The transcription factor NR4A1 (Nur77) controls bone marrow differentiation and the survival of Ly6C- monocytes.

The transcription factors that regulate differentiation into the monocyte subset in bone marrow have not yet been identified. Here we found that the orphan nuclear receptor NR4A1 controlled the differentiation of Ly6C- monocytes. Ly6C- monocytes, which function in a surveillance role in circulation, were absent from Nr4a1-/- mice. Normal numbers of myeloid progenitor cells were present in Nr4a1-/- mice, which indicated that the defect occurred during later stages of monocyte development. The defect was cell intrinsic, as wild-type mice that received bone marrow from Nr4a1-/- mice developed fewer patrolling monocytes than did recipients of wild-type bone marrow. The Ly6C- monocytes remaining in the bone marrow of Nr4a1-/- mice were arrested in S phase of the cell cycle and underwent apoptosis. Thus, NR4A1 functions as a master regulator of the differentiation and survival of 'patrolling' Ly6C- monocytes.

Adverse events and oncologic outcomes with combination lenvatinib and pembrolizumab for the treatment of recurrent endometrial cancer.

OBJECTIVE: To evaluate adverse events (AEs) of combination lenvatinib plus pembrolizumab for the treatment of recurrent endometrial cancer (EC) and to assess outcomes by lenvatinib starting dose. METHODS: We retrospectively reviewed patients with recurrent EC treated with lenvatinib plus pembrolizumab at our institution between 10/1/2019-11/30/2021. Starting dose of lenvatinib was defined as standard (20 mg) or reduced (10 mg/14 mg). AEs were manually extracted through chart review and graded using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. PFS, overall survival (OS), and duration of response (DOR) were analyzed. RESULTS: Forty-three patients were identified; median age was 67 years (range, 54-85). The most common histologies were serous (35%), endometrioid (23%), and carcinosarcoma (21%). Starting lenvatinib doses were 10 mg (n = 10), 14 mg (n = 10), and 20 mg (n = 23). Median number of cycles received was 8 (range, 1-42). Twenty-four patients (56%) required ≥1 lenvatinib dose reduction; 3 (7%) discontinued lenvatinib, and 1 (2%) discontinued pembrolizumab for intolerance or AE. Thirty-six patients (84%) experienced grade ≥ 3 AEs; hypertension, weight loss, anemia, fatigue, and thrombocytopenia were most common. The standard dose group experienced significantly shorter observed PFS vs the reduced dose group (P = .02). There was no difference in DOR (P = .09) or OS (P = .27) between the groups. CONCLUSION: In clinical practice, AEs associated with combination lenvatinib plus pembrolizumab were common and comparable to Study 309/KEYNOTE-775 findings. AEs were similar regardless of starting lenvatinib dose. Further dose optimization studies of lenvatinib plus pembrolizumab may be indicated in recurrent EC. Clinical trial data remain the gold standard to guide starting lenvatinib dosing.

Current Evidence-Based Systemic Therapy for Advanced and Recurrent Endometrial Cancer.

Endometrial cancer (EC) is the most common gynecologic malignancy, with worldwide increasing incidence and disease-associated mortality. Although most patients with EC are diagnosed with early-stage disease, systemic treatment options for patients with advanced or recurrent EC have historically been limited. EC-focused clinical trials and the ensuing therapeutic landscape have expanded since The Cancer Genome Atlas (TCGA) identified 4 distinct EC subgroups associated with differential survival. This endeavor revolutionized our understanding of the genomic characterization of EC as well as molecular drivers of this heterogeneous malignancy, leading to precision oncology approaches to therapeutics and advancement in treatment options. This review describes the current status of and recent advancements in therapeutic options for patients with advanced and recurrent EC. The NCCN Guidelines for Uterine Neoplasms provide detailed recommendations regarding the diagnosis, workup, and management of EC.

A Specific CNOT1 Mutation Results in a Novel Syndrome of Pancreatic Agenesis and Holoprosencephaly through Impaired Pancreatic and Neurological Development.

