Opioid and Non-Opioid Pharmacotherapy Use for Pain Management Among Privately Insured Pediatric Patients With Cancer in the United States.

BACKGROUND: This study examined the trends and patterns of opioid and non-opioid pharmacotherapy use among a large national sample of privately insured pediatric patients with cancer in the United States. MATERIALS AND METHODS: We identified pediatric (aged < 21) patients diagnosed with central nervous system (CNS), lymphoma, gonadal, leukemia, or bone cancer from MarketScan data 2005-2019. We examined the proportion of patients who filled a prescription for the following 5 types of pharmacotherapy: opioid, anticonvulsant, non-steroidal anti-inflammatory drug (NSAID), antidepressant, and muscle relaxant during active cancer treatment. We assessed the trends and patterns in pharmacotherapy using multivariable logistic regressions. RESULTS: Among 4174 patients included, 2979 (71%) had an opioid prescription; 746 (18%), 384 (9%), 202 (5%), and 169 (4%) had anticonvulsant, NSAID, antidepressant and muscle relaxant prescriptions, respectively. Multivariable logistic regression showed a nonlinear trend in the use of opioids among pediatric patients with cancer over time such that use slightly increased until 2012 (OR of 1.40 [95% CI, 1.12-1.73] for 2012 vs. 2006) but then decreased thereafter (OR of 0.51 [0.37-0.68] for 2018 vs. 2012). The use of anticonvulsants, NSAIDs, and muscle relaxants increased significantly linearly over time (all P < .005). CONCLUSION: There has been a downward trend in the use of opioids in recent years among pediatric patients with cancer and an upward trend in the use of non-opioid pharmacotherapy for pain management potentially as an alternative to opioids.

A comparative study of in vitro dose-response estimation under extreme observations.

Quantifying drug potency, which requires an accurate estimation of dose-response relationship, is essential for drug development in biomedical research and life sciences. However, the standard estimation procedure of the median-effect equation to describe the dose-response curve is vulnerable to extreme observations in common experimental data. To facilitate appropriate statistical inference, many powerful estimation tools have been developed in R, including various dose-response packages based on the nonlinear least squares method with different optimization strategies. Recently, beta regression-based methods have also been introduced in estimation of the median-effect equation. In theory, they can overcome nonnormality, heteroscedasticity, and asymmetry and accommodate flexible robust frameworks and coefficients penalization. To identify a reliable estimation method(s) to estimate dose-response curves even with extreme observations, we conducted a comparative study to review 14 different tools in R and examine their robustness and efficiency via Monte Carlo simulation under a list of comprehensive scenarios. The simulation results demonstrate that penalized beta regression using the mgcv package outperforms other methods in terms of stable, accurate estimation, and reliable uncertainty quantification.

Value of CTA/MRA in the setting of intraparenchymal hemorrhage in the emergency department.

PURPOSE: To assess the diagnostic yield of computed tomography angiography (CTA)/magnetic resonance angiography (MRA) brain and neck ordered in the emergency department (ED) for patients who have intraparenchymal hemorrhage (IPH) on their initial noncontrast CT (NCCT) of the head. METHODS: In this retrospective study, we reviewed 156 patients presenting to the ED with nontraumatic IPH, documented on NCCT. We assessed if the subsequent CTA/MRA was positive, and collected data regarding the location of the bleed, patients' age group, and presence/absence of associated SAH/IVH. Two neuroradiologists were asked to predict, based on age and NCCT appearance, whether the CTA/MRA would be positive or negative for demonstrating a vascular etiology of the hemorrhage. RESULTS: The yield of CTA/MRA head for patients above 75 years old was 2% (1/49), as the etiology for IPH in such age group was more commonly related to hypertensive bleed or amyloid angiopathy. The concomitant presence of subarachnoid hemorrhage (SAH) and intraventricular hemorrhage (IVH), particularly in patients younger than 75 years, correlated with a higher likelihood of a positive CTA. Statistically, the neuroradiologists were able to exclude a vascular source of the IPH based on CT appearance, bleed location, and patient's age in over 92% of cases. CONCLUSION: CTA/MRA for IPH has a lower yield in patients at older age and with deep gray matter distribution without SAH. Neuroradiologists were accurate at excluding a vascular source of the IPH in most cases. This study suggests that CTA/MRA can be omitted in certain scenarios, thereby preventing overutilization, and leading to optimal use of health care resources.

