Therapeutic strategies in male breast cancer: Clinical implications of chromosome 17 gene alterations and molecular subtypes

Male breast cancer (MBC) is a rare disease. To date, therapy is mainly based on studies and clinical experiences with breast cancer in women. Only little is known about molecular typing of MBC, particularly with regard to potential biological predictors for adjuvant therapy. In female breast cancer tumors with chromosome 17 centromere (CEP17) duplication, HER2 and/or Topoisomerase II alpha (Topo II-α) gene alterations have been suggested to be associated with poor prognosis and increased sensitivity to anthracycline-containing regimens.In a well characterized cohort of 96 primary invasive MBC, we studied CEP17, HER2 and Topo II-α alterations by fluorescence in-situ hybridization (FISH), and expression of hormone receptors (HR), HER2 and Ki67 by immunohistochemistry to define molecular subtypes. Tumor characteristics and follow-up data were available and correlated with molecular findings.HER2 amplification and Topo II-α amplification/deletion were exceptionally rare in MBC (6.3% and 3.1%, respectively). CEP17 polysomy were found in 9.4% of tumors. HER2, Topo II-α and CEP17 gene alterations were not correlated to patients outcome. 96.9% of our cases were HR positive. Triple negative tumors were found in only 3.1% of the cases. In nodal negative tumors luminal A subtypes were significantly associated with better overall survival.Our results provide evidence for a predominant male breast cancer phenotype, characterized by HR expression and a lack of HER2/Topo II-α alterations and CEP17 duplicates. Therefore, the impact of anthracycline sensitivity linked to HER2/Topo II-α alterations as found in female breast cancer has low clinical significance for this specific male breast cancer phenotype.     

Histone deacetylase inhibitors as potential therapeutic approaches for chordoma: An immunohistochemical and functional analysis

Chordomas are rare malignancies of the axial skeleton. Therapy is mainly restricted to surgery. This study investigates histone deacetylase (HDAC) inhibitors as potential therapeutics for chordomas. Immunohistochemistry (IHC) was performed using the HDAC 1–6 antibodies on 50 chordoma samples (34 primary tumors, 16 recurrences) from 44 patients (27 male, 17 female). Pan‐HDAC‐inhibitors Vorinostat (SAHA), Panobinostat (LBH‐589), and Belinostat (PXD101) were tested for their efficacy in the chordoma cell line MUG‐Chor1 via Western blot, cell cycle analysis, caspase 3/7 activity (MUG‐Chor1, UCh‐1), cleaved caspase‐3, and PARP cleavage. p‐Values below 0.05 were considered significant. IHC was negative for HDAC1, positive for HDAC2 in most (n = 36; 72%), and for HDACs 3–6 in all specimens available (n = 43; 86%). HDAC6 expression was strongest. SAHA and LBH‐589, but not PXD101 caused a significant increase of G2/M phase cells and of cleaved caspase‐3 (p = 0.0003, and p = 0.0014 after 72 h, respectively), and a peak of caspase 3/7 activity. PARP cleavage confirmed apoptosis. The presented chordoma series expressed HDACs 2–6 with strongest expression of HDAC6. SAHA and LBH‐589 significantly increased apoptosis and changed cell cycle distribution in vitro. HDAC‐inhibitors should be further evaluated as therapeutic options for chordoma. © 2013 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 31:1999–2005, 2013     

Eradication of chronic methicillin-resistant Staphylococcus aureus infection in cystic fibrosis patients. An observational prospective cohort study of 11 patients