We report a recurrent CNOT1 de novo missense mutation, GenBank: NM_016284.4; c.1603C>T (p.Arg535Cys), resulting in a syndrome of pancreatic agenesis and abnormal forebrain development in three individuals and a similar phenotype in mice. CNOT1 is a transcriptional repressor that has been suggested as being critical for maintaining embryonic stem cells in a pluripotent state. These findings suggest that CNOT1 plays a critical role in pancreatic and neurological development and describe a novel genetic syndrome of pancreatic agenesis and holoprosencephaly.

Understanding interest, barriers, and preferences related to yoga practice among cancer survivors.

PURPOSE: Despite growing evidence supporting the benefits of yoga for cancer-related symptom management, yoga usage among cancer survivors is low. To translate the evidence of yoga benefits into community practice, it is critical to understand interest in yoga as well as barriers and preferences that influence yoga usage among cancer survivors. METHOD: We conducted a cross-sectional survey study among cancer survivors, 18 years or older, with a primary diagnosis of cancer, and receiving treatment or follow-up care at outpatient clinics at five regional academic cancer center sites. We collected data and performed bivariate and multivariable analyses on self-reported yoga usage and interest in and barriers to practicing yoga, as well as preferred location and time for yoga practice. RESULTS: Of 857 participants, 70.0% had never practiced yoga and 52.3% were interested in practicing yoga. Among those interested, 52.5% had never practiced yoga. Lower interest was independently associated with being male (odds ratio [OR] = 0.30, 95% confidence interval [CI] = 0.20-0.44, p < 0.001), unemployed (OR = 0.60, 95% CI = 0.39-0.91, p = 0.016), and white (OR = 0.42, 95% CI = 0.23-0.78, p = 0.005). Commonly cited barriers among those who were interested but had never practiced were not aware of yoga benefits (36.3%), difficulty motivating (28.7%), experiencing symptoms (22.9%), and not enough time (22.0%). Participants indicated "on-site and at a studio near home" (41.5%) as preferred location and evenings (3-8 pm, 34.0%) as preferred time for yoga practice. CONCLUSION: Although more than 50% of patients indicated interest in practicing yoga, use of yoga is low among cancer survivors. Barriers and patient preferences for yoga practice need to be addressed to design effective yoga programs for this population.

Implementing a Watcher Program to Improve Timeliness of Recognition of Deterioration in Hospitalized Children.

PURPOSE: Early recognition and response to clinical deterioration is critical to patient safety. Failures or delays in recognition and response often manifest as emergency transfers to the intensive care unit (ICU). We describe implementation of a program to improve recognition and response to clinical deterioration within the pediatric inpatient acute care setting (i.e., medical-surgical, hematology-oncology, and intermediate care units). DESIGN AND METHODS: We assembled an inter-professional team including nurses, physicians, and hospital leaders to evaluate preventable patient harm events associated with failures in identifying and responding to clinical deterioration and resultant emergency transfers to the intensive care unit (ICU). We evaluated an existing situational awareness framework incorporating principles of high-reliability organizations, refined the framework utilizing internal event analyses data, and subsequently implemented a program reducing emergency transfers. RESULTS: Emergency transfers to the ICU from acute care settings decreased by more than 70%, and to date, this improvement has sustained. Nurses report increased satisfaction and empowerment to proactively escalate their concerns, respond to changes in a patient's condition, and reduce uncertainty about the plan of care. CONCLUSIONS: The program has enhanced situational awareness, reduced emergency transfers, and fostered a culture of accountability and collaboration in alignment with the organizational core value of safety. PRACTICE IMPLICATIONS: Developing a reliable system to support the healthcare team in recognizing and responding to clinical deterioration reduces the risk of care delays. Applying situational awareness to other high-risk situations, additional areas for program expansion were identified, to include emergency department admissions and behavioral health patients.

Impact of provider volume on front-line chemotherapy guideline compliance and overall survival in elderly patients with advanced ovarian cancer.