Prevalence of Moral Injury, Burnout, Anxiety, and Depression in Healthcare Workers 2 Years in to the COVID-19 Pandemic.

ABSTRACT: COVID-19 has led to marked increases in healthcare worker distress. Studies of these phenomena are often limited to a particular element of distress or a specific subset of healthcare workers. We administered the Moral Injury Symptom Scale for Healthcare Professionals, Copenhagen Burnout Inventory, Patient Health Questionnaire-9, and Generalized Anxiety Disorder-7 via online survey to 17,000 employees of a large academic medical center between December 2021 and February 2022. A total of 1945 participants completed the survey. Across all roles, the prevalence of moral injury, burnout, depression, and anxiety were 40.9%, 35.3%-60.6%, 25.4%, and 24.8%, respectively. Furthermore, 8.1% had been bothered by thoughts that they would be better off dead or of hurting themselves for "several days" or more frequently. Healthcare workers across all roles and practice settings are experiencing unsustainable levels of distress, with 1 in 12 regularly experiencing thoughts of self-harm.

Racial and Ethnic Disparities Among US Academic Dermatology Leadership and Its Influence on Resident Diversity.

BACKGROUND: Diversity in medicine improves mentorship and patient care. However, dermatology is one of the least diverse specialties. We analyzed the racial distributions across leadership positions at academic dermatology programs and explored potential influences on resident racial/ethnic composition.  Methods: A list of ACGME-accredited dermatology programs was obtained. Residency program websites, hospital websites, and publicly available data were used to ascertain race and ethnicity of academic dermatology leadership and residents. SAS version 9.4 was used to calculate descriptive statistics and associations between racial/ethnic composition of dermatologists in leadership positions and residents.  Results: URM individuals were significantly underrepresented across both leadership (6.9%) and resident (12.0%) positions. No statistically significant correlation was found between the percent of URM leadership and URM residents.  Conclusion: Diversity among the US population, medical students, dermatology trainees, and faculty are not reflected in departmental leadership in academic dermatology. This may influence URM recruitment into the field, retention of URM faculty and residents, and mentorship opportunities for URM dermatologists interested in leadership positions. Efforts are needed to improve disparities in representation across leadership roles in academic dermatology.  Fritsche M, Singh P, Zhou S, et al. Racial and ethnic disparities among US Academic Dermatology Leadership and its influence on resident diversity. J Drugs Dermatol. 2023;22(7):653-656. doi:10.36849/JDD.7114.

Covariate handling approaches in combination with dynamic borrowing for hybrid control studies.

Borrowing data from external control has been an appealing strategy for evidence synthesis when conducting randomized controlled trials (RCTs). Often named hybrid control trials, they leverage existing control data from clinical trials or potentially real-world data (RWD), enable trial designs to allocate more patients to the novel intervention arm, and improve the efficiency or lower the cost of the primary RCT. Several methods have been established and developed to borrow external control data, among which the propensity score methods and Bayesian dynamic borrowing framework play essential roles. Noticing the unique strengths of propensity score methods and Bayesian hierarchical models, we utilize both methods in a complementary manner to analyze hybrid control studies. In this article, we review methods including covariate adjustments, propensity score matching and weighting in combination with dynamic borrowing and compare the performance of these methods through comprehensive simulations. Different degrees of covariate imbalance and confounding are examined. Our findings suggested that the conventional covariate adjustment in combination with the Bayesian commensurate prior model provides the highest power with good type I error control under the investigated settings. It has desired performance especially under scenarios of different degrees of confounding. To estimate efficacy signals in the exploratory setting, the covariate adjustment method in combination with the Bayesian commensurate prior is recommended.