BackgroundChronic airway infection with methicillin-resistant Staphylococcus aureus (MRSA) in patients with cystic fibrosis (CF) is an increasing clinical problem, and therapeutic options are limited. Because chronic infection with MRSA can be associated with accelerated decline in lung function, eradication of MRSA is attempted in most CF centres today. The aim of this observational prospective cohort study was to determine whether it is possible to eradicate MRSA from airways of CF patients using prolonged oral antibiotic combination therapy together with topical decolonization measures.ResultsEleven CF patients, (median age: 9 years (range 1–43); median FEV₁: 91%pred (95%CI 74%–100%pred)) who were chronically infected with MRSA, were treated daily for six months with rifampicin and fusidic acid orally. This study did not include a patient control group. Two patients had to switch to an alternative schedule, using rifampicin and clindamycin, due to the resistance pattern of MRSA. Topical decolonization measures were applied to all patients and included mupirocin-containing nasal ointment in both nostrils three times daily for five days and chlorhexidine hair and body wash once daily for five days. Microbiological eradication was achieved in all patients at the end of the six-month eradication protocol, even when significant time (range 18 months to 9 years) had elapsed since initial isolation. In only one patient MRSA reappeared in the six-month follow-up period after the initial study period. Side-effects, like nausea, vomiting and diarrhoea were seen in five out of eleven patients, but did not lead to therapy cessation.ConclusionChronic MRSA infection can be eradicated from respiratory tract samples using a six month dual antibiotic regimen and topical MRSA decolonization measures.     

Cell-Based Therapy for the Deficient Urinary Sphincter

When sterile culture techniques of mammalian cells first became state of the art, there was tremendous anticipation that such cells could be eventually applied for therapeutic purposes. The discovery of adult human stem or progenitor cells further motivated scientists to pursue research in cell-based therapies. Although evidence from animal studies suggests that application of cells yields measurable benefits, in urology and many other disciplines, progenitor-cell-based therapies are not yet routinely clinically available. Stress urinary incontinence (SUI) is a condition affecting a large number of patients. The etiology of SUI includes, but is not limited to, degeneration of the urinary sphincter muscle tissue and loss of innervation, as well as anatomical and biomechanical causes. Therefore, different regimens were developed to treat SUI. However, at present, a curative functional treatment is not at hand. A progenitor-cell-based therapy that can tackle the etiology of incontinence, rather than the consequences, is a promising strategy. Therefore, several research teams have intensified their efforts to develop such a therapy for incontinence. Here, we introduce candidate stem and progenitor cells suitable for SUI treatment, show how the functional homogeneity and state of maturity of differentiated cells crucial for proper tissue integration can be assessed electrophysiologically prior to their clinical application, and discuss the trophic potential of adult mesenchymal stromal (or stem) cells in regeneration of neuronal function.     

Structural Brain Alterations Associated With Schizophrenia Preceded by Conduct Disorder: A Common and Distinct Subtype of Schizophrenia?

