Microglia Require CD4 T Cells to Complete the Fetal-to-Adult Transition.

The brain is a site of relative immune privilege. Although CD4 T cells have been reported in the central nervous system, their presence in the healthy brain remains controversial, and their function remains largely unknown. We used a combination of imaging, single cell, and surgical approaches to identify a CD69+ CD4 T cell population in both the mouse and human brain, distinct from circulating CD4 T cells. The brain-resident population was derived through in situ differentiation from activated circulatory cells and was shaped by self-antigen and the peripheral microbiome. Single-cell sequencing revealed that in the absence of murine CD4 T cells, resident microglia remained suspended between the fetal and adult states. This maturation defect resulted in excess immature neuronal synapses and behavioral abnormalities. These results illuminate a role for CD4 T cells in brain development and a potential interconnected dynamic between the evolution of the immunological and neurological systems. VIDEO ABSTRACT.

Factors associated with insomnia symptoms over three years among premenopausal women with breast cancer.

PURPOSE: We examined longitudinal trends and factors associated with insomnia over 3 years in a cohort of young breast cancer patients. METHODS: Women with stage I-III breast cancer at ≤ 45 years were recruited at five institutions from New York, Texas, and North Carolina, within 8 months of diagnosis (n = 836). Participants completed questionnaires every 6 months for 3 years. Linear mixed-effects models were used to examine insomnia over time, using the Women's Health Initiative Insomnia Rating Scale (WHIIRS). We evaluated the relations of insomnia with demographic (age, race, education, income, employment, marital status), clinical (cancer stage, histologic grade, chemotherapy, radiation, hormone therapy, surgery, tumor size, body mass index, hot flashes), and social/behavioral variables (smoking status, social support, physical activity, depressive symptoms). RESULTS: At baseline, 57% of participants met or exceeded the cut-off for clinical insomnia (WHIIRS score ≥ 9). Insomnia symptoms were most prevalent at baseline (p < 0.0001), but decreased significantly throughout follow-up (p < 0.001). However, 42% of participants still experienced insomnia symptoms 3 years after diagnosis. In multivariable models, older age (p = 0.02), hot flashes (p < 0.0001), and depressive symptoms (p < 0.0001) remained significantly associated with insomnia over time. CONCLUSIONS: Insomnia symptoms were most frequent closer to breast cancer diagnosis and treatment, but persisted for some women who were older and those reporting higher hot flashes and depressive symptoms. Survivorship care should include assessing insomnia symptoms, particularly during and immediately after primary treatment. Implementing early interventions for sleep problems may benefit young breast cancer survivors and improve their quality of life.

Central and peripheral myeloid-derived suppressor cell-like cells are closely related to the clinical severity of multiple sclerosis.

Multiple sclerosis (MS) is a highly heterogeneous demyelinating disease of the central nervous system (CNS) that needs for reliable biomarkers to foresee disease severity. Recently, myeloid-derived suppressor cells (MDSCs) have emerged as an immune cell population with an important role in MS. The monocytic-MDSCs (M-MDSCs) share the phenotype with Ly-6Chi-cells in the MS animal model, experimental autoimmune encephalomyelitis (EAE), and have been retrospectively related to the severity of the clinical course in the EAE. However, no data are available about the presence of M-MDSCs in the CNS of MS patients or its relation with the future disease aggressiveness. In this work, we show for the first time cells exhibiting all the bona-fide phenotypical markers of M-MDSCs associated with MS lesions, whose abundance in these areas appears to be directly correlated with longer disease duration in primary progressive MS patients. Moreover, we show that blood immunosuppressive Ly-6Chi-cells are strongly related to the future severity of EAE disease course. We found that a higher abundance of Ly-6Chi-cells at the onset of the EAE clinical course is associated with a milder disease course and less tissue damage. In parallel, we determined that the abundance of M-MDSCs in blood samples from untreated MS patients at their first relapse is inversely correlated with the Expanded Disability Status Scale (EDSS) at baseline and after a 1-year follow-up. In summary, our data point to M-MDSC load as a factor to be considered for future studies focused on the prediction of disease severity in EAE and MS.