Gamification educational intervention improves pediatric nurses' comfort and speed drawing up code-dose epinephrine.

PURPOSE: Drawing up weight-based doses of epinephrine is a vital skill for pediatric nurses; however, non-intensive care unit (ICU) nurses may not routinely perform this skill and may not be as efficient or comfortable doing so during pediatric resuscitations. This study aimed to evaluate the impact of a gamification program on non-ICU pediatric nurses' knowledge and skills regarding epinephrine for pediatric cardiac arrest. DESIGN AND METHODS: Comfort and time to draw up three doses of epinephrine during out-of-ICU in-hospital pediatric cardiac arrest were measured pre- and post- a gamification-centered educational intervention. RESULTS: Nursing comfort improved from 2.93 ± 1.90 to 6.68 ± 1.46 out of 10 (mean difference 3.6 +/- 2.1, p < 0.001). Overall time to draw up three doses of epinephrine decreased after the intervention by an average of 27.1 s (p = 0.019). The number of nurses who could complete the task in under 2 min improved from 23% to 59% (p = 0.031). CONCLUSIONS: At baseline few non-ICU nurses could draw up multiple weight-based doses of epinephrine in under two minutes. A gamification simulation-based educational intervention improved pediatric non-ICU nurses' comfort and speed drawing up epinephrine. PRACTICE IMPLICATIONS: Wide-spread implementation of gamification-centered educational initiatives could result in faster epinephrine administration and improved mortality rates from in-hospital pediatric cardiac arrest.

Posterior Averaging Information Criterion.

We propose a new model selection method, named the posterior averaging information criterion, for Bayesian model assessment to minimize the risk of predicting independent future observations. The theoretical foundation is built on the Kullback-Leibler divergence to quantify the similarity between the proposed candidate model and the underlying true model. From a Bayesian perspective, our method evaluates the candidate models over the entire posterior distribution in terms of predicting a future independent observation. Without assuming that the true distribution is contained in the candidate models, the new criterion is developed by correcting the asymptotic bias of the posterior mean of the in-sample log-likelihood against out-of-sample log-likelihood, and can be generally applied even for Bayesian models with degenerate non-informative priors. Simulations in both normal and binomial settings demonstrate superior small sample performance.

On Bayesian modeling of censored data in JAGS.

BACKGROUND: Just Another Gibbs Sampling (JAGS) is a convenient tool to draw posterior samples using Markov Chain Monte Carlo for Bayesian modeling. However, the built-in function dinterval() for censored data misspecifies the default computation of deviance function, which limits likelihood-based Bayesian model comparison. RESULTS: To establish an automatic approach to specifying the correct deviance function in JAGS, we propose a simple and generic alternative modeling strategy for the analysis of censored outcomes. The two illustrative examples demonstrate that the alternative strategy not only properly draws posterior samples in JAGS, but also automatically delivers the correct deviance for model assessment. In the survival data application, our proposed method provides the correct value of mean deviance based on the exact likelihood function. In the drug safety data application, the deviance information criterion and penalized expected deviance for seven Bayesian models of censored data are simultaneously computed by our proposed approach and compared to examine the model performance. CONCLUSIONS: We propose an effective strategy to model censored data in the Bayesian modeling framework in JAGS with the correct deviance specification, which can simplify the calculation of popular Kullback-Leibler based measures for model selection. The proposed approach applies to a broad spectrum of censored data types, such as survival data, and facilitates different censored Bayesian model structures.

Serotonin-Mediated Activation of Serotonin Receptor Type 1 Oppositely Modulates Voltage-Gated Calcium Channel Currents in Rat Sensory Neurons Innervating Hindlimb Muscle.

