Impact of Remote Symptom Monitoring With Electronic Patient-Reported Outcomes on Hospitalization, Survival, and Cost in Community Oncology Practice: The Texas Two-Step Study.

PURPOSE: There is raising interest to implement electronic patient-reported outcomes (ePROs) for symptom monitoring to enhance the quality of cancer care. Step 1 of the Texas Two-Step Study demonstrated successful implementation of an ePRO system in >200 sites of service of a large community oncology practice. We now report step 2 of this study which evaluates the impact of ePROs on outcomes among patients enrolled in the Centers for Medicare & Medicaid Services' Oncology Care Model (OCM) program. METHODS: This observational study focused on patients with metastatic cancer enrolled in OCM at large community oncology practice located in Texas between July 2020 and December 2020. Patients who completed ≥1 survey via the ePRO tool were included in the study group and were propensity score matched with patients in a control group. Adverse events (AEs; hospitalizations, emergency department visits, deaths) and total cost of care were a priori study outcomes. Mann-Whitney U and chi-square tests compared continuous and categorical variables, respectively, with multivariable logistic regression for adjustment of covariates. RESULTS: Of 831 patients with metastatic cancer, 458 matched patients (229/group) were identified, with 52% male and a mean age of 74 years. Mean total AEs were lower in the study group compared with control (0.98 v 1.41; P = .007), with decreased hospitalizations (20% v 32.5%; P = .002), emergency visits (38.4% v 42.3%; P > .05), and deaths (11.8% v 16.6%; P > .05). Average number of hospitalizations was lower (0.28 v 0.52; P = .003) with reduced mean duration of hospitalizations (1.9 vs 3.2 d; P = .03). The total cost of care was reduced by an average of $1,146 per member per month. CONCLUSION: Symptom monitoring with ePROs improved quality and value of cancer care delivery by reducing hospitalizations, emergency visits, and deaths while lowering cost of care in a large oncology practice.

Persistent fatigue among long-term non-Hodgkin lymphoma survivors.

This study describes the prevalence and persistence of fatigue among a cohort of long-term non-Hodgkin lymphoma (NHL) survivors. Mailed surveys assessed quality-of-life including fatigue (SF-36) at baseline and five years. Logistic regression was used to identify factors associated with prevalence of fatigue at baseline and persistence of fatigue across timepoints. More than one-quarter (27.7%) of the 555 NHL survivors reported clinically meaningful fatigue at baseline and 18.7% reported persistent fatigue at five years. One-third (34.4%) reported clinically meaningful worsening of fatigue over time. Independent associations with persistent fatigue included female gender, less education, past chemotherapy, increased comorbidities, and posttraumatic stress symptoms (P <.05). Our findings suggest that one in three NHL survivors experience clinically meaningful fatigue long after their diagnosis and initial treatment. Furthermore, we found that fatigue worsens or persists for many, highlighting the need for vigilance in assessing and treating fatigue in this population.

Implementation of Electronic Patient-Reported Outcomes for Symptom Monitoring in a Large Multisite Community Oncology Practice: Dancing the Texas Two-Step Through a Pandemic.

PURPOSE: Among patients receiving chemotherapy, symptom monitoring with electronic patient-reported outcomes (ePROs) is associated with improved clinical outcomes, satisfaction, and compliance with therapy. Standard approaches for ePRO implementation are not established, warranting evaluation in community cancer practices. We present implementation findings of ePRO symptom monitoring across a large multisite community oncology practice network. METHODS: Patients initiating a new systemic therapy at one of the 210 practice sites at Texas Oncology were invited to use the Navigating Cancer ePRO platform, with stepped-wedge implementation from July to December 2020. Participating patients received a weekly prompt by text message or e-mail to self-report common symptoms and well-being. Severe self-reported symptoms triggered a real-time notification to nursing triage to address the symptom. Enrollment and compliance were systematically tracked weekly with evaluation of barriers and facilitators to adoption and sustainability. RESULTS: Four thousand three hundred seventy-five patients planning systemic treatment were enrolled and participated. Seventy-three percent (1,841 of 2,522) of enrolled patients completed at least one ePRO assessment. Among these individuals, 64% (16,299 of 25,061) of available weekly ePRO assessments were completed. Over a 10-week period, compliance declined from 72% to 52%. Barriers currently being addressed include lack of a second reminder text or e-mail prompt, inconsistent discussion of reported ePROs by clinicians at visits, and COVID-related changes in workflow. Facilitators included ease of use and patient and staff engagement on the importance of PROs for symptom management. CONCLUSION: ePROs can be effectively implemented in community oncology practice. Utilization of ePROs is high but diminishes over time without attention to barriers. Ongoing work to address barriers and optimize compliance are underway.

