Search

Abstract Stereotactic radiotherapy is a term collectively used to describe the radiation treatment techniques that allow for the delivery of highly precise ionizing radiation. It is usually a high dose per session in single or few fractions. This treatment approach has been in medical use for over six decades and has primarily evolved in the last two decades. Many patients benefit from this unique non‐conventional radiotherapy approach. Its indications include various malignant, benign and functional problems in cranial and body sites. This technique is not widespread in developing countries compared to developed countries. This work is an educational narrative review for learners in radiation oncology. We aim to share the knowledge of this practice to improve precision radiation oncology globally. This review summarizes the basics of stereotactic radiotherapy, the technical prerequisites, the clinical considerations, the practical recommendations and the learning points from each site‐specific region.

Background: Palbociclib, the first available cyclin-dependent kinase 4/6 inhibitor, plus endocrine therapy is approved for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) metastatic breast cancer (MBC). This study compared real-world effectiveness of palbociclib plus letrozole versus letrozole in older patients with MBC in US clinical practice. Methods: This retrospective analysis included patients from the Flatiron Health longitudinal database. Overall, 796 women with HR+/HER2− MBC aged ≥65 years starting palbociclib plus letrozole or letrozole as first-line therapy between February 2015 and September 2018 were included. Patients were evaluated from treatment start until December 2018, death, or last visit, whichever came first. Real-world progression-free survival (rwPFS), overall survival (OS), and real-world best tumor responses (rwBTR) were endpoints. Stabilized inverse probability treatment weighting (sIPTW) balanced patient characteristics. Results: After sIPTW, 450 patients treated with palbociclib plus letrozole and 335 treated with letrozole were included; median age was 74.0 years. Median rwPFS was 22.2 (95% CI, 20.0–30.4) months for palbociclib plus letrozole versus 15.8 (12.9–18.9) months for letrozole (hazard ratio, 0.59 [0.47–0.74]; P

The impact of coronavirus disease 2019 (COVID-19) on the wellbeing of breast cancer (BC) patients is not well understood. This study described psychosocial problems among these patients in the United States (US) during the COVID-19 pandemic. Data were collected from BC patients via an online self-report survey between 30 March–6 July 2021 to assess the prevalence of COVID-19 diagnosis history and potential depression, health-related quality of life, COVID-related stress, and financial toxicity. Patients with early-stage (eBC) and metastatic (mBC) disease were compared. Of 669 patients included in the analysis, the prevalence of COVID-19 diagnosis history (10.9% versus 7.7%) and potential depression (33.7% versus 28.3%) were higher in mBC than eBC patients. Patients with eBC (versus mBC) had higher scores on nearly all Functional Assessment of Cancer Therapy-Breast scales (all, p < 0.001). For the Psychological Impact of Cancer subscales measuring negative coping strategies, the emotional distress score was the highest (9.1 ± 1.8) in the overall sample. Comprehensive Score for Financial Toxicity scores were higher in eBC than in mBC patients (24.2 ± 11.3 vs. 21.3 ± 10.2, p < 0.001). Overall, the COVID-19-related stress score was highest for danger/contamination fears (8.2 ± 5.6). In conclusion, impairments to psychosocial wellbeing among patients during the pandemic were observed, particularly financial toxicity and poor mental health and emotional functioning, with greater problems among mBC patients.