Conduct disorder (CD) prior to age 15 is a precursor of schizophrenia in a minority of cases and is associated with violent behavior through adulthood, after taking account of substance misuse. The present study used structural magnetic imaging to examine gray matter (GM) volumes among 27 men with schizophrenia preceded by CD (SZ+CD), 23 men with schizophrenia but without CD (SZ–CD), 27 men with CD only (CD), and 25 healthy (H) men. The groups with schizophrenia were similar in terms of age of onset and duration of illness, levels of psychotic symptoms, and medication. The 2 groups with CD were similar as to number of CD symptoms, lifelong aggressive behavior, and number of criminal convictions. Men with SZ+CD, relative to those with SZ–CD, displayed (1) increased GM volumes in the hypothalamus, the left putamen, the right cuneus/precuneus, and the right inferior parietal cortex after controlling for age, alcohol, and drug misuse and (2) decreased GM volumes in the inferior frontal region. Men with SZ+CD (relative to the SZ–CD group) and CD (relative to the H group) displayed increased GM volumes of the hypothalamus and the inferior and superior parietal lobes, which were not associated with substance misuse. Aggressive behavior, both prior to age 15 and lifetime tendency, was positively correlated with the GM volume of the hypothalamus. Thus, among males, SZ+CD represents a distinct subtype of schizophrenia. Although differences in behavior emerge in childhood and remain stable through adulthood, further research is needed to determine whether the differences in GM volumes result from abnormal neural development distinct from that of other males developing schizophrenia.Key words: conduct problems, antisocial behavior, violence, structural brain alterationsMany years ago, Lee Robins found that conduct disorder (CD) was a precursor of schizophrenia ¹ and later confirmed this finding. ^{2 , 3} Subsequent evidence concurs. For example, a prospective investigation that followed a birth cohort to age 26 determined that 40% of the cohort members who developed schizophreniform disorders had displayed CD prior to age 15. ⁴ The CD modules of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental (DSM) disorders (fourth edition, DSM-IV), SCID in short, were designed to diagnose CD prior to age 15 among adults. ⁵ Several studies have used this interview protocol, some supplementing self-reports with information from family members, school, social service, and justice files, to diagnose CD among adults with schizophrenia. Among men and women with schizophrenia in general psychiatric services, the prevalence of CD prior to age 15 ranged from 20% to 45%, ^{6 , 7} with higher rates in samples recruited from forensic hospitals and correctional facilities. ⁶ CD is a precursor of schizophrenia, and it is more common among people with schizophrenia than in the general population. ⁶ Among people with schizophrenia, CD prior to age 15 continues to be associated with antisocial and violent behavior through adult life after taking account of past and current substance misuse. ^6–12 Among people with schizophrenia, ^{10 , 13–17} as in the general population, ^18–20 those who present CD in childhood commit a disproportionate number of violent crimes. While some studies show that positive symptoms are associated with aggressive behavior even after taking account of CD, ²¹ those with CD are not distinguished from other patients with schizophrenia by profiles of positive and negative symptoms. ²² Prospective investigations show that adults with schizophrenia and prior CD (SZ+CD) displayed aggressive behavior, psychotic-like experiences as children, ²³ and poor academic achievement. ²⁴ Retrospective studies report that adults with SZ+CD, as compared to those with SZ–CD, obtained lower-than-average marks in elementary school, failed to graduate from secondary school, abused substances in adolescence, and experienced physical abuse. ^{6 , 24–27} Criminality and substance misuse are elevated among fathers and brothers of men with SZ+CD, whereas rates of mental illness are similar to that found among patients with SZ–CD. ^{6 , 27 , 28} Among the non–mentally ill men, a small group present CD from an early age, persistent antisocial and aggressive behavior through adulthood, and abnormalities in brain structure relative to healthy men. ^29–37 Results of structural magnetic resonance imaging studies (sMRI) measuring gray matter (GM) volumes are inconsistent regarding the type (larger or smaller) and regions of abnormality. ^{32 , 35–37} Among men with SZ+CD, however, there no studies. ^{38 , 39} A few studies of brain structure have been conducted among men with schizophrenia who display different ages of onset and patterns of aggressive behavior, including persistent aggressive behavior and poor response to antipsychotic medication, no previous aggressive behavior and 1 violent offence, no aggressive behavior prior to onset followed by persistent aggression, and finally the largest group comprising those who show conduct problems from childhood that persist across their life span. The extant literature is limited and difficult to aggregate, but it does suggest differences specific to each pattern of violent behavior. ^38–43 Two studies examined male offenders with schizophrenia: one compared those with and without comorbid antisocial personality disorder (ASPD), which requires, by definition, CD prior to age 15; ⁴⁴ and another compared those with and without high psychopathy scores. ⁴⁵ Both included small samples and reported fewer neuropsychological deficits among the antisocial participants in tests tapping the dorsolateral prefrontal and the orbital frontal cortex (OFC) functions. ³⁸ A recent meta-analysis reported that among persons with schizophrenia, those defined very broadly as antisocial, as compared to the nonantisocial, were characterized by lower intelligence quotients (IQs) and memory dysfunction, whereas compared to non–mentally ill antisocial participants, they exhibited deficits in IQ, attention, executive function, and memory. ⁴⁶ Among patients with schizophrenia, scores on the Life History of Aggression (LHA) measure were associated with increased diffusivity in the inferior frontal white matter and lower functional connectivity between the amygdala and the ventral prefrontal cortex. ³⁹ Diffusivity has been associated with increased cerebrospinal fluid (CSF). ⁴⁷ Functional MRI (fMRI) studies of violent offenders with schizophrenia observed decreased frontal basal activation during a Go/NoGo task, increased activity in the motor, premotor, and anterior cingulate regions among those with ASPD, ⁴⁸ and attenuated amygdala activation to fearful faces among those with high psychopathy scores. ⁴⁹ Thus, among men with schizophrenia, at least one in five people presents CD prior to age 15 and persistent antisocial and aggressive behavior. Identifying distinctive subtypes of schizophrenia may facilitate etiological research ⁵⁰ and inform the development of effective treatments for both the illness and the antisocial and aggressive behavior. ⁵¹ Both schizophrenia ⁵² and CD ^{53 , 54} are neurodevelopmental disorders. In both disorders, from conception onwards, combinations of genes, in addition and in interaction with environmental events, are thought to modify brain structure and function. Thus, we reasoned that when schizophrenia develops in parallel with CD, neurodevelopment would be distinct from both that associated with schizophrenia and that associated with CD. We hypothesized that in adulthood, men with SZ+CD would show cognitive and structural brain abnormalities relative to healthy men, and both similarities and differences relative to men with SZ–CD and those with CD and no mental illness.Almost all persons with childhood onset of CD and persistence of antisocial and aggressive behavior in adulthood also display childhood onset and persistent pattern of substance misuse. ^55–57 This is true among those with and without schizophrenia. ^{22 , 26–28} Although substance misuse is an integral part of a heritable pattern of lifelong antisocial behavior, ⁵⁸ disentangling the cognitive and structural abnormalities consequent to substance use from those associated with persistent antisocial and aggressive behavior is necessary to understand the mechanisms underlying these behaviors. However, neither statistical controls nor studying groups of antisocial persons without substance misuse provide an ideal solution to this problem. ⁵⁹ Further, prospective studies indicate that heavy cannabis use in adolescence may play a causal role in schizophrenia ^{60 , 61} by altering brain development, ^{62 , 63} and 1 study has shown that among persons experiencing a first episode of psychosis, CD increased the likelihood of cannabis use before age 14. ⁶⁴ In addition, histories of substance misuse that can be obtained from middle-aged adults are imprecise measures of different phenomena—past and current use by type, combinations, and doses of substances. This led us to obtain careful histories of use of substances and to statistically control for group differences in use.Four groups of men, with SZ+CD, SZ–CD, CD, and no schizophrenia or history of CD (H), were compared on sociodemographic, clinical, and forensic characteristics, and their GM brain volumes were assessed using sMRI.     