PURPOSE: We sought to evaluate whether provider volume or other factors are associated with chemotherapy guideline compliance in elderly patients with epithelial ovarian cancer (EOC). METHODS: We queried the SEER-Medicare database for patients ≥66 years, diagnosed with FIGO stage II-IV EOC from 2004 to 2013 who underwent surgery and received chemotherapy within 7 months of diagnosis. We compared NCCN guideline compliance (6 cycles of platinum-based doublet) and chemotherapy-related toxicities across provider volume tertiles. Factors associated with guideline compliance and chemotherapy-related toxicities were assessed using logistic regression. Overall survival (OS) was compared across volume tertiles and Cox proportional-hazards model was created to adjust for case-mix. RESULTS: 1924 patients met inclusion criteria. The overall rate of guideline compliance was 70.3% with a significant association between provider volume and compliance (64.5% for low-volume, 72.2% for medium-volume, 71.7% for high-volume, p = .02). In the multivariate model, treatment by low-volume providers and patient age ≥ 80 years were independently associated with worse chemotherapy-guideline compliance. In the survival analysis, there was a significant difference in median OS across provider volume tertiles with median survival of 32.8 months (95%CI 29.6, 36.4) low-volume, 41.9 months (95%CI 37.5, 46.7) medium-volume, 42.1 months (95%CI 38.8, 44.2) high-volume providers, respectively (p < .01). After adjusting for case-mix, low-volume providers were independently associated with higher rates of mortality (aHR 1.25, 95%CI: 1.08, 1.43). CONCLUSIONS: In a modern cohort of elderly Medicare patients with advanced EOC, we found higher rates of non-compliant care and worse survival associated with treatment by low-volume Medicare providers. Urgent efforts are needed to address this volume-outcomes disparity.

Trends in Female Representation on NCCN Guideline Panels.

BACKGROUND: NCCN produces highly influential disease-specific oncology clinical practice guidelines. Because the number of women in academic oncology has increased, we assessed whether the composition of NCCN Guidelines Panels reflected this trend. METHODS: Using historical guidelines requested from NCCN, we investigated time trends for female representation on 21 NCCN Guidelines Panels and analyzed the trends for female-predominant cancers (breast, ovarian, uterine, and cervical) compared with all cancers. RESULTS: From 2013 to 2019, there was an increase from 123 women of 541 total panelists (22.7%) to 175 women of 542 panelists (32.3%). Within the 4 female-predominant cancers, the increase was more rapid: from 30 of 101 total panelists (29.7%) to 66 of 118 panelists (56.4%). Excluding female-predominant cancers, increases were minimal. CONCLUSIONS: There could be multiple explanations for these differing trends, including the possibility of more rapid increases in the underlying pool of female physician-scientists in female-predominant specialties or more efforts to increase the representation of women in decisions about the standard of care in cancers predominantly affecting women.

Impact of Provider Imaging Practices on Survival Outcomes in Advanced Ovarian Cancer.

BACKGROUND: This study sought to describe how high- versus low-frequency surveillance imaging practices among providers at Memorial Sloan Kettering Cancer Center (MSKCC) impact overall survival (OS) and time to recurrence of patients with advanced epithelial ovarian cancer in first remission. METHODS: The study cohort included patients with stage II-IV high-grade epithelial ovarian cancer diagnosed in January 2001 through January 2017 who experienced recurrence after initial platinum-based chemotherapy. To determine usual imaging practices for providers at MSKCC, median frequency of CT or MRI of the abdomen/pelvis was calculated among patients with a long-term remission (defined as at least 1 year) treated by each provider. Cox proportional hazards models were used to examine differences in OS and time to recurrence among patients treated by providers with high versus low imaging frequency practices, with additional subgroup analysis among patients with elevated CA-125 levels >35 U/mL at diagnosis. Chi-square tests were used to examine differences in the proportion of patients who enrolled in clinical trials or underwent secondary cytoreductive surgery (SCS) by imaging frequency. RESULTS: A total of 543 patients were treated by providers with high imaging frequency (>1 scan every 12 months) and 141 were treated by providers with low imaging frequency (≤1 scan every 12 months). Time to recurrence was shorter among patients treated by providers with high versus low imaging frequency (18.0 vs 19.2 months; hazard ratio, 1.33; P=.003). Results were similar when restricted to patients with elevated CA-125 levels at diagnosis. There was no significant difference in OS, clinical trial enrollment, or SCS by imaging practice. CONCLUSIONS: Within the limitations of this retrospective analysis, patients with advanced ovarian cancer treated by high-frequency-imaging providers had earlier detection of recurrence. Future analyses in a larger population are warranted to elucidate the risks versus benefits of surveillance imaging.