Abstract Background A Phase II study was undertaken to evaluate the safety and efficacy of the neoadjuvant socazolimab, a novel PD-L1 inhibitor, in combination with nab-paclitaxel and cisplatin for locally advanced esophageal squamous cell carcinoma (ESCC). Methods Sixty-four patients were randomly divided between the Socazolimab + nab-paclitaxel + cisplatin (TP) arm (n = 32) and the control arm (n = 32), receiving either socazolimab (5 mg/kg intravenously (IV), day 1) or a placebo with nab-paclitaxel (125 mg/m2 IV, day 1/8) and cisplatin (75 mg/m2 IV, day 1) repeated every 21 days for four cycles before surgery. The primary endpoint was major pathological response (MPR), and the secondary endpoints were pathological complete response (pCR), R0 resection rate, event-free survival (EFS), overall survival (OS), and safety. Results A total of 29 (90.6%) patients in each arm underwent surgery, and 29 (100%) and 28 (98.6%) patients underwent R0 resection in the Socazolimab + TP and Placebo + TP arms, respectively. The MPR rates were 69.0 and 62.1% (95% Confidence Interval (CI): 49.1–84.0% vs. 42.4–78.7%, P = 0.509), and the pCR rates were 41.4 and 27.6% (95% CI: 24.1–60.9% vs. 13.5–47.5%, P = 0.311) in the Socazolimab + TP and Placebo + TP arms, respectively. Significantly higher incidence rates of ypT0 (37.9% vs. 3.5%; P = 0.001) and T downstaging were observed in the Socazolimab + TP arm than in the Placebo + TP arm. The EFS and OS outcomes were not mature. Conclusions The neoadjuvant socazolimab combined with chemotherapy demonstrated promising MPR and pCR rates and significant T downstaging in locally advanced ESCC without increasing surgical complication rates. Trial registration Registration name (on clinicaltrials.gov): A Study of Anti-PD-L1 Antibody in Neoadjuvant Chemotherapy of Esophageal Squamous Cell Carcinoma. Registration number: NCT04460066.

Abstract Data on real-world effectiveness of cyclin-dependent kinase 4/6 inhibitor combination therapy versus endocrine therapy alone are limited. The Flatiron Health Analytic Database was used to assess overall survival (OS) in patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2−) metastatic breast cancer (MBC) treated with first-line palbociclib plus an aromatase inhibitor (AI) versus an AI alone in routine US clinical practice. In total, 2888 patients initiated treatment during February 3, 2015–March 31, 2020, with a potential ≥6-month follow-up (cutoff date, September 30, 2020). After stabilized inverse probability treatment weighting, median OS (95% CI) is significantly longer among palbociclib versus AI recipients (49.1 [45.2–57.7] versus 43.2 [37.6–48.0] months; hazard ratio, 0.76 [95% CI, 0.65–0.87]; P

BackgroundElderly patients are generally underrepresented in oncology clinical trials; therefore, real-world data are needed to inform clinical management of elderly patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2−) metastatic breast cancer (mBC). This subanalysis of the P-REALITY X study (NCT05361655) evaluated palbociclib treatment patterns and comparative effectiveness of palbociclib plus an aromatase inhibitor (AI) versus an AI alone among patients with HR+/HER2− mBC aged ≥ 75 years treated in routine clinical practice in the United States.MethodsThis retrospective observational cohort study used electronic health records from the Flatiron Health Analytic Database. Palbociclib treatment patterns, overall survival (OS), real-world progression-free survival (rwPFS), and time to chemotherapy (TTC) were evaluated. Three methods were used for comparative analyses: (1) an unadjusted analysis, (2) stabilized inverse probability treatment weighting (sIPTW; primary analysis), and (3) propensity score matching (PSM; sensitivity analysis).ResultsA total of 961 patients aged ≥ 75 years with HR+/HER2− mBC were identified who started palbociclib plus an AI (n = 313) or an AI alone (n = 648) as first-line (1L) therapy between February 2015 and March 2020 (data cut-off: September 30, 2020). Among patients in the palbociclib plus an AI group with a documented palbociclib starting dose (n = 306), approximately 75% started palbociclib at 125 mg/day, and approximately 40% experienced dose adjustment. After sIPTW, patients treated with palbociclib plus an AI versus an AI alone had significantly improved OS (median of 43.0 vs. 32.4 months; hazard ratio [HR], 0.66 [95% confidence interval (CI), 0.51–0.84]; P = 0.0007), rwPFS (median of 20.0 vs. 15.0 months; HR, 0.72 (0.59–0.89); P = 0.0021), and TTC (median of 40.2 vs. 27.4 months; HR, 0.69 [0.55–0.87]; P = 0.0014). These significant improvements in OS, rwPFS, and TTC remained consistent in the unadjusted analysis and after PSM.ConclusionThis real-world comparative analysis demonstrated that 1L palbociclib plus an AI is associated with improved effectiveness compared with an AI alone among patients with HR+/HER2− mBC aged ≥ 75 years. These findings support palbociclib plus an AI as a standard-of-care 1L treatment for elderly patients with HR+/HER2− mBC.