Reaching Populations to Address Disparities in Cancer Care Delivery: Results From a Six-Site Initiative.

BACKGROUND: Large segments of the US population do not receive quality cancer care due to pervasive and systemic inequities, which can increase morbidity and mortality. Multicomponent, multilevel interventions can address inequities and improve care, but only if they reach communities with suboptimal access. Intervention studies often underenroll individuals from historically excluded groups. METHODS: The Alliance to Advance Patient-Centered Cancer Care includes 6 grantees across the United States who implemented unique multicomponent, multilevel intervention programs with common goals of reducing disparities, increasing engagement, and improving the quality of care for targeted populations. The Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework informed the evaluation efforts across sites. Each Alliance site identified their intended populations, which included underrepresented minorities (eg, Black and Latinx persons), individuals who prefer a language other than English, and rural residents. We evaluated the demographic characteristics of participants to determine program reach. RESULTS: Between 2018 and 2020, a total of 2,390 of 5,309 potentially eligible participants were enrolled across the 6 sites. The proportion of enrolled individuals with selected characteristics included 38% (n=908) Black adults, 24% (n=574) Latinx adults, 19% (n=454) preferring a language other than English, and 30% (n=717) rural residents. The proportion of those enrolled who were the intended population was commensurate to the proportion with desired characteristics in those identified as potentially eligible. CONCLUSIONS: The grantees met or exceeded enrollments from their intended populations who have been underserved by quality cancer care into patient-centered intervention programs. Intentional application of recruitment/engagement strategies is needed to reach individuals from historically underserved communities.

Feasibility of an embedded palliative care clinic model for patients with an advanced thoracic malignancy.

PURPOSE: Early palliative care (PC) with standard oncology care has demonstrated improved patient outcomes, but multiple care delivery models are utilized. This study prospectively evaluated the feasibility of an embedded PC clinic model and collected patient-reported outcomes (PROs) and caregiver needs. METHODS: In this observational study of embedded outpatient PC for patients with advanced thoracic malignancies treated at The Ohio State University Thoracic Oncology clinic, patients received same-day coordinated oncology and palliative care visits at one clinic location. PC encounters included comprehensive symptom assessment and management, advanced care planning, and goals of care discussion. Multiple study assessments were utilized. We describe the feasibility of evaluating PROs and caregiver needs in an embedded PC model. RESULTS: Forty patients and 28 caregivers were enrolled. PROs were collected at baseline and follow-up visits. Over a 12-month follow-up, 36 patients discontinued study participation due to hospice enrollment, death, study withdrawal, or COVID restrictions. At baseline, 32 patients (80%) rated distress as moderate-severe with clinically significant depression (44%) and anxiety (36%). Survey completion rates significantly decreased over time: 3 months (24 eligible, 66% completed), 6 months (17 eligible; 41% completed), 9 months (9 eligible; 44% completed), and 12 months (4 eligible; 50% completed). CONCLUSION: We found that an embedded PC clinic was feasible, although there were challenges encountered in longitudinal collection of PROs due to high study attrition. Ongoing assessment and expansion of this embedded PC model will continue to identify strengths and challenges to improve patient and caregiver outcomes.

Dynamic CCN3 expression in the murine CNS does not confer essential roles in myelination or remyelination.

