Travel-Time barriers to specialized cancer care for adolescents and young adults with acute leukemia.

BACKGROUND: Prior studies demonstrate that 20-50% of adolescents and young adults (AYA, age 15-39 years) with acute lymphoblastic leukemia (ALL) receive care at specialty cancer centers (SCC); yet a significant survival benefit has been observed for patients at these sites. Our objective was to identify patients at risk of severe geographic barriers to SCC-level care. METHODS: We used data from the North American Association of Central Cancer Registries Cancer in North America database to identify AYA ALL patients diagnosed between 2004-2016 across 43 U.S. states. We calculated driving distance and travel time from counties where participants lived to the closest SCC sites. We then used multivariable logistic regression models to examine the relationship between sociodemographic characteristics of counties where AYA ALLs resided and the need to travel >1 hour to obtain care at an SCC. RESULTS: Among 11,813 AYA ALL patients, 43.4% were 25-39 years old, 65.5% were male, 32.9% were Hispanic, and 28.7% had public insurance. We found 23.6% of AYA ALL patients from 60.8% of included U.S. counties would be required to travel >1 hour one-way to access an SCC. Multivariable models demonstrate that patients living in counties that are non-metropolitan, with lower levels of educational attainment, with higher income inequality, lower internet access, located in primary care physician shortage areas and with fewer hospitals providing chemotherapy services are more likely to travel >1 hour to access an SCC. CONCLUSIONS: Substantial travel-related barriers exist to accessing care at SCCs across the U.S, particularly for patients living in areas with greater concentrations of historically marginalized communities.

Impact of Specialized Treatment Setting on Survival in Adolescent and Young Adult ALL.

PURPOSE: Unlike children with ALL who receive cancer care primarily at specialized cancer centers (SCCs; National Cancer Institute and/or Children's Oncology Group centers), adolescents and young adults (AYAs; 15-39 years) receive care in a variety of settings. Using population-based data, we describe where AYAs with ALL receive treatment and determine associations with overall survival (OS). METHODS: Data from the 2004 to 2018 California (CA, n = 2,283), New York (NY, n = 795), and Texas (TX, n = 955) state cancer registries were used to identify treatment setting of AYAs with newly diagnosed ALL. Multivariable Cox proportional hazards regression models evaluated associations with OS. RESULTS: Seventy percent were older than 18 years, and 65% were male. A majority in CA (63%) and TX (64%) were Hispanic while most in NY were non-Hispanic White (50%). Treatment at an SCC occurred in 48.2% (CA), 44.4% (NY), and 19.5% (TX). Across states, AYAs who were older or uninsured were less likely to receive treatment at an SCC. Treatment at an SCC was associated with superior OS in CA (hazard ratio [HR], 0.73; 95% CI, 0.63 to 0.85) and TX (HR, 0.61; 95% CI, 0.45 to 0.83); a nonsignificant association was seen in NY (HR, 0.83; 95% CI, 0.64 to 1.08). CONCLUSION: Only 20%-50% of AYA patients with ALL received frontline treatment at SCCs. Treatment of ALL at an SCC was associated with superior survival, highlighting the importance of policy efforts to improve access and reduce inequities in AYA ALL care.

A molecular mechanism for the generation of ligand-dependent differential outputs by the epidermal growth factor receptor.

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that couples the binding of extracellular ligands, such as EGF and transforming growth factor-α (TGF-α), to the initiation of intracellular signaling pathways. EGFR binds to EGF and TGF-α with similar affinity, but generates different signals from these ligands. To address the mechanistic basis of this phenomenon, we have carried out cryo-EM analyses of human EGFR bound to EGF and TGF-α. We show that the extracellular module adopts an ensemble of dimeric conformations when bound to either EGF or TGF-α. The two extreme states of this ensemble represent distinct ligand-bound quaternary structures in which the membrane-proximal tips of the extracellular module are either juxtaposed or separated. EGF and TGF-α differ in their ability to maintain the conformation with the membrane-proximal tips of the extracellular module separated, and this conformation is stabilized preferentially by an oncogenic EGFR mutation. Close proximity of the transmembrane helices at the junction with the extracellular module has been associated previously with increased EGFR activity. Our results show how EGFR can couple the binding of different ligands to differential modulation of this proximity, thereby suggesting a molecular mechanism for the generation of ligand-sensitive differential outputs in this receptor family.

Higher ultraviolet radiation during early life is associated with lower risk of childhood type 1 diabetes among boys.

