of CM vs EM parents reported having a headache within the previous 3 months ( P < .001). Conclusions Parental migraine negatively impacts adolescent children, extending our understanding of the family burden of migraine and emphasizing the potential benefit to children of optimizing migraine care.

BACKGROUNDThe amount of time available to pathologists with which to perform research is becoming limited due to an increasing manpower shortage in pathology, decreased reimbursement, and increased workload. This is occurring at the same time as demands escalate for pathologists to develop new companion tests, correlate the molecular findings with traditional methods, and assist in the development of individualized medicine. This study examined whether cytotechnologists may be integrated into a research team that uses their expertise in understanding pathology and clinical disease to provide interpretations of experiments that traditionally were performed by pathologists.METHODSCytotechnologists worked with pathologists to choose blocks for tissue microarrays (TMAs) and to interpret immunohistochemically stained TMA slides. The pathologist met with the cytotechnologist to review the study design. The cytotechnologists reviewed the slides and blocks and chose the most appropriate blocks for the TMA. Either 10% or all of the slides/blocks selected for TMA construction were reviewed by the supervising pathologist. The final selections were given to the TMA technologist to make the TMA. A minimum of 10% of the immunohistochemically stained TMA slides were reviewed by the supervising pathologist.RESULTSA total of 32 TMAs were created with 6 cytotechnologists collaborating with 6 pathologists. Immunohistochemical stains of 190 TMAs were interpreted by 4 cytotechnologists collaborating with 3 pathologists. All the TMAs and TMA interpretation data were used successfully for the research for which they were designed.CONCLUSIONSThe collaboration of cytotechnologists and pathologists in research can improve the quality of effort and increase satisfaction and productivity. Cancer Cytopathol 2018;126:232‐5. © 2018 American Cancer Society.

Children with glycogen storage disease type I (GSD I) lack the ability to convert glucose 6-phosphate to glucose and yet are able to produce glucose endogenously. To test the hypothesis that the source of this glucose is increased cycling of glucose moieties through hepatic glycogen, six children with GSD I were studied on two occasions during which they received enteral glucose for 6 h at 35 or 50 mumol.kg-1.min-1 along with [6,6-2H2]glucose to measure plasma glucose flux and [1-13C]galactose to label intrahepatic uridyl diphosphate (UDP)-glucose. After 3 h, acetaminophen was given to estimate UDP-glucose flux (reflecting the rate of glycogen synthesis). Mean steady-state plasma glucose concentrations (4.8 +/- 0.2 vs. 5.8 +/- 0.1 mM) and total flux (34.8 +/- 1.7 vs. 47.5 +/- 2.0 mumol.kg-1.min-1) were increased (P < 0.05 or better) on the high-infusion day. Endogenous glucose production was detectable only on the low-infusion day (2.0 +/- 0.5 mumol.kg-1.min-1). UDP-glucose flux was increased (P < 0.05) on the high-infusion day (25.8 +/- 1.6 vs. 34.7 +/- 4.1), ruling out cycling of glucose moieties through glycogen with release of glucose by debrancher enzyme as the source of glucose production.

To validate a method to “biochemically biopsy” the immediate precursor of intrahepatic glycogen [uridyl diphosphate (UDP)-glucose] using acetaminophen and to assess how fasting affects the direct and indirect pathways of glycogen synthesis, dogs were fasted overnight (group 1, n = 5) or for 2.5 days (group 2, n = 5) and then given a 4-h duodenal infusion of unlabeled glucose, [3-3H]glucose, and [U-14C]lactate to label hepatic glycogen via the direct and indirect pathways, respectively, and [1-13C]galactose to measure intrahepatic UDP-glucose flux. After 3 h for equilibration, acetaminophen was given and urine was collected for acetaminophen glucuronide. Multiple liver biopsies were obtained. The mean 3H/14C ratios of glucose derived from glycogen (10.4 +/- 4.1 and 1.1 +/- 0.3 for groups 1 and 2, respectively) and glucose derived from acetaminophen glucuronide (11.5 +/- 4.0 and 1.0 +/- 0.1 for groups 1 and 2, respectively) were similar. Fasting significantly increased UDP-glucose flux, the rate of glycogen synthesis, and the contribution of the indirect pathway. We conclude that, in dogs, 1) no functional hepatic zonation exists with regard to acetaminophen glucuronidation and liver glycogen synthesis and 2) with appropriate choice of isotopic tracers and study design, UDP-glucose flux can accurately reflect rates of hepatic glycogen synthesis.