CCN3 is a matricellular protein that promotes oligodendrocyte progenitor cell differentiation and myelination in vitro and ex vivo. CCN3 is therefore a candidate of interest in central nervous system (CNS) myelination and remyelination, and we sought to investigate the expression and role of CCN3 during these processes. We found CCN3 to be expressed predominantly by neurons in distinct areas of the CNS, primarily the cerebral cortex, hippocampus, amygdala, suprachiasmatic nuclei, anterior olfactory nuclei, and spinal cord gray matter. CCN3 was transiently up-regulated following demyelination in the brain of cuprizone-fed mice and spinal cord lesions of mice injected with lysolecithin. However, CCN3-/- mice did not exhibit significantly different numbers of oligodendroglia or differentiated oligodendrocytes in the healthy or remyelinating CNS, compared to WT controls. These results suggest that despite robust and dynamic expression in the CNS, CCN3 is not required for efficient myelination or remyelination in the murine CNS in vivo.

Sugar-Sweetened and Artificially Sweetened Beverages and Risk of Liver Cancer and Chronic Liver Disease Mortality.

Importance: Approximately 65% of adults in the US consume sugar-sweetened beverages daily. Objective: To study the associations between intake of sugar-sweetened beverages, artificially sweetened beverages, and incidence of liver cancer and chronic liver disease mortality. Design, Setting, and Participants: A prospective cohort with 98 786 postmenopausal women aged 50 to 79 years enrolled in the Women's Health Initiative from 1993 to 1998 at 40 clinical centers in the US and were followed up to March 1, 2020. Exposures: Sugar-sweetened beverage intake was assessed based on a food frequency questionnaire administered at baseline and defined as the sum of regular soft drinks and fruit drinks (not including fruit juice); artificially sweetened beverage intake was measured at 3-year follow-up. Main Outcomes and Measures: The primary outcomes were (1) liver cancer incidence, and (2) mortality due to chronic liver disease, defined as death from nonalcoholic fatty liver disease, liver fibrosis, cirrhosis, alcoholic liver diseases, and chronic hepatitis. Cox proportional hazards regression models were used to estimate multivariable hazard ratios (HRs) and 95% CIs for liver cancer incidence and for chronic liver disease mortality, adjusting for potential confounders including demographics and lifestyle factors. Results: During a median follow-up of 20.9 years, 207 women developed liver cancer and 148 died from chronic liver disease. At baseline, 6.8% of women consumed 1 or more sugar-sweetened beverage servings per day, and 13.1% consumed 1 or more artificially sweetened beverage servings per day at 3-year follow-up. Compared with intake of 3 or fewer servings of sugar-sweetened beverages per month, those who consumed 1 or more servings per day had a significantly higher risk of liver cancer (18.0 vs 10.3 per 100 000 person-years [P value for trend = .02]; adjusted HR, 1.85 [95% CI, 1.16-2.96]; P = .01) and chronic liver disease mortality (17.7 vs 7.1 per 100 000 person-years [P value for trend <.001]; adjusted HR, 1.68 [95% CI, 1.03-2.75]; P = .04). Compared with intake of 3 or fewer artificially sweetened beverages per month, individuals who consumed 1 or more artificially sweetened beverages per day did not have significantly increased incidence of liver cancer (11.8 vs 10.2 per 100 000 person-years [P value for trend = .70]; adjusted HR, 1.17 [95% CI, 0.70-1.94]; P = .55) or chronic liver disease mortality (7.1 vs 5.3 per 100 000 person-years [P value for trend = .32]; adjusted HR, 0.95 [95% CI, 0.49-1.84]; P = .88). Conclusions and Relevance: In postmenopausal women, compared with consuming 3 or fewer servings of sugar-sweetened beverages per month, those who consumed 1 or more sugar-sweetened beverages per day had a higher incidence of liver cancer and death from chronic liver disease. Future studies should confirm these findings and identify the biological pathways of these associations.

Implementing patient navigation programs: Considerations and lessons learned from the Alliance to Advance Patient-Centered Cancer Care.