Population-level ecological studies show type 1 diabetes incidence is inversely correlated with ambient ultraviolet radiation (UVR) levels. We conducted a nested case-control study using administrative datasets to test this association at the individual level. Cases (n = 1819) were children born in Western Australia (WA) from 1980-2014, diagnosed with type 1 diabetes at ≤ 16 years. Controls (n = 27,259) were randomly selected from all live births in WA, matched to cases by sex and date of birth. Total ambient erythemal ultraviolet radiation (UVR) doses for each trimester of pregnancy and first year of life were estimated for each individual, using daily NASA satellite data that were date- and geographically-specific. Conditional logistic regression tested the association between UVR dose and case-control status. Type 1 diabetes risk was 42% lower in boys of mothers with third-trimester UVR dose in the highest (compared to the lowest) quartile (p = 0.04). Higher UVR in the first year of life was associated with lower type 1 diabetes risk among boys (p = 0.01). UVR dose was not associated with type 1 diabetes risk in girls. Higher UVR in late pregnancy and early life appear to interact with sex-specific factors to lower type 1 diabetes risk among boys in Western Australia.

Use of linked administrative and laboratory data to confirm that serum 25(OH)D levels in pregnant women can be predicted from satellite estimates of ultraviolet radiation.

BACKGROUND: Serum 25 hydroxyvitamin D [25(OH)D] levels of pregnant women have been linked to various health outcomes in their offspring. Satellite-derived ultraviolet radiation (UVR) data have been used as a proxy for 25(OH)D levels, as individual-level cohort studies are time-consuming, costly and only feasible for common outcomes. METHODS: Data on 25(OH)D levels from a public laboratory database were linked to data from the Western Australian Midwives' Notification System and daily erythemal UVR dose from NASA satellites. Regression analysis was used to identify the time period prior to venesection where daily UVR dose best predicted 25(OH)D levels. A predictive model was used to validate the use of daily UVR dose as a proxy for personal sun exposure during pregnancy. RESULTS: Data from 19 173 pregnancies in women aged 18-43 years in Western Australia were included. The daily UVR dose averaged over the 90 days before venesection was the strongest UVR predictor of 25(OH)D level (a 5% increase per 1000 J m-2; equal to 3.3 nmol L-1 at the median of 66 nmol L-1). Ethnicity was the strongest predictor of 25(OH)D levels (21% lower in non-Caucasian vs Caucasian: equal to 7.2 nmol L-1 difference). Other significant predictors were gestation, age, year, parity, socio-economic status, remoteness, medical conditions and season. CONCLUSION: NASA-derived erythemal UVR dose in the 90 days prior to venesection is a significant predictor of 25(OH)D levels in pregnant women. Linked administrative data can be used to investigate associations between UVR during pregnancy and health outcomes in offspring.

Smartphone Global Positioning System (GPS) Data Enhances Recovery Assessment After Breast Cancer Surgery.

PURPOSE: We sought to determine whether smartphone GPS data uncovered differences in recovery after breast-conserving surgery (BCS) and mastectomy, and how these data aligned with self-reported quality of life (QoL). METHODS: In a prospective pilot study, adult smartphone-owners undergoing breast surgery downloaded an application that continuously collected smartphone GPS data for 1 week preoperatively and 6 months postoperatively. QoL was assessed with the Short-Form-36 (SF36) via smartphone delivery preoperatively and 4 and 12 weeks postoperatively. Endpoints were trends in daily GPS-derived distance traveled and home time, as well as SF36 Physical (PCS) and Mental Component Scores (MCS) comparing BCS and mastectomy patients. RESULTS: Thirty-one patients were included. Sixteen BCS and fifteen mastectomy patients were followed for a mean of 201 (SD 161) and 174 (107) days, respectively. There were no baseline differences in demographics, PCS/MCS, home time, or distance traveled. Through 12 weeks postoperatively, mastectomy patients spent more time at home [e.g., week 4: 16.7 h 95% CI (14.3, 19.6) vs. 11.0 h (9.4, 12.9), p < 0.001] and traveled shorter distances [e.g., week 4: 52.5 km 95% CI (36.1, 76.0) vs. 107.7 km (75.8-152.9), p = 0.009] compared with BCS patients. There were no significant QoL differences throughout the study as measured by the MCS [e.g., week 4 difference: 7.83 95% CI (- 9.02, 24.7), p = 0.362] or PCS [e.g., week 4 difference: 8.14 (- 6.67, 22.9), p = 0.281]. GPS and QoL trends were uncorrelated (ρ < ± 0.26, p > 0.05). CONCLUSIONS: Differences in BCS and mastectomy recovery were successfully captured using smartphone GPS data. These data may describe currently unmeasured aspects of physical and mental recovery, which could supplement traditional and QoL outcomes to inform shared decision-making.

Measuring Goal-Concordant Care: Results and Reflections From Secondary Analysis of a Trial to Improve Serious Illness Communication.