Self-management Needs of Adults With Congenital Heart Disease.

BACKGROUND: Adults with congenital heart disease (CHD) are an emerging adult heart disease subset, now outnumbering the pediatric population with CHD. OBJECTIVE: We aimed to gain understanding and knowledge of what adults with CHD perceive as important for self-management and describe these needs across demographic factors, developmental characteristics, lesion severity, and quality of life. METHODS: We used a descriptive mixed-methods online survey merging 4 instruments: Adult CHD Self-management Experience Questionnaire; Adult CHD Demographic Questionnaire; Adaptive Behavior Assessment System, Third Edition; and Stanford Quality of Life Visual Numeric. Participants with CHD 18 to 30 years of age with initial defect repair before 12 months of age were recruited through support from the Adult Congenital Heart Association, clinic adult CHD support groups, and newspaper advertising. Thematic analysis for short-answer questions, descriptive analysis for demographic data and the visual numeric, and intrument-specific scoring assistant software for the Adaptive Behavior Assessment System were used. RESULTS: We received 22 responses from 13 women and 9 men. These individuals represented 15 different heart defect diagnoses, mostly of moderate or complex lesion severity. Most had postsecondary education and were employed. Four prominent themes emerged related to self-management: desire for connectivity-psychological support; a plan for the future-education about health and life expectations; coping needs-skills for mental stress; and access to care-navigation of healthcare systems. CONCLUSIONS: Future longitudinal research and replication studies with larger samples are needed. Educational materials and targeted interventions that promote self-management benefit the aging adult with CHD population.

A study investigating the validity of an accelerometer in quantification of step count in adult hospital inpatients recovering from critical illness.

OBJECTIVE: To determine the validity of the ActiGraph GT3X accelerometer in step count quantification when compared to observed step count in hospitalised adults recovering from critical illness. SETTING: Large National Health Service (NHS) Hospitals Trust. SUBJECTS: In total, 20 hospital ward-based adults (age: mean 62.3, SD 11.5) who had required greater than 48 hours of mechanical ventilation in the intensive care unit. MAIN MEASURES: Participants walked self-selected distances and speeds as part of a semi-structured movement protocol not exceeding 3 hours. Two ActiGraph GT3X accelerometers were worn, one on the thigh and one on the ankle of the non-dominant leg. Accelerometer-recorded step counts were compared against observed step counts. RESULTS: In total, 31 separate walking episodes were analysed. A mean (SD) of 45.87 (±19.72) steps was calculated for observed step count (range 15-90). Mean differences (95% limits of agreement) of -0.84 steps (-3.88 to 2.2) for the ankle placement and -17.7 steps (-40.63 to 5.25) for the thigh were calculated. Intraclass correlation coefficients (95% confidence intervals) of 0.99 (0.99 to 1.0) and 0.46 (-0.1 to 0.78) were determined for the ankle and thigh, respectively. Placement sites were well tolerated by 95% of participants. CONCLUSION: An ankle-mounted ActiGraph GT3X accelerometer demonstrates validity in quantification of step count in hospitalised adults recovering from critical illness. A thigh placement was not considered valid.

Racial disparities in chemotherapy administration for early-stage breast cancer: a systematic review and meta-analysis.

PURPOSE: We conducted a systematic review and meta-analysis to measure the extent to which race is associated with delayed initiation or receipt of inadequate chemotherapy among women with early-stage breast cancer. METHODS: We performed a systematic search of all articles published from January 1987 until June 2017 within four databases: PubMed/Medline, EMBASE, CINAHL, and Cochrane CENTRAL. Eligible studies were US-based and examined the influence of race on chemotherapy delays, cessation, or dose reductions among women with stage I, II, or III breast cancer. Data were pooled using a random effects model. RESULTS: A total of twelve studies were included in the quantitative analysis. Blacks were significantly more likely than whites to have delays to initiation of adjuvant therapy of 90 days or more (OR 1.41, 95% CI 1.06-1.87; X² = 31.05, p < 0.00001; I² = 90%). There was no significant association between race and chemotherapy dosing. Due to overlap between studies assessing the relationship between race and completion of chemotherapy, we conducted two separate analyses. Black patients were significantly more likely to discontinue chemotherapy, however, this was no longer statistically significant when larger numbers of patients with more advanced (stage III) breast cancer were included. CONCLUSIONS: These results suggest that black breast cancer patients experience clinically relevant delays in the initiation of adjuvant chemotherapy more often than white patients, which may in part explain the increased mortality observed among black patients.

