Abstract Context Breast cancer survivors (BCS) face adverse physical and psychological symptoms, often co-occurring. Biologic and psychological factors may link symptoms within clusters, ...distinguishable by prevalence and/or severity. Few studies have examined the effects of behavioral interventions or treatment of symptom clusters. Objectives The aim of this study was to identify symptom clusters among post-treatment BCS and determine symptom cluster improvement following the Mindfulness-Based Stress Reduction for Breast Cancer (MBSR(BC)) program. Methods Three hundred twenty-two Stage 0–III post-treatment BCS were randomly assigned to either a six-week MBSR(BC) program or usual care. Psychological (depression, anxiety, stress, and fear of recurrence), physical (fatigue, pain, sleep, and drowsiness), and cognitive symptoms and quality of life were assessed at baseline, six, and 12 weeks, along with demographic and clinical history data at baseline. A three-step analytic process included the error-accounting models of factor analysis and structural equation modeling. Results Four symptom clusters emerged at baseline: pain, psychological, fatigue, and cognitive. From baseline to six weeks, the model demonstrated evidence of MBSR(BC) effectiveness in both the psychological (anxiety, depression, perceived stress and QOL, emotional well-being) ( P = 0.007) and fatigue (fatigue, sleep, and drowsiness) ( P < 0.001) clusters. Results between six and 12 weeks showed sustained effects, but further improvement was not observed. Conclusion Our results provide clinical effectiveness evidence that MBSR(BC) works to improve symptom clusters, particularly for psychological and fatigue symptom clusters, with the greatest improvement occurring during the six-week program with sustained effects for several weeks after MBSR(BC) training. Trial Registration Name and URL of Registry: ClinicalTrials.gov . Registration number: NCT01177124.
A Saskatchewan multi-incident family was clinically characterized with Parkinson disease (PD) and Lewy body pathology. PD segregates as an autosomal-dominant trait, which could not be ascribed to any ...known mutation. DNA from three affected members was subjected to exome sequencing. Genome alignment, variant annotation and comparative analyses were used to identify shared coding mutations. Sanger sequencing was performed within the extended family and ethnically matched controls. Subsequent genotyping was performed in a multi-ethnic case-control series consisting of 2928 patients and 2676 control subjects from Canada, Norway, Taiwan, Tunisia, and the USA. A novel mutation in receptor-mediated endocytosis 8/RME-8 (DNAJC13 p.Asn855Ser) was found to segregate with disease. Screening of cases and controls identified four additional patients with the mutation, of which two had familial parkinsonism. All carriers shared an ancestral DNAJC13 p.Asn855Ser haplotype and claimed Dutch-German-Russian Mennonite heritage. DNAJC13 regulates the dynamics of clathrin coats on early endosomes. Cellular analysis shows that the mutation confers a toxic gain-of-function and impairs endosomal transport. DNAJC13 immunoreactivity was also noted within Lewy body inclusions. In late-onset disease which is most reminiscent of idiopathic PD subtle deficits in endosomal receptor-sorting/recycling are highlighted by the discovery of pathogenic mutations VPS35, LRRK2 and now DNAJC13. With this latest discovery, and from a neuronal perspective, a temporal and functional ecology is emerging that connects synaptic exo- and endocytosis, vesicular trafficking, endosomal recycling and the endo-lysosomal degradative pathway. Molecular deficits in these processes are genetically linked to the phenotypic spectrum of parkinsonism associated with Lewy body pathology.
Purpose
Leptomeningeal disease is a rare and devastating presentation of advanced stage metastatic breast cancer with historically poor overall survival. We assessed the safety and feasibility of ...intrathecal (IT) trastuzumab in HER2+ leptomeningeal disease.
Methods
A total of 13 patients were treated at our institution with IT trastuzumab beginning November 2012 and followed until November 2017. Outcomes including craniospinal progression as well as overall survival (OS) following initiation of IT trastuzumab were assessed from review of the clinical chart and radiologic examinations.
Results
The median age of patients was 48 (range 29–75). Median time from breast cancer diagnosis to development of brain metastases was 87.7 months with a median of 4.6 months from brain metastases diagnosis to the development of leptomeningeal disease. Previous whole brain radiotherapy was received by the majority of patients (92%) and prior surgery for brain metastases was performed in 23%. Median duration of IT trastuzumab treatment was 6.4 months. Median time from IT trastuzumab start to craniospinal progression was 5.7 months with 6- and 12-month Kaplan–Meier rates of 41 and 21%, respectively. Sustained responses > 6 months were achieved in 4 patients. Median survival from the start of IT trastuzumab was 10.6 months with 6- and 12-month OS rates of 68 and 47%, respectively. IT trastuzumab was well tolerated with one patient developing ventriculitis, which resolved with IV antibiotics.
Conclusions
IT trastuzumab was well tolerated with prolongation of OS over historical controls. IT trastuzumab should be considered for management of HER2+ leptomeningeal disease patients.