BACKGROUND: Six multidisciplinary cancer centers were selected and funded by the Merck Foundation (2017-2021) to collaborate in the Alliance to Advance Patient-Centered Cancer Care ("Alliance"), an initiative to improve patient access, minimize health disparities, and enhance the quality of patient-centered cancer care. These sites share their insights on implementation and expansion of their patient navigation efforts. METHODS: Patient navigation represents an evidence-based health care intervention designed to enhance patient-centered care and care coordination. Investigators at 6 National Cancer Institute-designated cancer centers outline their approaches to reducing health care disparities and synthesize their efforts to ensure sustainability and successful transferability in the management of patients with cancer and their families in real-world health care settings. RESULTS: Insights are outlined within the context of patient navigation program effectiveness and supported by examples from Alliance cancer center sites: 1) understand the patient populations, particularly underserved and high-risk patients; 2) capitalize on the existing infrastructure and institutional commitment to support and sustain patient navigation; and 3) build capacity by mobilizing community support outside of the cancer center. CONCLUSIONS: This process-level article reflects the importance of collaboration and the usefulness of partnering with other cancer centers to share interdisciplinary insights while undergoing intervention development, implementation, and expansion. These collective insights may be useful to staff at other cancer centers that look to implement, enhance, or evaluate the effectiveness of their patient navigation interventions.

The relationship between sleep and weight change among women diagnosed with breast cancer participating in the Women's Health Initiative.

PURPOSE: Short and long sleep duration and poor sleep quality are risk factors for weight gain and cancer mortality. The purpose of this study is to investigate the relationship between sleep and weight change among postmenopausal breast cancer survivors. METHODS: Women participating in the Women's Health Initiative who were diagnosed with incident breast cancer between year one and year three were included. Self-reported sleep duration was categorized as ≤ 5 h (short), 6 h, 7-8 h (optimal), and ≥ 9 h (long). Self-reported sleep quality was categorized as poor, average, and above average. Post-diagnosis weight change was the difference of weight closest to, but preceding diagnosis, and year 3 weight. We used linear regression to evaluate sleep duration and sleep quality associations with post-diagnosis weight change adjusted for potential confounders. RESULTS: Among 1156 participants, 63% were weight stable after diagnosis; average weight gain post cancer diagnosis was 3.2 kg. Six percent of women reported sleeping ≤ 5 h, 26% reported 6 h, 64% reported 7-8 h, and 4% reported ≥ 9 h. There were no differences in adjusted estimates of weight change among participants with short duration (0.37 kg; 95% CI - 0.88, 1.63), or long duration (- 0.56 kg; 95% CI - 2.03, 0.90) compared to optimal duration, nor was there a difference among poor quality (- 0.51 kg; 95% CI - 1.42, 0.41) compared to above average quality. CONCLUSION: Among postmenopausal breast cancer survivors, sleep duration and quality were not associated with weight change after breast cancer diagnosis. Future studies should consider capturing change in adiposity and to expand beyond self-reported sleep.

Bayesian semiparametric joint modeling of longitudinal explanatory variables of mixed types and a binary outcome.

Many prospective biomedical studies collect longitudinal clinical and lifestyle data that are both continuous and discrete. In some studies, there is interest in the association between a binary outcome and the values of these longitudinal measurements at a specific time point. A common problem in these studies is inconsistency in timing of measurements and missing follow-ups which can lead to few measurements at the time of interest. Some methods have been developed to address this problem, but are only applicable to continuous measurements. To address this limitation, we propose a new class of joint models for a binary outcome and longitudinal explanatory variables of mixed types. The longitudinal model uses a latent normal random variable construction with regression splines to model time-dependent trends in mean with a Dirichlet Process prior assigned to random effects to relax distribution assumptions. We also standardize timing of the explanatory variables by relating the binary outcome to imputed longitudinal values at a set time point. The proposed model is evaluated through simulation studies and applied to data from a cancer survivor study of participants in the Women's Health Initiative.

Social Support, social ties, and cognitive function of women with breast cancer: findings from the Women's Health Initiative (WHI) Life and Longevity After Cancer (LILAC) Study.