Serotonin (5-HT) is a multifaceted neurotransmitter that has been described to play a role as a peripheral inflammatory mediator when released in ischemic or injured muscle. Dorsal root ganglia (DRG) neurons are key sensors of noxious stimuli that are released under inflammatory conditions or mechanical stress. Little information is available on the specific 5-HT receptor subtypes expressed in primary afferents that help regulate reflex pressor responses. In the present study, the whole-cell patch-clamp technique was employed to examine the modulation of voltage-gated calcium channel (CaV) 2.2 currents by 5-HT and to identify the 5-HT receptor subtype(s) mediating this response in acutely dissociated rat DRG neurons innervating triceps surae muscle. Our results indicate that exposure of 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI)-labeled DRG neurons to 5-HT can exert three modulatory effects on CaV currents: high inhibition, low inhibition, and enhancement. Both 5-HT-mediated inhibition responses were blocked after pretreatment with pertussis toxin (PTX), indicating that 5-HT receptors are coupled to CaV2.2 via Gα i/o protein subunits. Application of selective serotonin receptor type 1 (5-HT1) agonists revealed that modulation of CaV2.2 currents occurs primarily after 5-HT1A receptor subtype stimulation and minimally from 5-HT1D activation. Finally, the intrathecal administration of the selective 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), significantly (P < 0.05) decreased the pressor response induced by intra-arterial administration of lactic acid. This suggests that 5-HT1A receptors are expressed presynaptically on primary afferent neurons innervating triceps surae muscle. Our findings indicate that preferential stimulation of 5-HT1 receptors, expressed on thin fiber muscle afferents, serves to regulate the reflex pressor response to metabolic stimuli. SIGNIFICANCE STATEMENT: The monoamine serotonin (5-HT), released under ischemic conditions, can contribute to the development of inflammation that negatively affects the exercise pressor reflex. The 5-HT receptor subtype and signaling pathway that underlies calcium channel modulation in dorsal root ganglia afferents, innervating hindlimb muscles, are unknown. We show that 5-HT can either block (primarily via serotonin receptor type 1 (5-HT1)A subtypes) or enhance voltage-gated calcium channel (CaV2.2) currents. Our findings suggest 5-HT exhibits receptor subtype selectivity, providing a complexity of cellular responses.

Association of staffing with Incidence of delayed retinal break or detachment after posterior vitreous detachment in a resident urgent care clinic.

PURPOSE: To compare the incidence rate of delayed retinal break or detachment after diagnosis of acute, symptomatic posterior vitreous detachment (PVD) in a resident-run urgent care clinic (UCC) when staffed by a retina attending, non-retina ophthalmology attending, optometrist, or ophthalmology resident only. METHODS: Retrospective consecutive case series. Of the 594 patients with acute, symptomatic PVD evaluated in the UCC at Penn State Eye Center between 1/1/2016 and 10/10/2019, 454 were included in the study; 140 were excluded because they were diagnosed with a retinal break or detachment on presentation to the UCC, had media opacity precluding examination, or had no follow-up within one year. Demographics, presenting examination findings, and type of staffing were recorded; subsequent visits up to 1 year were analyzed for presence of delayed retinal break or detachment. RESULTS: Among 491 eyes of 454 patients with a mean follow-up of 147 days, ten delayed breaks (10/491, 2.0%) and three delayed detachments (3/491, 0.6%) were discovered. Incidence rates of delayed breaks and detachments were 1.8% (5/282) and 0.7% (2/282), respectively, in the retina attending group, 1.0% (1/105) and 1.0% (1/105) in the non-retina ophthalmology attending group, 4.7% (3/64) and 0% (0/64) in the optometrist group, and 2.5% (1/40) and 0% (0/40) in the ophthalmology resident only group. There was no statistically significant difference in the incidence of delayed break or detachment among the staffing groups (P = 0.7312), but this study was underpowered to detect a statistically significant difference among staffing groups. Patients with a delayed break or detachment were more likely to have lattice degeneration (P = 0.0265) or a history of retinal break in the contralateral eye (P = 0.0014), and most eyes (10 [76.9%]) with a delayed break or detachment were left eyes (P = 0.0466). CONCLUSIONS: The overall rate of delayed retinal break or detachment in the current study is similar to previously published rates among retinal physician and retinal fellow examiners. Although no statistically significant difference among staffing groups in the incidence rates of delayed retinal tears or detachments was identified in the study, it is important to note that the optometry and ophthalmology resident only groups had higher incidence rates of delayed retinal breaks than did the retina and non-retina ophthalmology attending groups, and this may be clinically important. Larger cohort studies would be needed in order to have the power to detect statistically significant differences among staffing groups. Varied staffing for acute, symptomatic PVD may assist with resource allocation in similar settings.