Validity and reliability of accelerometry in identification of lying, sitting, standing or purposeful activity in adult hospital inpatients recovering from acute or critical illness: a systematic review.

OBJECTIVE: To investigate the validity and reliability of accelerometers to detect lying, sitting and standing postures or purposeful activity in hospitalized adults recovering from acute or critical illness. DATA SOURCES: CINAHL, MEDLINE, EMBASE, AMED, Cochrane Library, PEDro, PsycINFO and SPORTDiscuss were searched from inception to June 2017. Professional networks and reference lists of relevant articles were also searched. The main selection criteria were hospitalized adults with acute or critical illness and studies investigating the validity or reliability of accelerometers to identify body position or purposeful activity. REVIEW METHODS: Two authors individually assessed study eligibility and independently undertook methodological quality assessment and data extraction from selected articles. A narrative synthesis of the data was undertaken. RESULTS: Fifteen studies, collectively enrolling 385 hospitalized participants, were identified. Populations included stroke, the elderly, acute exacerbation of chronic respiratory disease, abdominal surgery and those recovering from critical illness. Correlations of r = 0.36 to 0.98 and levels of agreement of κ = 0.28 to 0.98 were reported for identification of lying, sitting or standing postures. Correlations of r = 0.4 to 0.8 with general activity were found, with r = 0.94 and 0.96 reported for step count. The reliability of accelerometry measurement was investigated in one study evaluating step count quantification (intraclass correlation coefficient (ICC) = 0.99, 95% confidence interval (CI) = 0.99-1.00). CONCLUSION: The validity of accelerometers to determine lying, sitting and standing postures or quantify purposeful activity within hospitalized acute or critically ill populations is variable. The reliability of accelerometry measurement within this setting remains largely unexplored.

The Emotional Cost of Caring for Others: One Pediatric Hospital's Journey to Reduce Compassion Fatigue.

OBJECTIVE: This study examined the prevalence of compassion fatigue and life stress of pediatric nurses. BACKGROUND: Distressing patient situations over time may affect nurses' professional quality of life and result in compassion fatigue. If not addressed, compassion fatigue may have personal and organizational consequences. METHODS: Using a descriptive, correlational design, a convenience sample of 268 nurses completed a web-based survey. RESULTS: High compassion satisfaction and moderate to low burnout and secondary traumatic stress were described by 49% of participants. Education was statistically associated with burnout and secondary traumatic stress. Life stress scores were significantly associated with age, experience, organizational tenure, and professional engagement. Narrative commentary yielded 5 themes: staffing, recognition, boundaries, expectations, and hopelessness. Organizational initiatives to prevent or mitigate compassion fatigue focused on awareness, balance, and connections. CONCLUSIONS: Nurses are negatively impacted by the emotional cost of caring. Future studies need to identify interventions to minimize compassion fatigue.

Alkaline ceramidase 1 is essential for mammalian skin homeostasis and regulating whole-body energy expenditure.

The epidermis is the outermost layer of skin that acts as a barrier to protect the body from the external environment and to control water and heat loss. This barrier function is established through the multistage differentiation of keratinocytes and the presence of bioactive sphingolipids such as ceramides, the levels of which are tightly regulated by a balance of ceramide synthase and ceramidase activities. Here we reveal the essential role of alkaline ceramidase 1 (Acer1) in the skin. Acer1-deficient (Acer1(-/-) ) mice showed elevated levels of ceramide in the skin, aberrant hair shaft cuticle formation and cyclic alopecia. We demonstrate that Acer1 is specifically expressed in differentiated interfollicular epidermis, infundibulum and sebaceous glands and consequently Acer1(-/-) mice have significant alterations in infundibulum and sebaceous gland architecture. Acer1(-/-) skin also shows perturbed hair follicle stem cell compartments. These alterations result in Acer1(-/-) mice showing increased transepidermal water loss and a hypermetabolism phenotype with associated reduction of fat content with age. We conclude that Acer1 is indispensable for mammalian skin homeostasis and whole-body energy homeostasis. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Single-Cell Analysis of B Cell/Antibody Cross-Reactivity Using a Novel Multicolor FluoroSpot Assay.