PURPOSE: This study examined associations between self-reported cognitive functioning and social support as well as social ties among women with breast cancer. METHODS: The study included 3351 women from the Women's Health Initiative Life and Longevity After Cancer cohort who were diagnosed with breast cancer stages I-III. Social support was assessed using a modified Medical Outcomes Study (MOS) Social Support Survey, and marital status was obtained from the baseline questionnaire. We also assessed social ties (e.g., number of friends, relatives, living children) and cognitive function (Functional Assessment of Cancer Therapy-Cognitive Function [FACT-COG]) on the year-1-follow up questionnaire. Multivariable quantile regression was used to estimate the changes in median cognitive scores. Kruskal-Wallis tests were used to assess the association of cognitive function with social ties. RESULTS: The majority of participants were non-Hispanic White (93.3%), presently married (49%), with at least a 4-year college degree (53.2%), and had been diagnosed with localized breast cancer (79%). A 10-point higher social support score correlated to a 0.32 higher (better) median cognitive score (p < 0.001). Women who were presently married tended to have better cognition than women who were divorced/separated or widowed (p = 0.01). Significant associations were also present for having close relatives (p < 0.001) or friends (p < 0.001), with cognitive scores being higher in those with at least one close relative or friend compared to none. CONCLUSION: Women reporting higher social support and greater numbers of friends or relatives have higher cognitive functioning. Compared to divorced or separated women, married women were likely to have higher cognitive functioning. These findings suggest that social support assessments have the potential to help identify women at higher risk of cognitive decline.

Health-related quality of life outcomes for the LEAP study-CALGB 70305 (Alliance): A lymphedema prevention intervention trial for newly diagnosed breast cancer patients.

BACKGROUND: Lymphedema is an adverse effect of breast cancer treatment that causes swelling and pain in the arm and hand. We tested 2 lymphedema prevention interventions and their impact on health-related quality of life (HRQOL) in a group-randomized trial at 38 cooperative group sites within the United States. METHODS: Patients were recruited before breast surgery. Sites were randomly assigned to education-only (EO) lymphedema prevention or education plus exercise and physical therapy (LEAP). Lymphedema was defined as a ≥10% difference in arm volume at any time from baseline to 18 months postsurgery. HRQOL was assessed using the Functional Assessment of Cancer Therapy-Breast plus 4 lymphedema items (FACT-B+4). Longitudinal mixed model regression analysis, adjusting for key demographic and clinical variables, examined participants' HRQOL by intervention group and lymphedema status. RESULTS: A total of 547 patients (56% LEAP) were enrolled and completed HRQOL assessments. The results revealed no differences between the interventions in preventing lymphedema (P = .37) or HRQOL (FACT-B+4 total score; P = .8777). At 18 months, the presence of lymphedema was associated with HRQOL at borderline significance (P = .0825). However, African American patients reported greater lymphedema symptoms (P = .0002) and better emotional functioning (P = .0335) than patients of other races or ethnicities. Lower HRQOL during the intervention was associated with younger age (P ≤ .0001), Eastern Cooperative Oncology Group performance status >0 (P = .0002), ≥1 positive lymph nodes (P = .0009), having no education beyond high school (P < .0001), having undergone chemotherapy (P = .0242), and having had only axillary node dissection or sentinel node biopsy versus both (P = .0007). CONCLUSION: The tested interventions did not differ in preventing lymphedema or in HRQOL outcomes. African American women reported greater HRQOL impacts due to lymphedema symptoms than women of other races or ethnicities.

A randomized study to prevent lymphedema in women treated for breast cancer: CALGB 70305 (Alliance).