Utilization and costs of epidermal growth factor receptor mutation testing and targeted therapy in Medicare patients with metastatic lung adenocarcinoma.

BACKGROUND: Guidelines in 2013 and 2014 recommended Epidermal Growth Factor Receptor (EGFR) testing for metastatic lung adenocarcinoma patients as the efficacy of targeted therapies depends on the mutations. However, adherence to these guidelines and the corresponding costs have not been well-studied. METHODS: We identified 2362 patients at least 65 years old newly diagnosed with metastatic lung adenocarcinoma from January 2013 to December 2015 using the SEER-Medicare database. We examined the utilization patterns of EGFR testing and targeted therapies including erlotinib and afatinib. We further examined the costs of both EGFR testing and targeted therapy in terms of Medicare costs and patient out-of-pocket (OOP) costs. RESULTS: The EGFR testing rate increased from 38% in 2013 to 51% and 49% in 2014 and 2015 respectively. The testing rate was 54% among the 394 patients who received erlotinib, and 52% among the 42 patients who received afatinib. The median Medicare and OOP costs for testing were $1483 and $293. In contrast, the costs for targeted therapy were substantially higher with median 30-day costs at $6114 and $240 for erlotinib and $6239 and $471 for afatinib. CONCLUSION: This population-based study suggests that testing guidelines improved the use of EGFR testing, although there was still a large proportion of patients receiving targeted therapy without testing. The costs of targeted therapy were substantially higher than the testing costs, highlighting the need to improve adherence to testing guidelines in order to improve clinical outcomes while reducing the economic burden for both Medicare and patients.

A Multicenter Retrospective Evaluation of Specialized Laboratory Investigations in the Workup of Pediatric Patients With New-Onset Supraventricular Tachycardia.

INTRODUCTION: Specialized laboratory evaluation of supraventricular tachycardia in children may occur, but the utility is unknown. The study objectives are to assess the type, frequency, and results of specialized laboratory testing performed in pediatric patients presenting with new-onset supraventricular tachycardia. We hypothesized that when specialized laboratory testing occurs (particularly for cardiac failure, toxicologic, inflammatory, and thyroid diseases), the results are generally within normal limits. METHODS: This is a retrospective descriptive study using an electronic health record database (TriNetX, Inc). We collected and evaluated the following data of subjects aged younger than 18 years with a first-time supraventricular tachycardia diagnosis: demographics, diagnostic codes, deaths, and laboratory codes/results (natriuretic peptide B, natriuretic peptide B prohormone N-terminal, troponin I, toxicology testing, inflammatory markers, and thyroid studies). RESULTS: A total of 621 subjects (524 [84.4%] without laboratory testing, 97 [15.6%] with laboratory testing) were included. Thyroid studies (65 [10.5%]) were the most frequent laboratory study performed followed by cardiovascular specific studies (35 [5.6%]), inflammatory markers (21 [3.4%]), and toxicology tests (10 [1.6%]) (P = .002). Obtained laboratory testing was more frequent with older subjects, females, and need for emergency, hospital, and critical care services. DISCUSSION: Cardiac-specific and noncardiac laboratory testing is frequently ordered for pediatric patients who present with supraventricular tachycardia. Thyroid studies were the most common laboratory testing ordered, but abnormal results only occurred in less than a quarter of subjects. These findings may highlight a quality improvement opportunity for emergency nurses and practitioners in the practice of obtaining laboratory tests to better reflect high-value evidence-based care for this vulnerable population.

Acupuncture for Cancer-Related Anorexia: a Review of the Current Evidence.