Pruritus in patients with solid tumors: an overlooked supportive care need.

PURPOSE: Pruritus is a common symptom in cutaneous malignancies, but its impact on patients with solid tumors is unclear. We explored the impact and management of pruritus in patients with solid tumors, using patient-reported outcomes (PRO) data from a real-world registry. METHODS: From 2006 to 2011, patients seen in the Duke Cancer Institute reported their symptoms via the Patient Care Monitor v2.0, a validated PRO tool that includes a 0-10-point question about pruritus severity. From > 25,000 encounters, 203 patients reported severe pruritus (> 6/10) on at least one visit and 506 total visits were abstracted where patients reported either moderate or severe pruritus (> 3/10). From this cohort, we abstracted demographics, diagnosis, stage, cancer therapy, anti-pruritic therapy, and clinicians' responses. RESULTS: Mean age was 59.8 (SD 13.3), 134 (66%) were female, 125 (62%) were Caucasian, and 65 (32%) were African American. Breast cancer was the most common tumor (36.5%), followed by lung cancer (23.2%). Mean pruritus severity score was 6.8 (SD 1.8) for patients on chemotherapy, 6.9 (SD 1.8) for patients on targeted therapy alone or in combination, and 7.1(SD 1.8) for patients off treatment. Overall, 67% of patients reported at least two episodes of moderate-severe pruritus (mean # of visits 4.2 (SD 2.7)). Despite frequent report of severe and persistent pruritus, this was mentioned in just 28% of clinician notes and an intervention was recommended/prescribed in only 7% of visits. CONCLUSIONS: Pruritus is an under-addressed symptom in patients with solid tumors. Additional research is needed to understand the burden of pruritus in affected populations.

The Surprise Question and Identification of Palliative Care Needs among Hospitalized Patients with Advanced Hematologic or Solid Malignancies.

BACKGROUND: Little is known about quality of life (QOL), depression, and end-of-life (EOL) outcomes among hospitalized patients with advanced cancer. OBJECTIVE: To assess whether the surprise question identifies inpatients with advanced cancer likely to have unmet palliative care needs. DESIGN: Prospective cohort study and long-term follow-up. SETTING/SUBJECTS: From 2008 to 2010, we enrolled 150 inpatients at Duke University with stage III/IV solid tumors or lymphoma/acute leukemia and whose physician would not be surprised if they died in less than one year. MEASUREMENTS: We assessed QOL (FACT-G), mood (brief CES-D), and EOL outcomes. RESULTS: Mean FACT-G score was quite low (66.9; SD 11). Forty-five patients (30%) had a brief CES-D score of ≥4 indicating a high likelihood of depression. In multivariate analyses, better QOL was associated with less depression (OR 0.91, p < 0.0001), controlling for tumor type, education, and spiritual well-being. Physicians correctly estimated death within one year in 101 (69%) cases, yet only 37 patients (25%) used hospice, and 4 (2.7%) received a palliative care consult; 89 (60.5%) had a do-not-resuscitate order, and 63 (43%) died in the hospital. CONCLUSIONS: The surprise question identifies inpatients with advanced solid or hematologic cancers having poor QOL and frequent depressive symptoms. Although physicians expected death within a year, EOL quality outcomes were poor. Hospitalized patients with advanced cancer may benefit from palliative care interventions to improve mood, QOL, and EOL care, and the surprise question is a practical method to identify those with unmet needs.

Lifestyle Interventions to Improve Cardiorespiratory Fitness and Reduce Breast Cancer Recurrence.

As patients are living longer after a cancer diagnosis, survivorship is becoming increasingly important in cancer care. The sequelae of multimodality therapies include weight gain and decreased cardiorespiratory fitness, which increase cardiovascular risk. Evidence suggests that physical activity reduces the risk of breast cancer recurrence and death. Avoidance of weight gain after therapy also improves outcomes after a diagnosis of breast cancer. Prospective randomized trials must be performed to determine the benefits of specific physical activity and dietary habits for survivors of breast cancer. This review outlines the important physiologic changes that occur with antineoplastic therapy and the important role of exercise and diet.