Dengue is a major public health problem globally. It is caused by four antigenically distinct serotypes of dengue virus (DENV1-4), and although serotype-specific and strongly neutralizing cross-reactive immune responses against the four DENV serotypes are thought to be protective, subneutralizing Abs can contribute to increased disease severity upon secondary infection with a different DENV serotype. Understanding the breadth of the immune response in natural DENV infections and in vaccinees is crucial for determining the correlates of protection or disease severity. Transformation of B cell populations to generate mAbs and ELISPOT assays have been used to determine B cell and Ab specificity to DENV; however, both methods have technical limitations. We therefore modified the conventional ELISPOT to develop a Quad-Color FluoroSpot to provide a means of examining B cell/Ab serotype specificity and cross-reactivity on a single-cell basis. Abs secreted by B cells are captured by an Fc-specific Ab on a filter plate. Subsequently, standardized concentrations of all four DENV serotypes are added to allow equal stoichiometry for Ag binding. After washing, the spots, representing individual B cells, are visualized using four fluorescently labeled DENV serotype-specific detection mAbs. This method can be used to better understand the breadth and magnitude of B cell responses following primary and secondary DENV infection or vaccination and their role as immune correlates of protection from subsequent DENV infections. Furthermore, the Quad-Color FluoroSpot assay can be applied to other diseases caused by multiple pathogen serotypes in which determining the serotype or subtype-specific B cell response is important.

Online Focus Groups with Parents And Adolescents with Heart Transplants: Challenges and Opportunities.

Pediatric heart transplant recipients are scarce and widely dispersed. Previous studies of adolescents in this population were limited to small homogenous samples. Although online focus groups are an emerging data collection method, its use in pediatric populations has not been fully realized. The purpose of this study was to explore the feasibility of using online focus groups with pediatric populations. Adolescents (aged 13 to 21 years) at least 6 months post-heart transplant and their parents were recruited from two children's hospitals. An online discussion forum (iTracks) was used to conduct asynchronous focus groups with separate parent and adolescent groups. Six parents and four adolescents participated in the discussions. iTracks provided a framework for conducting focus groups in dispersed populations. Access to the discussion transcripts enhanced data analysis and eliminated transcription costs. Overall, online discussion forums were a feasible and cost-effective option to conduct online focus groups in this pediatric population.

Comparative effectiveness of mitoxantrone plus prednisone versus prednisone alone in metastatic castrate-resistant prostate cancer after docetaxel failure.

BACKGROUND: Mitoxantrone was approved for use in metastatic castrate-resistant prostate cancer (mCRPC) based on pain palliation without observed survival benefit in a small phase III trial in 1996. To re-evaluate for possible survival benefits in a larger contemporary sample and to demonstrate analytic uses of the newly available Project Data Sphere online resource, we used data from control arms of completed clinical trials to compare survival and toxicity among patients with postdocetaxel mCRPC treated with mitoxantrone and prednisone. PATIENTS AND METHODS: Control arm data from two phase III randomized control trials, SUN 1120 and TROPIC, were used to examine the efficacy of mitoxantrone plus prednisone (n = 305) versus prednisone alone (n = 257) among patients with postdocetaxel mCRPC. Propensity score matching was used to balance patient characteristics between the separate trials, conditioned on age and key prognostic variables of survival. The primary outcome was overall survival. Secondary endpoints evaluated safety. RESULTS: Median survival was similar among patients receiving mitoxantrone plus prednisone versus prednisone alone (385 days vs. 336 days; deceleration factor = 0.04; 95% confidence interval: -0.12 to 0.22). Prevalence of several any-grade toxicity, including fatigue, back pain, and peripheral neuropathy, was increased among patients who received mitoxantrone. CONCLUSION: There was no significant survival benefit for mitoxantrone plus prednisone over prednisone alone among men with mCRPC after docetaxel therapy. This finding is consistent with prior studies showing no survival advantage with mitoxantrone in the predocetaxel setting. Furthermore, our data suggest that mitoxantrone may be associated with increased toxicity compared with prednisone alone.