BACKGROUND: Lymphedema affects many women who are treated for breast cancer. We examined the effectiveness of an education-only (EO) versus education plus sleeve compression/exercise intervention (lymphedema education and prevention [LEAP]) on lymphedema incidence and range of motion (ROM) in a group-randomized trial across 38 cooperative group sites. METHODS: The treating institution was randomly assigned to either EO or LEAP by a study statistician. All patients at a treating institution participated in the same intervention (EO or LEAP) to minimize contamination bias. Participants completed surveys, arm volume measurements, and self-reported ROM assessments before surgery and at 12 and 18 months after surgery. Lymphedema was defined as a ≥10% difference in limb volume at any time post-surgery up to 18 months after surgery or diagnosis by a health provider. Cochran-Mantel-Haenszel tests were used to compare lymphedema-free rates between groups, stratified by lymph node surgery type. Self-reported ROM differences were compared between groups. RESULTS: A total of 554 participants (56% LEAP) were included in the analyses. At 18 months, lymphedema-free rates were 58% (EO) versus 55% (LEAP) (P = .37). ROM for both arms was greater in LEAP versus EO at 12 months; by 18 months, most women reported full ROM, regardless of group. In LEAP, only one-third wore a sleeve ≥75% of the time; 50% performed lymphedema exercises at least weekly. CONCLUSION: Lymphedema incidence did not differ by intervention group at 18 months. Poor adherence in the LEAP group may have contributed. However, physical therapy may speed recovery of ROM. Further research is needed to effectively reduce the incidence and severity of lymphedema in patients who have breast cancer.

Aging Phenotypes and Restoring Functional Deficits in Older Adults With Hematologic Malignancy.

BACKGROUND: Gauging fitness remains a challenge among older adults with hematologic malignancies, and interventions to restore function are lacking. We pilot a structured exercise intervention and novel biologic correlates of aging using epigenetic clocks and markers of immunosenescence to evaluate changes in function and clinical outcomes. METHODS: Older adults (n=30) with hematologic malignancy actively receiving treatment were screened and enrolled in a 6-month exercise intervention, the Otago Exercise Programme (OEP). The impact of the OEP on geriatric assessment metrics and health-related quality of life were captured. Clinical outcomes of overall survival and hospital utilization (inpatient length of stay and emergency department use) in relationship to geriatric deficits were analyzed. RESULTS: Older adults (median age, 75.5 years [range, 62-83 years]) actively receiving treatment were enrolled in the OEP. Instrumental activities of daily living and physical health scores (PHS) increased significantly with the OEP intervention (median PHS: visit 1, 55 [range, 0-100]; visit 2, 70 [range, 30-100]; P<.01). Patient-reported Karnofsky performance status increased significantly, and the improvement was sustained (median [range]: visit 1, 80 [40-100]; visit 3, 90 [50-100]; P=.05). Quality of life (Patient-Reported Outcome Measurement Information System [PROMIS]) improved significantly by the end of the 6-month period (median [range]: visit 1, 32.4 [19.9-47.7]; visit 3, 36.2 [19.9-47.7]; P=.01]. Enhanced measures of gait speed and balance, using the Short Physical Performance Battery scores, were associated with a 20% decrease in risk of death (hazard ratio, 0.80; 95% CI, 0.65-0.97; P=.03) and a shorter hospital length of stay (decrease of 1.29 days; 95% CI, -2.46 to -0.13; P=.03). Peripheral blood immunosenescent markers were analyzed in relationship to clinical frailty and reports of mPhenoAge epigenetic analysis are preliminarily reported. Chronologic age had no relationship to overall survival, length of stay, or emergency department utilization. CONCLUSIONS: The OEP was effective in improving quality of life, and geriatric tools predicted survival and hospital utilization among older adults with hematologic malignancies.

Feasibility of implementing a text-based symptom-monitoring program of endometrial, ovarian, and breast cancer patients during treatment.