Trehalose upregulates progranulin expression in human and mouse models of GRN haploinsufficiency: a novel therapeutic lead to treat frontotemporal dementia.

BACKGROUND: Progranulin (PGRN) is a secreted growth factor important for neuronal survival and may do so, in part, by regulating lysosome homeostasis. Mutations in the PGRN gene (GRN) are a common cause of frontotemporal lobar degeneration (FTLD) and lead to disease through PGRN haploinsufficiency. Additionally, complete loss of PGRN in humans leads to neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Importantly, Grn-/- mouse models recapitulate pathogenic lysosomal features of NCL. Further, GRN variants that decrease PGRN expression increase the risk of developing Alzheimer's disease (AD) and Parkinson's disease (PD). Together these findings demonstrate that insufficient PGRN predisposes neurons to degeneration. Therefore, compounds that increase PGRN levels are potential therapeutics for multiple neurodegenerative diseases. RESULTS: Here, we performed a cell-based screen of a library of known autophagy-lysosome modulators and identified multiple novel activators of a human GRN promoter reporter including several common mTOR inhibitors and an mTOR-independent activator of autophagy, trehalose. Secondary cellular screens identified trehalose, a natural disaccharide, as the most promising lead compound because it increased endogenous PGRN in all cell lines tested and has multiple reported neuroprotective properties. Trehalose dose-dependently increased GRN mRNA as well as intracellular and secreted PGRN in both mouse and human cell lines and this effect was independent of the transcription factor EB (TFEB). Moreover, trehalose rescued PGRN deficiency in human fibroblasts and neurons derived from induced pluripotent stem cells (iPSCs) generated from GRN mutation carriers. Finally, oral administration of trehalose to Grn haploinsufficient mice significantly increased PGRN expression in the brain. CONCLUSIONS: This work reports several novel autophagy-lysosome modulators that enhance PGRN expression and identifies trehalose as a promising therapeutic for raising PGRN levels to treat multiple neurodegenerative diseases.

Effects of changing skin mechanics on the differential sensitivity to surface compliance by tactile afferents in the human finger pad.

It is not known how changes in skin mechanics affect the responses of cutaneous mechanoreceptors in the finger pads to compression forces. We used venous occlusion to change the stiffness of the fingers and investigated whether this influenced the firing of low-threshold mechanoreceptors to surfaces of differing stiffness. Unitary recordings were made from 10 slowly adapting type I (SAI), 10 fast adapting type I (FAI) and 9 slowly adapting type II (SAII) units via tungsten microelectrodes inserted into the median nerve at the wrist. A servo-controlled stimulator applied ramp-and-hold forces (1, 2, and 4 N) at a constant loading and unloading rate (2 N/s) via a flat 2.5-cm-diameter silicone disk over the center of the finger pad. Nine silicone disks (objects), varying in compliance, were used. Venous occlusion, produced by inflating a sphygmomanometer cuff around the upper arm to 40 ± 5 mmHg, was used to induce swelling of the fingers and increase the compliance of the finger pulp. Venous occlusion had no effect on the firing rates of the SAI afferents, nor on the slopes of the relationship between mean firing rate and object compliance at each amplitude, but did significantly reduce the slopes for the FAI afferents. Although the SAII afferents possess a poor capacity to encode changes in object compliance, mean firing rates were significantly lower during venous occlusion. The finding that venous occlusion had no effect on the firing properties of SAI afferents indicates that these afferents preserve their capacity to encode changes in object compliance, despite changes in skin mechanics.

FUS is phosphorylated by DNA-PK and accumulates in the cytoplasm after DNA damage.

Abnormal cytoplasmic accumulation of Fused in Sarcoma (FUS) in neurons defines subtypes of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). FUS is a member of the FET protein family that includes Ewing's sarcoma (EWS) and TATA-binding protein-associated factor 2N (TAF15). FET proteins are predominantly localized to the nucleus, where they bind RNA and DNA to modulate transcription, mRNA splicing, and DNA repair. In ALS cases with FUS inclusions (ALS-FUS), mutations in the FUS gene cause disease, whereas FTLD cases with FUS inclusions (FTLD-FUS) do not harbor FUS mutations. Notably, in FTLD-FUS, all FET proteins accumulate with their nuclear import receptor Transportin 1 (TRN1), in contrast ALS-FUS inclusions are exclusively positive for FUS. In the present study, we show that induction of DNA damage replicates several pathologic hallmarks of FTLD-FUS in immortalized human cells and primary human neurons and astrocytes. Treatment with the antibiotic calicheamicin γ1, which causes DNA double-strand breaks, leads to the cytoplasmic accumulation of FUS, TAF15, EWS, and TRN1. Moreover, cytoplasmic translocation of FUS is mediated by phosphorylation of its N terminus by the DNA-dependent protein kinase. Finally, we observed elevated levels of phospho-H2AX in FTLD-FUS brains, indicating that DNA damage occurs in patients. Together, our data reveal a novel regulatory mechanism for FUS localization in cells and suggest that DNA damage may contribute to the accumulation of FET proteins observed in human FTLD-FUS cases, but not in ALS-FUS.