Automation may enable high-quality cervical cancer radiation on shorter treatment planning timelines.

Introduction: The epidemic of gun violence in the United States (US) is exacerbated by frequent mass shootings. In 2021, there were 698 mass shootings in the US, resulting in 705 deaths and 2,830 injuries. This is a companion paper to a publication in JAMA Network Open, in which the nonfatal outcomes of victims of mass shootings have been only partially described. Methods: We gathered clinical and logistic information from 31 hospitals in the US about 403 survivors of 13 mass shootings, each event involving greater than 10 injuries, from 2012–19. Local champions in emergency medicine and trauma surgery provided clinical data from electronic health records within 24 hours of a mass shooting. We organized descriptive statistics of individual-level diagnoses recorded in medical records using International Classification of Diseases codes, according to the Barell Injury Diagnosis Matrix (BIDM), a standardized tool that classifies 12 types of injuries within 36 body regions. Results: Of the 403 patients who were evaluated at a hospital, 364 sustained physical injuries—252 by gunshot wound (GSW) and 112 by non-ballistic trauma—and 39 were uninjured. Fifty patients had 75 psychiatric diagnoses. Nearly 10% of victims came to the hospital for symptoms triggered by, but not directly related to, the shooting, or for exacerbations of underlying conditions. There were 362 gunshot wounds recorded in the Barell Matrix (1.44 per patient). The Emergency Severity Index (ESI) distribution was skewed toward higher acuity than typical for an emergency department (ED), with 15.1% ESI 1 and 17.6% ESI 2 patients. Semi-automatic firearms were used in 100% of these civilian public mass shootings, with 50 total weapons for 13 shootings (Route 91 Harvest Festival, Las Vegas. 24). Assailant motivations were reported to be associated with hate crimes in 23.1%. Conclusion: Survivors of mass shootings have substantial morbidity and characteristic injury distribution, but 37% of victims had no GSW. Law enforcement, emergency medical systems, and hospital and ED disaster planners can use this information for injury mitigation and public policy planning. The BIDM is useful to organize data regarding gun violence injuries. We call for additional research funding to prevent and mitigate interpersonal firearm injuries, and for the National Violent Death Reporting System to expand tracking of injuries, their sequelae, complications, and societal costs.

Purpose: There is a vital need to train radiation therapy professionals in low- and middle-income countries (LMICs) to develop sustainable cancer treatment capacity and infrastructure. LMICs have started to introduce intensity modulated radiation therapy (IMRT), which is the standard of care in high-income countries, because of improved outcomes and reduced toxicities. This work reports the efficacy of a complementary asynchronous plus synchronous virtual-training approach on improving radiation therapy professions’ self-confidence levels and evaluating participants’ attitudes toward asynchronous and synchronous didactic hands-on learning in 3 LMICs. Methods and Materials: Training was provided to 37 participants from Uganda, Guatemala, and Mongolia, which included 4 theoretical lectures, 4 hands-on sessions, and 8 self-guided online videos. The 36-day training focused on IMRT contouring, site-specific target/organ definition, planning/optimization, and quality assurance. Participants completed pre- and postsession confidence surveys on a 0 to 10 scale, which was converted to a 5-point Likert rating scale to evaluate the training outcomes. The pros and cons of the 3 different training formats were compared. Results: The participants included 15 (40.5%) radiation oncologists, 11 (29.7%) medical physicists, 6 (16.2%) radiation therapists, and 5 (13.5%) dosimetrists. Approximately 50% had more than 10 years of radiation therapy experience, 70.8% had no formal IMRT training, and only 25% had IMRT at their institutions. The average experience and confidence levels in using IMRT at baseline were 3.2 and 2.9, which increased to 5.2 and 4.9 (P < .001) after the theoretical training. After the hands-on training, the experience and confidence levels further improved to 5.4 and 5.5 (P < .001). After the self-guided training, the confidence levels increased further to 6.9 (P < .01). Among the 3 different training sessions, hands-on trainings (58.3%) were most helpful for the development of participants’ IMRT skills, followed by theoretical sessions with 25%. Conclusions: After completing the training sessions, Uganda and Mongolia started IMRT treatments. Remote training provides an excellent and feasible e-learning platform to train radiation therapy professionals in LMICs. The training program improved the IMRT confidence levels and treatment delivery. The hands-on trainings were most preferred.