PURPOSE: To evaluate the feasibility of implementing systematic patient symptom monitoring during treatment using a smartphone. METHODS: Endometrial [n = 50], ovarian [n = 70] and breast [n = 193] cancer patients participated in text-based symptom reporting for up to 12 months. In order to promote equity, patients without a smartphone were provided with a device, with the phone charges paid by program funds. Each month, patients completed the Patient Health Questionnaire (PHQ-9), and 4 single items assessing fatigue, sleep quality, pain, and global quality of life during the past 7 days rated on a 0 (low) -10 (high) scale. Patients' responses were captured using REDCap, with oncologists receiving monthly feedback. Lay navigators provided assistance to patients with non-medical needs. RESULTS: Patients utilizing this voluntary program had an overall mean age of 60.5 (range 26-87), and 85% were non-Hispanic white. iPhones were provided to 42 patients, and navigation services were used by 69 patients. Average adherence with monthly surveys ranged between 75-77%, with breast patients having lower adherence after 5 months. The most commonly reported symptoms across cancer types were moderate levels (scores of 4-7) of fatigue and sleep disturbance. At 6 months, 71-77% of all patients believed the surveys were useful to them and their health care team. CONCLUSIONS: We established the feasibility of initiating and managing patients in a monthly text-based symptom-monitoring program. The provision of smartphones and patient navigation were unique and vital components of this program.

A descriptive pilot study of structural and functional social network ties among women in the women's health initiative (WHI) study.

Few studies examine the network structure and function of older women's health discussion networks. We sought to assess the feasibility and acceptability of collecting social network data via telephone from 72 women from the Women's Health Initiative study and to describe structural and functional characteristics. Women were socially connected and had dense networks. Women were emotionally close to network members, but their networks were not used to facilitate communication with health-care providers. One-third of network members was not influential on health-related decision-making. Collecting social network data via telephone is feasible and an acceptable, though un-preferred, mode of data collection.

CCN3 is dynamically regulated by treatment and disease state in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is an immune-mediated disease that damages myelin in the central nervous system (CNS). We investigated the profile of CCN3, a known regulator of immune function and a potential mediator of myelin regeneration, in multiple sclerosis in the context of disease state and disease-modifying treatment. METHODS: CCN3 expression was analysed in plasma, immune cells, CSF and brain tissue of MS patient groups and control subjects by ELISA, western blot, qPCR, histology and in situ hybridization. RESULTS: Plasma CCN3 levels were comparable between collective MS cohorts and controls but were significantly higher in progressive versus relapsing-remitting MS and between patients on interferon-ß versus natalizumab. Higher body mass index was associated with higher CCN3 levels in controls as reported previously, but this correlation was absent in MS patients. A significant positive correlation was found between CCN3 levels in matched plasma and CSF of MS patients which was absent in a comparator group of idiopathic intracranial hypertension patients. PBMCs and CD4+ T cells significantly upregulated CCN3 mRNA in MS patients versus controls. In the CNS, CCN3 was detected in neurons, astrocytes and blood vessels. Although overall levels of area immunoreactivity were comparable between non-affected, demyelinated and remyelinated tissue, the profile of expression varied dramatically. CONCLUSIONS: This investigation provides the first comprehensive profile of CCN3 expression in MS and provides rationale to determine if CCN3 contributes to neuroimmunological functions in the CNS.

Prevalence and correlates of job and insurance problems among young breast cancer survivors within 18 months of diagnosis.