Background: Emerging research and colloquial dialogues increasingly point to an uptick in non-binary gender identity endorsement, however research has failed to parallel this increase. For example, ...existing literature often conflates gender identity with sexual orientation, lumping TGNC people under the LGBTQ umbrella, thus rendering the "T" silent in the process. Further, extant research adheres to a binary (i.e., dichotomous male/female) conceptualization of gender, thus excluding individuals who identify as genderqueer, gender non-conforming, or otherwise non-binary as well as those who do not identify with the construct of gender at all (e.g., agender).
Method: This qualitative investigation utilized individual interviews with 15 TGNC adults. Data analysis employed two data-driven phases, first identifying themes consistent across the 15 transcripts to identify nuances in TGNC identity formation often missed by theory-driven models and second, establishing similarities and differences between binary and non-binary narratives.
Results: Results indicated that various helpful and challenging factors played a stronger role than chronology, physical transition, or activism across all participants which contrasts findings in extant literature. Further, while binary and non-binary narratives were similar in many regards, several noteworthy distinctions emerged. For example, the concepts of "passing or blending", intersections of gender identity with sexual orientation, and navigating identity presentation and disclosure were described differently for binary and non-binary participants.
Conclusions: Historically, the "T" in "LGBTQ" has often been rendered silent. These results indicate that non-binary narratives have been rendered doubly silent. Given the increasing preponderance of non-binary identifications and the unique needs and experiences of non-binary participants, it is crucial that professional and lay communities alike begin to take two steps moving forward: 1) explicitly acknowledge the existence of non-binary TGNC identities and 2) work to achieve fluency regarding the unique needs and experiences of this population.
Long-term data establishes the efficacy of radiotherapy in the adjuvant management of breast cancer. New dose and fractionation schemas have evolved and are available, each with unique risks and ...rewards. Current efforts are ongoing to tailor radiotherapy to the unique biology of breast cancer. In this review, we discuss our efforts to personalize radiotherapy dosing using genomic data and the implications for future clinical trials. We also explore immune mechanisms that may contribute to a tumor’s unique radiation sensitivity or resistance.
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Background: Pembro is an anti-PD-1 antibody with single agent activity in HER2– metastatic BC. I-SPY 2 is a multicenter, phase 2 platform trial which evaluates novel neoadjuvant ...therapies; the primary endpoint is pathological complete response (pCR, ypT0/Tis ypN0). We report current efficacy results, with final results at ASCO. Methods: Patients (pts) with invasive BC ≥2.5 cm by exam or ≥2 cm by imaging are assigned weekly paclitaxel x 12 (control) +/- an experimental agent, followed by doxorubicin/cyclophosphamide x 4. Combinations of hormone-receptor (HR), HER2, & MammaPrint (MP) status define the 8 signatures studied. MP low HR+ BC is excluded. Adaptive randomization is based on each arm’s Bayesian probability of superiority over control. Graduation by signature is based on an arm’s Bayesian predictive probability of a successful 1:1 randomized phase 3 trial with a pCR endpoint. We provide raw & Bayesian estimated pCR rates adjusted for covariates, time effects over the course of the trial, & serial MRI modeling for pts not yet assessed for pCR surgically. Results: 69 pts were randomized to pembro (HER2- subsets only) from Dec 2015 until it graduated in Nov 2016. 46 pts have undergone surgery (table); the other 23 have on-therapy MRI assessments. In 29 HR–/HER2– (TNBC) pts, pembro increased raw & estimated pCR rates by >50% & 40%, respectively; in 40 HR+/HER– pts, it did so by 13% and 21%. 5 pts had immune-related grade 3 adverse events (AEs); 1 hypophysitis & 4 adrenal insufficiency. 4 pts presented after completion of AC (149-179 d after starting pembro); 1 presented prior to AC (37 d after starting pembro). 7 pts had grade 1-2 thyroid abnormalities. Conclusion: Pembro added to standard therapy improved pCR rates in all HER2- BCs that meet I-SPY 2 eligibility, especially in TNBC. Immune-mediated AEs were observed; pt follow up is ongoing. Clinical trial information: NCT01042379. Table: see text
Approximately 25% of patients with early-stage breast cancer who receive (neo)adjuvant chemotherapy experience a recurrence within 5 years. Improvements in therapy are greatly needed.
To determine if ...pembrolizumab plus neoadjuvant chemotherapy (NACT) in early-stage breast cancer is likely to be successful in a 300-patient, confirmatory randomized phase 3 neoadjuvant clinical trial.
The I-SPY2 study is an ongoing open-label, multicenter, adaptively randomized phase 2 platform trial for high-risk, stage II/III breast cancer, evaluating multiple investigational arms in parallel. Standard NACT serves as the common control arm; investigational agent(s) are added to this backbone. Patients with ERBB2 (formerly HER2)-negative breast cancer were eligible for randomization to pembrolizumab between November 2015 and November 2016.
Participants were randomized to receive taxane- and anthracycline-based NACT with or without pembrolizumab, followed by definitive surgery.