Associations among attachment characteristics,patients’ assessment of therapeutic factors,and treatment outcome following inpatient psychodynamic group psychotherapy

Abstract

Within a multisite study, including 289 inpatients from six different hospitals who underwent interpersonal-psychodynamic group psychotherapy, associations among attachment characteristics, therapeutic factors, and treatment outcome were investigated. Attachment characteristics were assessed with an interview-based measure (Adult Attachment Prototype Rating [AAPR]) as well as an attachment self-report (Bielefeld Questionnaire of Client Expectations [BQCE]). Therapeutic factors were measured retrospectively with the Düsseldorf Therapeutic Factors Questionnaire and treated as an individual- as well as a hospital-specific characteristic. On an individual level, only the group climate factor independently predicted treatment outcome (i.e., Symptom Checklist-90-R Global Severity Index and Inventory of Interpersonal Problems mean). If simultaneously but separately included into a path model, analyses revealed independent significant effects of AAPR-Security and BQCE-Security on group climate. If modeled as a latent variable (common attachment security), a substantially higher proportion of group climate variance could be explained. Further analyses revealed interactions between particular therapeutic factors and attachment characteristics, indicating a particular importance of these therapeutic factors for different attachment categories.     

Genetic fate mapping of type‐1 stem cell‐dependent increase in newborn hippocampal neurons after electroconvulsive seizures