BACKGROUND: The prevalence and correlates of job and insurance problems were examined among a cohort of young U.S. breast cancer survivors during the first 18-months following diagnosis. METHODS: Participants were 708 women diagnosed at ≤45 years with stage I-III breast cancer. 90% were non-Hispanic white, 76% were married/partnered and 67% had ≥4-year college degree. Univariable and multivariable logistic regression examined the associations between demographic, lifestyle and clinical factors with job and insurance problems. RESULTS: 18-months after diagnosis, 56% of participants worked full-time, 16% part-time, 18% were homemakers and/or students, 4.5% were unemployed, and 2.4% were disabled. The majority (86%) had private insurance. Job-related problems were reported by 40% of women, and included believing they could not change jobs for fear of losing health insurance (35.0%), being fired (2.3%), and being demoted, denied promotion or denied wage increases (7.8%). Greater job-related problems were associated with being overweight vs. under/normal weight (p = 0.006), income <$50,000/per year (p = 0.01), and working full-time vs. part-time (p = 0.003). Insurance problems were reported by 27% of women, and included being denied health insurance (2.6%), health insurance increases (4.3%), being denied health benefit payments (14.8%) or denied life insurance (11.4%). Insurance problems were associated with being under/normal weight vs. obese (p = 0.01), not being on hormone therapy (p < 0.001), and a tumor size > 5 cm vs. < 2 cm (p = 0.01). CONCLUSIONS: Young survivors experienced significant job- and insurance-related issues following diagnosis. To the extent possible, work and insurance concerns should be addressed prior to treatment to inform work expectations and avoid unnecessary insurance difficulties.

Perspectives of Survivorship Care Plans Among Older Breast Cancer Survivors: A Pilot Study.

The Commission on Cancer's standard 3.3 represents a paradigm shift in the care of cancer survivors, recommending that survivors receive a treatment summary and survivorship care plan (SCPs). A focus on older breast cancer survivors is needed, as they are the majority of the breast cancer population and their experiences and perspectives of SCPs is limited in the literature. This pilot study utilized a mixed methods approach (focus groups and self-report questionnaire data) to gather information on older (≥65 years) breast cancer survivors' perspectives of their SCPs, cancer survivorship, and communication with their health-care providers. The questionnaire was completed individually by the participants prior to the focus group and contained items on basic demographics and their health status following cancer treatment. The focus groups indicated that only a minority of women actually developed a SCP. Those who developed a SCP in collaboration with their providers valued the personal care and attention received. However, some participants reported poor communication with their providers and within their health-care team, resulting in frustration and confusion. Participants' suggestions for ideal SCPs included better education and personalization, particularly in appropriate nutrition and exercise, and managing side effects and comorbidities. Lastly, the women believed that additional long-term care resources, such as health coaches, were important in improving their survivorship. These findings provide insight into enhancing the content, communication, and application of SCPs to improve the survivorship experience of older breast cancer survivors.

Meningeal inflammation and cortical demyelination in acute multiple sclerosis.

OBJECTIVE: Cortical gray matter (GM) pathology, involving demyelination and neurodegeneration, associated with meningeal inflammation, could be important in determining disability progression in multiple sclerosis (MS). However, we need to know more about how cortical demyelination, neurodegeneration, and meningeal inflammation contribute to pathology at early stages of MS to better predict long-term outcome. METHODS: Tissue blocks from short disease duration MS (n = 12, median disease duration = 2 years), progressive MS (n = 21, disease duration = 25 years), non-diseased controls (n = 11), and other neurological inflammatory disease controls (n = 6) were quantitatively analyzed by immunohistochemistry, immunofluorescence, and in situ hybridization. RESULTS: Cortical GM demyelination was extensive in some cases of acute MS (range = 1-48% of total cortical GM), and subpial lesions were the most common type (62%). The numbers of activated (CD68+ ) microglia/macrophages were increased in cases with subpial lesions, and the density of neurons was significantly reduced in acute MS normal appearing and lesion GM, compared to controls (p < 0.005). Significant meningeal inflammation and lymphoid-like structures were seen in 4 of 12 acute MS cases. The extent of meningeal inflammation correlated with microglial/macrophage activation (p < 0.05), but not the area of cortical demyelination, reflecting the finding that lymphoid-like structures were seen adjacent to GM lesions as well as areas of partially demyelinated/remyelinated, cortical GM. INTERPRETATION: Our findings demonstrate that cortical demyelination, neuronal loss, and meningeal inflammation are notable pathological hallmarks of acute MS and support the need to identify early biomarkers of this pathology to better predict outcome. Ann Neurol 2018;84:829-842.