PURPOSE OF REVIEW: Loss of appetite/anorexia is extremely common among cancer patients, affecting as many as half of newly diagnosed patients and 70% of patients with advanced disease. Effective management of this disabling symptom of cancer remains a major challenge in the field of oncology. We conducted a systematic review of the current evidence on acupuncture and/or moxibustion as an intervention for cancer-related anorexia. RECENT FINDINGS: Acupuncture, as a part of traditional Chinese medicine practice, has demonstrated effectiveness in managing many cancer- and treatment-related symptoms, especially chemotherapy-induced or postoperative nausea. However, the efficacy of acupuncture in treating cancer-related anorexia/loss of appetite is not clear. The current level of evidence is insufficient to make a definitive conclusion on the benefit of acupuncture/moxibustion for treating chronic cancer-related anorexia/appetite problems. Future large randomized controlled trials of high methodological quality are needed.

Impact of a Severe Rocky Mountain Spotted Fever Case on Treatment Practices at an Academic Institution Within a Nonendemic Area.

INTRODUCTION: Rocky Mountain spotted fever (RMSF) is a bacterial disease associated with morbidity and mortality when untreated. The primary study objectives are to describe clinician diagnostic and treatment practices in a nonendemic area after the occurrence of an unrecognized severe pediatric presumed RMSF case (index case). We hypothesized that inpatient diagnostic testing frequency and initiation of empiric treatment will increase after the index case. METHODS: We performed a retrospective chart review of patients aged less than 18 y evaluated for RMSF at Penn State Hershey Children's Hospital between 2010 and 2019. We divided the study population into 2 groups (preindex and postindex) and evaluated patient characteristics, RMSF testing completion, and timing of doxycycline administration. RESULTS: Fifty-four patients (14 [26%] preindex and 40 [74%] postindex) were included. Age (median [25th percentile, 75th percentile]) decreased from 14.5 y (8.6, 16) preindex to 8.3 y (3.6, 14) postindex. Twelve (86%) preindex and 31 (78%) postindex patients received empiric doxycycline (P=0.70). Four years after the index case, a decrease in empiric and urgent initiation of doxycycline administration was noted. One case of severe RMSF was diagnosed 4 y after the index case. CONCLUSIONS: Our study found that inpatient RMSF testing increased after the index case, but not all patients received empiric treatment. This may represent an underappreciation of RMSF severity even after a recent devastating case. We suggest that when severe rare but possibly reversible diseases, such as RMSF occur, all clinicians are educated on the diagnostic and treatment approach to reduce the morbidity and mortality risk.

Time-resolved FRET and NMR analyses reveal selective binding of peptides containing the LC3-interacting region to ATG8 family proteins.

Selective autophagy sequesters cytoplasmic cargo for lysosomal degradation via the binding of autophagy receptors to Atg8 (autophagy-related 8) family proteins on the autophagic membrane. The sole yeast Atg8 gene has six mAtg8 (mammalian Atg8) homologs, including the MAP1LC3 (microtubule-associated protein-1 light chain 3) family and the GABA receptor-associated proteins. Selective autophagy receptors interact with two conserved hydrophobic pockets (termed the W-site and L-site) of mATG8 proteins through a linear motif called the LC3-interacting region (LIR) with the general composition (W/F/Y)XX(I/L/V). To address a lack in our knowledge regarding LIR peptide specificity toward each mATG8 homolog, here we used competitive time-resolved FRET to sensitively and quantitatively characterize the interactions between LIRs and mAtg8. We report that 14 representative LIR-containing peptides display differential binding affinities toward the mAtg8 proteins and identified the LIR domain peptide of TP53INP1 as exhibiting high affinity for all six mATG8 proteins. Using peptide truncation studies, we found that both N- and C-terminal acidic residues, as well as the C-terminal Cys residue of the TP53INP1 LIR peptide, are required for its high-affinity binding to LC3A and LC3B, whereas binding to the GABARAP subfamily proteins was facilitated by residues either N-terminal or C-terminal to the core motif. Finally, we used NMR chemical shift perturbation analysis to gain molecular insights into these findings. Collectively, our results may aid in the development of molecules that selectively disrupt specific mATG8-LIR interactions to dissect the biological roles of the six mATG8 homologs for potential therapeutic applications.