CONTEXT: Many consider goal-concordant care (GCC) to be the most important of advance care planning and palliative care. Researchers face significant challenges in attempting to measure this outcome. We conducted a randomized controlled trial to assess the effects of a system-level intervention to improve serious illness communication on GCC and other outcomes. OBJECTIVES: To describe our measurement approach to GCC, present findings from a post-hoc analysis of trial data, and discuss lessons learned about measuring GCC. METHODS: Using trial data collected to measure GCC, we analyzed ratings and rankings from a nonvalidated survey of patient priorities in the setting of advanced cancer, the Life Priorities Scale, and compared outcomes with correlative measures. RESULTS: Participants commonly rated several predetermined and literature-derived priorities as important but did so in ways that were commonly incongruent with rankings. Ratings were frequently stable over time; rankings less so. Rankings are more likely to help assess the degree to which care is goal concordant but may be best augmented by corollary measures that signal achievement of a given priority. CONCLUSION: Measuring GCC remains a fundamental challenge to palliative care researchers. Ratings attest to the fact that many things matter to patients; however, rankings can better determine what matters most. Insights gained from our experience may guide future research aiming to use this outcome to assess the effect of intervention to improve serious illness care.

Patient and clinician experience of a serious illness conversation guide in oncology: A descriptive analysis.

BACKGROUND/OBJECTIVE: Oncology guidelines recommend earlier communication with patients about prognosis and goals-of-care in serious illness. However, current evidence leaves gaps in our understanding of the experience of these conversations. This analysis evaluates the patient and clinician experience of a conversation using a Serious Illness Conversation Guide (SICG). DESIGN/SETTING: Secondary analysis from a cluster-randomized clinical trial in a northeastern cancer center. PARTICIPANTS: Physicians, advanced practice clinicians, and patients with advanced cancer who received the intervention. INTERVENTION: SICG, clinician training, systems-changes. MAIN OUTCOMES AND MEASURES: The patient questionnaire assessed perceptions of the conversation and impact on anxiety, hopefulness, peacefulness, sense of control over medical decisions, closeness with their clinician, and behaviors. The clinician questionnaire assessed feasibility, acceptability, and impact on satisfaction in their role. RESULTS: We enrolled 54 clinicians and 163 patients; 41 clinicians and 118 patients had a SICG discussion. Most patients described the conversation as worthwhile (79%) and reported no change or improvement in their sense of peacefulness, hopefulness, and anxiety (on average 79%); 56% reported feeling closer with their clinician. Qualitative patient data described positive behavior changes, including enhanced planning for future care and increased focus on personal priorities. Nearly 90% of clinicians agreed that the SICG facilitated timely, effective conversations, and 70% reported increased satisfaction in their role. CONCLUSION: Conversations using a SICG were feasible, acceptable, and were associated with positive experiences for both patients and clinicians in oncology in ways that align with national recommendations for serious illness communication. This trial is registered at ClinicalTrials.gov: NCT01786811 https://clinicaltrials.gov/ct2/show/NCT01786811.

Identification of inflammatory mediators associated with metastasis of oral squamous cell carcinoma in experimental and clinical studies: systematic review.

Metastasis, whether regional or distant, remains the main cause of morbidity and recurrence in oral cancer. The accumulating evidence suggests that inflammatory mediators are strong drivers for cancer progression and spread. However, the precise role of these inflammatory mediators in mediating specific metastatic stage is poorly understood due to lack of integration/validation of experimental research data and the clinical trials, i.e., the data produced from research is not translated to clinical therapeutic targets. This, in turn, results in the lack of developing reliable biomarker that can be used for accurate diagnosis/prognosis of the tumour spread. We have performed a systematic review to assess the role of inflammatory mediators as potential markers for diagnosis/prognosis of oral squamous cell carcinoma (OSCC) metastasis. We carried out a systematic search the PubMed, Web of Science, Embase and Scopus databases under the guidelines for Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Australian National Health and Medical Research Council (NHMRC). Articles were divided into two groups; experimental (in-vivo) and clinical studies. The REporting recommendations for tumour MARKer prognostic studies Scale (REMARK) was used to assess the quality of the studies for the clinical search while Animal research: Reporting In-vivo experiments (ARRIVE) guidelines were used to assess the quality of the animal studies. Sixteen articles in the clinical group and four articles in the experimental group were included in the final review. We identified nine inflammatory mediators; CXCR4, CXCL12 (SDF-1), CCR7, IL-6, IL-18, CCL20 (MIP-3), CXCL1 (GRO-1), CCL3, CXCR2. This panel of inflammatory mediators can provide a framework for hypothesis testing of the potential value of these mediators in metastatic prognosis. We recommend carrying a large cohort study with data pooling for adequate assessment and testing of the inflammatory panel of mediators.

Effect of the Serious Illness Care Program in Outpatient Oncology: A Cluster Randomized Clinical Trial.