Oncogenic viral prevalence in invasive vulvar cancer specimens from human immunodeficiency virus-positive and -negative women in Botswana.

OBJECTIVE: The primary aim of this study was to describe the prevalence of select oncogenic viruses within vulvar squamous cell carcinoma (VSCC) and their association with human immunodeficiency virus (HIV) status in women in Botswana, where the national HIV prevalence is the third highest in the world. METHODS: A cross-sectional study of biopsy-confirmed VSCC specimens and corresponding clinical data was conducted in Gaborone, Botswana. Polymerase chain reaction (PCR) and immunohistochemistry (IHC) viral testing were done for Epstein-Barr virus, human papillomavirus (HPV) strains, and Kaposi sarcoma herpesvirus, and PCR viral testing alone was done for John Cunningham virus. RESULTS: Human papillomavirus prevalence by PCR was 100% (35/35) among tested samples. Human papillomavirus type 16 was the most prevalent HPV strain (82.9% by PCR, 94.7% by either PCR or IHC). Kaposi sarcoma herpesvirus prevalence by PCR had a significant association with HIV status (P = 0.013), but not by IHC (P = 0.650). CONCLUSIONS: The high burden of HPV, specifically HPV16, in vulvar squamous cell cancer in Botswana suggests a distinct HPV profile that differs from other studied populations, which provides increased motivation for HPV vaccination efforts. Oncogenic viruses Kaposi sarcoma herpesvirus and Epstein-Barr virus were also more prevalent in our study population, although their potential role in vulvar squamous cell cancer pathology is unclear.

Differential sensitivity to surface compliance by tactile afferents in the human finger pad.

We undertook a neurophysiological investigation of the responses of low-threshold mechanoreceptors in the human finger pad to surfaces of differing softness. Unitary recordings were made from 26 slowly adapting type I (SAI), 17 fast-adapting type I (FAI), and 9 slowly adapting type II (SAII) afferents via tungsten microelectrodes inserted into the median nerve at the wrist. A servo-controlled stimulator applied ramp-and-hold forces (1, 2, 4 N) at a constant loading and unloading rate (2 N/s) via a flat silicone disc over the center of the finger pad. Nine discs were used, which linearly increased in stiffness across the range. Population responses of the SAI afferents showed the greatest sensitivity to compliance, with a steep monotonic increase in mean firing rate with increasing stiffness (decreasing compliance) of the surface during the loading and plateau (but not unloading) phases. FAI afferents also showed a linear increase in firing during the loading but not unloading phase, although the slope was significantly lower than that of the SAI afferents at all amplitudes. Conversely, SAII afferents were influenced by object compliance only in certain conditions. Given their high density in the finger pads and their linear relationship between firing rate and object compliance during the loading and plateau phases, SAI afferents (together with FAI afferents during the loading phase) are ideally suited to contributing information on surface compliance to the overall estimation of softness, but the SAII afferents appear to play only a minor role.

Progranulin does not bind tumor necrosis factor (TNF) receptors and is not a direct regulator of TNF-dependent signaling or bioactivity in immune or neuronal cells.