Cell surface vimentin-positive circulating tumor cell-based relapse prediction in a long-term longitudinal study of postremission neuroblastoma patients.

Neuroblastoma (NB) is a deadly childhood disease that carries a 50% chance of relapse for anyone in remission and similar level of 5-year survival. We investigated the value of our proprietary approach-cell surface vimentin (CSV) positive circulating tumor cells (CTC) to monitor treatment response and predict relapse in NB patients under remission in a Phase II long-term preventative clinical trial. We longitudinally analyzed peripheral blood samples from 93 patients for 27 cycles (~25 months) and discovered that the presence of CSV+ CTCs in the first two sequential samples (baseline, cycle 4 [month 3-4]) was a significant indicator of earlier relapse. We observed strong correlation between relapse-free survival (RFS) and lack of CSV+ CTCs in first 4 cycles of therapy (95%). There was sensitivity reaching 100% in predicting RFS in patients who had neither CSV+ CTCs nor MycN amplification. Of note, the low number of CSV+ CTCs seems equivalent to low tumor load because the prevention therapy difluoromethylornithine yields faster reduction of relapse risk when none or only 1-2 CSV+ CTCs (every 6 mL) are present in the blood samples compared to >3 CSV+ CTCs. To the best of our knowledge, this is the first study that directly observes CTCs in under remission NB patients for relapse prediction and the first to gather sequential CSV+ CTC data in any study in a long-term longitudinal manner.

Dose-dependent effect of aerobic exercise on inflammatory biomarkers in a randomized controlled trial of women at high risk of breast cancer.

BACKGROUND: Increased levels of inflammation are associated with many diseases, including cancer. Physical activity can lower breast cancer risk as well as levels of inflammation. The Women In Steady Exercise Research (WISER) Sister trial was a randomized controlled trial that investigated the effects of a dosed, moderate to vigorous, aerobic exercise intervention on levels of inflammation in premenopausal women who were at high risk of developing breast cancer. METHODS: Participants were randomized to control (<75 minutes per week; 41 patients), low-dose exercise (150 minutes per week; 38 patients), or high-dose exercise (300 minutes per week; 37 patients) groups. The 5-menstrual cycles-long, home-based treadmill exercise intervention gradually increased in minutes per week and intensity up to a maximum of 80% of the age-predicted maximum heart rate. Blood was collected at baseline and at follow-up and assayed for chemokine (C-C motif) ligand 2 (CCL2), interleukin 10 (IL-10), interleukin 12 (IL-12), and tumor necrosis factor α (TNF-α). RESULTS: A linear dose-response relationship was observed for the proinflammatory biomarkers CCL2 (%Δ of -5.44% in the control group, -0.03% in the low-dose exercise group, and 1.54% in the high-dose exercise group), IL-12 (%Δ of -21.5% in the control group, 38.2% in the low-dose exercise group, and 25.8% in the high-dose exercise group,) and TNF-α (%Δ of -4.69% in the control group, 9.51% in the low-dose exercise group, and 15.7% in the high-dose exercise group) but not for the anti-inflammatory biomarker IL-10 (%Δ of 5.05% in the control group, 6.05% in the low-dose exercise group, and 10.6% in the high-dose exercise group). For IL-12 and TNF-α, the percentage change was significantly higher in the low-dose (IL-12: P < .001; and TNF-α: P = .01) and high-dose (IL-12: P < .001; and TNF-α: P < .001) exercise groups compared with the control group. CONCLUSIONS: Moderate to vigorous aerobic exercise appeared to increase levels of proinflammatory biomarkers in a dose-dependent manner in a population of healthy women at high risk of developing breast cancer. The results of the current study suggest that for healthy premenopausal women, the mechanism of reduced breast cancer risk observed in physically active individuals may not be a result of reduced levels of inflammation.

Long-term causes of death among pediatric patients with cancer.