Importance: High-quality conversations between clinicians and seriously ill patients about values and goals are associated with improved outcomes but occur infrequently. Objective: To examine feasibility, acceptability, and effect of a communication quality-improvement intervention (Serious Illness Care Program) on patient outcomes. Design, Setting, and Participants: A cluster randomized clinical trial of the Serious Illness Care Program in an outpatient oncology setting was conducted. Patients with advanced cancer (n = 278) and oncology clinicians (n = 91) participated between September 1, 2012, and June 30, 2016. Data analysis was performed from September 1, 2016, to December 27, 2018. All analyses were conducted based on intention to treat. Interventions: Tools, training, and system changes. Main Outcomes and Measures: The coprimary outcomes included goal-concordant care (Life Priorities) and peacefulness (Peace, Equanimity, and Acceptance in the Cancer Experience questionnaire) at the end of life. Secondary outcomes included therapeutic alliance (Human Connection Scale), anxiety (Generalized Anxiety Disorder 7 scale), depression (Patient Health Questionnaire 9), and survival. Uptake and effectiveness of clinician training, clinician use of the conversation tool, and conversation duration were evaluated. Results: Data from 91 clinicians in 41 clusters (72.9% participation; intervention, n = 48; control, n = 43; 52 [57.1%] women) and 278 patients (45.8% participation; intervention, n = 134; control, n = 144; 148 [53.2%] women) were analyzed. Forty-seven clinicians (97.9%) rated the training as effective (mean [SD] score, 4.3 [0.7] of 5.0 possible); of 39 who received a reminder, 34 (87.2%) completed at least 1 conversation (median duration, 19 minutes; range, 5-70). Peacefulness, therapeutic alliance, anxiety, and depression did not differ at baseline. The coprimary outcomes were evaluated in 64 patients; no significant differences were found between the intervention and control groups. However, the trial demonstrated significant reductions in the proportion of patients with moderate to severe anxiety (10.2% vs 5.0%; P = .05) and depression symptoms (20.8% vs 10.6%; P = .04) in the intervention group at 14 weeks after baseline. Anxiety reduction was sustained at 24 weeks (10.4% vs 4.2%; P = .02), but depression reduction was not sustained (17.8% vs 12.5%; P = .31). Survival and therapeutic alliance did not differ between groups. Conclusions and Relevance: The results of this cluster randomized clinical trial were null with respect to the coprimary outcomes of goal-concordant care and peacefulness at the end of life. Methodologic challenges for the primary outcomes, including measure selection and sample size, limit the conclusions that can be drawn from the study. However, the significant reductions in anxiety and depression in the intervention group are clinically meaningful and require further study. Trial Registration: ClinicalTrials.gov identifier: NCT01786811.

Multisource Evaluation of Surgeon Behavior Is Associated With Malpractice Claims.

OBJECTIVE: We merged direct, multisource, and systematic assessments of surgeon behavior with malpractice claims, to analyze the relationship between surgeon 360-degree reviews and malpractice history. BACKGROUND: Previous work suggests that malpractice claims are associated with a poor physician-patient relationship, which is likely related to behaviors captured by 360-degree review. We hypothesize that 360-degree review results are associated with malpractice claims. METHODS: Surgeons from 4 academic medical centers covered by a common malpractice carrier underwent 360-degree review in 2012 to 2013 (n = 385). Matched, de-identified reviews and malpractice claims data were available for 264 surgeons from 2000 to 2015. We analyzed 23 questions, highlighting positive and negative behaviors within the domains of education, excellence, humility, openness, respect, service, and teamwork. Regression analysis with robust standard error was used to assess the potential association between 360-degree review results and malpractice claims. RESULTS: The range of claims among the 264 surgeons was 0 to 8, with 48.1% of surgeons having at least 1 claim. Multiple positive and negative behaviors were significantly associated with the risk of having malpractice claims (P < 0.05). Surgeons in the bottom decile for several items had an increased likelihood of having at least 1 claim. CONCLUSION: Surgeon behavior, as assessed by 360-degree review, is associated with malpractice claims. These findings highlight the importance of teamwork and communication in exposure to malpractice. Although the nature of malpractice claims is complex and multifactorial, the identification and modification of negative physician behaviors may mitigate malpractice risk and ultimately result in the improved quality of patient care.

Oral contraceptives and cervical cancer: critique of a recent review.

A recent review article by Smith et al. in The Lancet purports to find a causal relationship between long-term use of oral contraceptives (OCs) and cervical cancer. While we endorse the search for such a relationship, we felt it important to critically examine Smith et al.'s review process and, as a result, we have questions about the validity of their conclusions. In our view, the findings of published articles as presented by Smith et al. do not confirm a causal connection between long-term use of OCs and cervical cancer. Our goal is not to conduct another formal review of the evidence, but to evaluate whether Smith et al. have met the burden of proof for establishing a causal relationship. Given the importance of OCs to women the world over, we urge reproductive health professionals to consider this issue carefully before accepting that a causal relationship exists.