Progranulin (PGRN) is a secreted glycoprotein expressed in neurons and glia that is implicated in neuronal survival on the basis that mutations in the GRN gene causing haploinsufficiency result in a familial form of frontotemporal dementia (FTD). Recently, a direct interaction between PGRN and tumor necrosis factor receptors (TNFR I/II) was reported and proposed to be a mechanism by which PGRN exerts anti-inflammatory activity, raising the possibility that aberrant PGRN-TNFR interactions underlie the molecular basis for neuroinflammation in frontotemporal lobar degeneration pathogenesis. Here, we report that we find no evidence for a direct physical or functional interaction between PGRN and TNFRs. Using coimmunoprecipitation and surface plasmon resonance (SPR) we replicated the interaction between PGRN and sortilin and that between TNF and TNFRI/II, but not the interaction between PGRN and TNFRs. Recombinant PGRN or transfection of a cDNA encoding PGRN did not antagonize TNF-dependent NFκB, Akt, and Erk1/2 pathway activation; inflammatory gene expression; or secretion of inflammatory factors in BV2 microglia and bone marrow-derived macrophages (BMDMs). Moreover, PGRN did not antagonize TNF-induced cytotoxicity on dopaminergic neuroblastoma cells. Last, co-addition or pre-incubation with various N- or C-terminal-tagged recombinant PGRNs did not alter lipopolysaccharide-induced inflammatory gene expression or cytokine secretion in any cell type examined, including BMDMs from Grn+/- or Grn-/- mice. Therefore, the neuroinflammatory phenotype associated with PGRN deficiency in the CNS is not a direct consequence of the loss of TNF antagonism by PGRN, but may be a secondary response by glia to disrupted interactions between PGRN and Sortilin and/or other binding partners yet to be identified.

Rapid transepithelial transport of prions following inhalation.

Prion infection and pathogenesis are dependent on the agent crossing an epithelial barrier to gain access to the recipient nervous system. Several routes of infection have been identified, but the mechanism(s) and timing of in vivo prion transport across an epithelium have not been determined. The hamster model of nasal cavity infection was used to determine the temporal and spatial parameters of prion-infected brain homogenate uptake following inhalation and to test the hypothesis that prions cross the nasal mucosa via M cells. A small drop of infected or uninfected brain homogenate was placed below each nostril, where it was immediately inhaled into the nasal cavity. Regularly spaced tissue sections through the entire extent of the nasal cavity were processed immunohistochemically to identify brain homogenate and the disease-associated isoform of the prion protein (PrP(d)). Infected or uninfected brain homogenate was identified adhering to M cells, passing between cells of the nasal mucosa, and within lymphatic vessels of the nasal cavity at all time points examined. PrP(d) was identified within a limited number of M cells 15 to 180 min following inoculation, but not in the adjacent nasal mucosa-associated lymphoid tissue (NALT). While these results support M cell transport of prions, larger amounts of infected brain homogenate were transported paracellularly across the respiratory, olfactory, and follicle-associated epithelia of the nasal cavity. These results indicate that prions can immediately cross the nasal mucosa via multiple routes and quickly enter lymphatics, where they can spread systemically via lymph draining the nasal cavity.

Identifying early signs of aggression: psychometric properties of the Cardiff infant contentiousness scale.

Our aim was to develop an age-appropriate measure of early manifestations of aggression. We constructed a questionnaire about normative developmental milestones into which a set of items measuring infants' use of physical force against people and expressed anger were included. These items comprise the Cardiff Infant Contentiousness Scale (CICS). Evidence for the reliability and validity of the CICS is provided from analyses of a sample of N=310 British infants, assessed at a mean age of 6 months as part of a larger longitudinal study of the development of aggression. The informants' CICS ratings demonstrated reasonable levels of internal consistency and interrater agreement. Informants' ratings were validated by observations of infants' distress in response to restraint in a car seat. Longitudinal analyses revealed that contentiousness was stable over time and that contentiousness at 6 months predicted infants' later use of force with peers. When used in the company of other methods, the simple four-item CICS scale could serve as a useful screen for early manifestations of aggressiveness in human infants.

Directed differentiation of pluripotent cells to neural lineages: homogeneous formation and differentiation of a neurectoderm population.

During embryogenesis the central and peripheral nervous systems arise from a neural precursor population, neurectoderm, formed during gastrulation. We demonstrate the differentiation of mouse embryonic stem cells to neurectoderm in culture, in a manner which recapitulates embryogenesis, with the sequential and homogeneous formation of primitive ectoderm, neural plate and neural tube. Formation of neurectoderm occurs in the absence of extraembryonic endoderm or mesoderm and results in a stratified epithelium of cells with morphology, gene expression and differentiation potential consistent with positionally unspecified neural tube. Differentiation of this population to homogeneous populations of neural crest or glia was also achieved. Neurectoderm formation in culture allows elucidation of signals involved in neural specification and generation of implantable cell populations for therapeutic use.