The primary end point was pathologic complete response (pCR). Secondary end points were residual cancer burden (RCB) and 3-year event-free and distant recurrence-free survival. Investigational arms graduated when demonstrating an 85% predictive probability of success in a hypothetical confirmatory phase 3 trial.
Of the 250 women included in the final analysis, 181 were randomized to the standard NACT control group (median range age, 47 24.77 years). Sixty-nine women (median range age, 50 27-71 years) were randomized to 4 cycles of pembrolizumab in combination with weekly paclitaxel followed by AC; 40 hormone receptor (HR)-positive and 29 triple-negative. Pembrolizumab graduated in all 3 biomarker signatures studied. Final estimated pCR rates, evaluated in March 2017, were 44% vs 17%, 30% vs 13%, and 60% vs 22% for pembrolizumab vs control in the ERBB2-negative, HR-positive/ERBB2-negative, and triple-negative cohorts, respectively. Pembrolizumab shifted the RCB distribution to a lower disease burden for each cohort evaluated. Adverse events included immune-related endocrinopathies, notably thyroid abnormalities (13.0%) and adrenal insufficiency (8.7%). Achieving a pCR appeared predictive of long-term outcome, where patients with pCR following pembrolizumab plus chemotherapy had high event-free survival rates (93% at 3 years with 2.8 years' median follow-up).
When added to standard neoadjuvant chemotherapy, pembrolizumab more than doubled the estimated pCR rates for both HR-positive/ERBB2-negative and triple-negative breast cancer, indicating that checkpoint blockade in women with early-stage, high-risk, ERBB2-negative breast cancer is highly likely to succeed in a phase 3 trial. Pembrolizumab was the first of 10 agents to graduate in the HR-positive/ERBB2-negative signature.
ClinicalTrials.gov Identifier: NCT01042379.
Mutations in leucine-rich repeat kinase 2 (Lrrk2) are the most common genetic cause of Parkinson's disease (PD), a neurodegenerative disorder affecting 1-2% of those >65 years old. The ...neurophysiology of LRRK2 remains largely elusive, although protein loss suggests a role in glutamatergic synapse transmission and overexpression studies show altered dopamine release in aged mice. We show that glutamate transmission is unaltered onto striatal projection neurons (SPNs) of adult LRRK2 knockout mice and that adult animals exhibit no detectable cognitive or motor deficits. Basal synaptic transmission is also unaltered in SPNs of LRRK2 overexpressing mice, but they do exhibit clear alterations to D2-receptor-mediated short-term synaptic plasticity, behavioral hypoactivity and impaired recognition memory. These phenomena are associated with decreased striatal dopamine tone and abnormal dopamine- and cAMP-regulated phosphoprotein 32 kDa signal integration. The data suggest that LRRK2 acts at the nexus of dopamine and glutamate signaling in the adult striatum, where it regulates dopamine levels, presynaptic glutamate release via D2-dependent synaptic plasticity and dopamine-receptor signal transduction.
Abstract
At a time of growing enrollment among adult learners, student bodies are increasingly age diverse. Identifying and reducing age-related bias on campus may be multipurpose in supporting those ...who experience ageism while promoting professional skills to combat ageism in students' future careers. The extant literature has primarily focused on ageism in the workplace and ageism experienced by faculty and staff in higher education while less has focused on ageism experienced by adult students and the possible disruption this creates to feeling included as part of the campus community. We present data from a mixed methods study of adult learners assessing the extent to which they experience and are impacted by age-related bias on campus. Data are used to justify faculty and student training to improve intergenerational contact in the classroom and beyond under the broader umbrella of DEI initiatives.
Abnormal accumulation of TDP-43 into cytoplasmic or nuclear inclusions with accompanying nuclear clearance, a common pathology initially identified in amyotrophic lateral sclerosis (ALS) and ...frontotemporal dementia (FTD), has also been found in Alzheimer’ disease (AD). TDP-43 serves as a splicing repressor of nonconserved cryptic exons and that such function is compromised in brains of ALS and FTD patients, suggesting that nuclear clearance of TDP-43 underlies its inability to repress cryptic exons. However, whether TDP-43 cytoplasmic aggregates are a prerequisite for the incorporation of cryptic exons is not known. Here, we assessed hippocampal tissues from 34 human postmortem brains including cases with confirmed diagnosis of AD neuropathologic changes along with age-matched controls. We found that cryptic exon incorporation occurred in all AD cases exhibiting TDP-43 pathology. Furthermore, incorporation of cryptic exons was observed in the hippocampus when TDP-43 inclusions was restricted only to the amygdala, the earliest stage of TDP-43 progression. Importantly, cryptic exon incorporation could be detected in AD brains lacking TDP-43 inclusion but exhibiting nuclear clearance of TDP-43. These data supports the notion that the functional consequence of nuclear depletion of TDP-43 as determined by cryptic exon incorporation likely occurs as an early event of TDP-43 proteinopathy and may have greater contribution to the pathogenesis of AD than currently appreciated. Early detection and effective repression of cryptic exons in AD patients may offer important diagnostic and therapeutic implications for this devastating illness of the elderly.
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