BACKGROUND: The objectives of this study were to characterize the risk of death (1) from the primary cancer vs competing cause of death; and (2) from various causes of death vs the general poplation. The relative risk of death after a pediatric cancer diagnosis versus the general population and the risk of death from a primary cancer diagnosis versus competing causes of death. METHODS: This retrospective, population-based study used the Surveillance, Epidemiology, and End Results database (1980-2015) and included patients aged 0 to 19 years at the time of diagnosis. Observed deaths were calculated; the risk of death versus the general population was assessed with standardized mortality ratios (SMRs). Competing risk models for the cause of death were performed. RESULTS: There were 58,356 patients who were diagnosed, and the mortality rate was 22.8%. To assess causes of death, 6996 patients who died during the study period were included (45,580 total person-years at risk): 5128 (73%) died of their primary cancer, and 1868 (27%) died of a competing cause. Among all patients, the rate of death from the index cancer was higher than the rate of death from another cause within the first 5 years after diagnosis. The risk of death from a nonprimary cancer began to supersede the rate of death from the primary cancer 10 years after diagnosis for patients with germ cell tumors, lymphomas, and sarcomas. SMRs for the primary cancer were highest within the first 5 years after diagnosis for all cancers (SMRs, 100-50,000; P < .0001). The risk of death from competing causes (heart disease, suicide, and sepsis) was elevated (SMR, >100; P < .001). The risk of dying of heart disease was high, especially for patients with astrocytomas (SMR, 47.84; 95% confidence interval [CI], 27.87-76.59) and neuroblastomas (SMR, 98.59; 95% CI, 47.28-181.32). The risk of dying of suicide was high in most patients, particularly for those with osteosarcomas (SMR, 111.40; 95% CI, 2.82-620.69), Hodgkin lymphomas (SMR, 62.35; 95% CI, 34.89-102.83), and gonadal germ cell tumors (SMR, 28.97; 95% CI, 12.51-57.09). CONCLUSIONS: The cause of death for patients with gonadal germ cell tumors, lymphomas, and sarcomas is more commonly a secondary cancer or noncancerous cause than the primary disease; their risk of death from competing causes (heart disease, suicide, and sepsis) rises throughout life.

Prolonged Opioid Use After Surgery for Early-Stage Breast Cancer.

INTRODUCTION: This study examined the patterns of prolonged opioid use and the factors associated with higher risk of prolonged opioid use among opioid-naïve working-age patients with early-stage breast cancer. METHODS: Using MarketScan data, the study identified 23,440 opioid-naïve patients who received surgery for breast cancer between January 2000 and December 2014 and filled at least one opioid prescription attributable to surgery. Prolonged opioid use was defined as one or more prescriptions for opioids within 90 to 180 days after surgery and defined extra-prolonged opioid use as one or more opioid prescriptions between 181 and 365 days after surgery. Multivariable logistic regressions were performed to ascertain factors associated with prolonged and extra-prolonged use of opioids. FINDINGS: Of the 23,440 patients, 4,233 (18%) had prolonged opioid use, and 2,052 (9%) had extra-prolonged opioid use. Patients who received mastectomy plus reconstruction had the highest rate of prolonged opioid use (38%) followed by mastectomy alone (15%). A multivariable logistic regression confirmed that patients with mastectomy and reconstruction had the highest odds ratio of prolonged opioid use compared to lumpectomy and whole breast irradiation (adjusted odds ratio, 5.6; 95% confidence interval, 5.1-6.1). Mean daily opioid dose was consistently high without any obvious dosage reduction among patients with opioid use. INTERPRETATION: This large observational study showed a high rate of prolonged opioid use among patients who received surgery for early-stage breast cancer and found significant difference in prolonged opioid use by treatment type. IMPLICATIONS FOR PRACTICE: This large observational study found a high rate of prolonged opioid use among working-age patients with early-stage breast cancer who received curative surgery, especially among patients who received mastectomy. Among patients with opioid use, the mean daily opioid dose was consistently high without any obvious dosage tapering. This study highlights the need to emphasize appropriate opioid therapy and potential dosage reduction or discontinuation among patients with early-stage breast cancer who received surgical interventions.