Electroconvulsive therapy (ECT) is a uniquely effective treatment for major depressive disorder. An increase in hippocampal neurogenesis is implicated in the recovery from depression. We used an inducible genetic mouse model in which only GFAP‐expressing stem‐like cells (type‐1 cells) and their progeny are selectively labeled with the reporter protein β‐galactosidase to track the process of neurogenesis in the dentate gyrus over 3 months following electroconvulsive seizures (ECS), the mouse equivalent of ECT. All ECS protocols tested induced a transient increase in type‐1 cell divisions. While this led to an expansion of the type‐1 cell pool after high‐frequency ECS sessions for 5 consecutive days (5‐ECS), asymmetric divisions drove neurogenesis by giving rise to Doublecortin (DCX)‐expressing neuroblasts that matured into NeuN+ neurons. Significantly, the increase in newly generated DCX+ and NeuN+ cells after 5‐ECS could be traced back to proliferating type‐1 cells. Low‐frequency continuation ECS (c‐ECS) consisting of five single ECS sessions administered every 2 weeks resulted in a similar increase in newborn neurons as the high‐frequency 5‐ECS protocol. Moreover, the combination of 5‐ECS and c‐ECS led to a further significant increase in newborn neurons, suggesting a cellular mechanism responsible for the propitious effects of high‐frequency ECT followed by continuation ECT in severely depressed patients. The ability of high‐ and low‐frequency ECS to induce normally quiescent type‐1 cells to proliferate and generate new neurons sets it apart from other antidepressant treatments and may underlie the superior clinical efficacy of ECT. © 2013 Wiley Periodicals, Inc.     

Head‐pelvis coupling is increased during turning in patients with Parkinson's disease and freezing of gait

Turning is the most important trigger for freezing of gait (FOG). The aim of this study was to investigate the relationship between impaired head‐pelvis rotation during turning and FOG. Head, trunk, and pelvic rotation were measured at onset and throughout a 180‐degree turn in 13 freezers and 14 nonfreezers (OFF medication). We also studied 14 controls at preferred and slow speed to investigate the influence of turn velocity on axial rotation. Location and duration of FOG episodes were defined during the turn. At turning onset, head rotation preceded thorax and pelvic rotation in all groups, but this craniocaudal sequence disappeared when FOG occurred. Maximum head‐pelvis separation was significantly greater in controls, compared to freezers and nonfreezers (35.4 versus 25.7 and 27.3 degrees; P < 0.01), but this finding was speed dependent. Timing of maximum head‐pelvis separation was delayed in freezers, compared to nonfreezers and controls, irrespective of turn velocity. This delay was correlated with increased neck rigidity (R = 0.62; P = 0.02) and worsened during FOG trials. FOG occurred more often at the end of the turn, when difference in rotation velocity between head and pelvis was greatest. Even after controlling for speed and disease severity, turning in freezers was characterized by delayed head rotation and a closer coupling between head and pelvis, especially in turns where FOG occurred. These changes may be attributed to delayed preparation for the change in walking direction and, as such, contribute to FOG. © 2013 Movement Disorder Society     

Neural response to emotional stimuli during experimental human endotoxemia

Increases in peripheral cytokines during acute inflammation may affect various neuropsychological functions. The aim of this functional magnetic resonance imaging (fMRI) study was to investigate the effects of acute endotoxemia on mood and the neural response to emotionally aversive visual stimuli in healthy human subjects. In a double‐blind, randomized crossover study, 18 healthy males received a bolus injection of bacterial lipopolysaccharide (LPS; 0.4 ng/kg) or saline. Plasma levels of pro‐ and anti‐inflammatory cytokines and cortisol as well as mood ratings were analyzed together with the blood‐oxygen‐level dependent (BOLD) response during the presentation of aversive versus neutral pictures. Endotoxin administration induced pronounced transient increases in plasma levels of TNF‐α, IL‐1ra, IL‐6, IL‐10, and cortisol. Positive mood was decreased and state anxiety increased. In addition, activation of right inferior orbitofrontal cortex (OFC) in response to emotional visual stimuli was significantly increased in the LPS condition. Increased prefrontal activation during the presentation of emotional material may reflect enhanced cognitive regulation of emotions as an adaptive response during an acute inflammation. These findings may have implications for the putative role of inflammatory processes in the pathophysiology of depression. Hum Brain Mapp 34:2217–2227, 2013. © 2012 Wiley Periodicals, Inc.     

Correction to: The Bright Side of Grit in Burnout-Prevention: Exploring Grit in the Context of Demands-Resources Model among Chinese High School Students

Child Psychiatry & Human Development - A correction to this paper has been published: https://doi.org/10.1007/s10578-021-01198-3