Introduction: Access to radiation therapy in low- and middle-income countries (LMICs) could be improved with modern hypofractionated radiation therapy schedules, although their adoption remains limited. We aimed to evaluate perceptions regarding hypofractionation and the effect of a dedicated curriculum in an LMIC. Methods and Materials: We developed a pilot e-learning hypofractionation curriculum focused on breast, prostate, rectal cancer, and high-grade glioma in Colombia. International educators taught 13 weekly, 90-minute sessions. Participants completed pre- and postcurriculum questionnaires regarding hypofractionation attitudes, 1 to 5 Likert-scale self-confidence, and practices for 12 clinical scenarios. Physicians’ responses were categorically scored “1” (for hypofractionation or ultrahypofractionation) or “0” (for conventional fractionation). We used the paired t test to measure pre- versus postcurriculum differences in self-confidence and the McNemar test to detect differences in hypofractionation selection. Results: Across 19 cities in Colombia, 147 clinicians enrolled: 61 radiation oncologists, 6 radiation oncology residents, 59 medical physicists, 18 physics residents, and 3 other staff. Among physicians, education was the greatest barrier to select hypofractionation, common in ultrahypofractionation for prostate (77.6%) and breast cancer (74.6%) and less common for moderate hypofractionation of prostate (61.2%) and breast cancer (52.2%). Additional perceived barriers included unfamiliarity with clinic protocols (7%-22%), clinical experience (5%-15%), personal preference (3%-16%), and lack of technology (3%-20%), with variation across different clinical settings. After the curriculum, paired (n = 38) physicians’ selection of hypofractionation increased across all disease sites (mean aggregate score 6.2/12 vs 8.2/12, P

PURPOSETechnology advancements ushered in a new era of how we reimagine our human interaction, with videoconferencing becoming commonplace in educational, professional, and social settings. These tools became the new paradigm in online/virtual education for all institutions around the world. Particularly in global health, where the traditional norm for support relied on traveling and onsite visits, we face a ripe opportunity for innovation.METHODSFrom 2019 to present, Rayos Contra Cancer has conducted remote operations by organizing the efforts of volunteer educators and moderators who are radiotherapy professionals or trainees from across the United States and other parts of the world. On average, each program consists of 17 virtual sessions. The hour-long sessions are conducted over Zoom and include didactics, question-and-answer dialogue with participants, and sample cases. The educators are seasoned and accomplished radiation oncologists, physicists, dosimetrists, and radiation therapists who teach single or multiple topics in a program. Participants are radiotherapy professionals or trainees affiliated with a radiotherapy clinic in a low- and middle-income country.RESULTSThe number of participant clinics ranged from 2 to 120 per program. Our combined programs have resulted in over 2,000 unique participants spanning approximately 500 unique centers in 54 countries with the support of over 200 unique educators and moderators from centers in 18 countries.CONCLUSIONWhen the world shut down, we were forced to reimagine how we approached global health education. Our data show tremendous growth year to year and from one curriculum to another. The feedback from our participants demonstrates that our approach is an effective way to engage practitioners in radiotherapy centers with fewer resources.

PURPOSEWith the existing oncology disparities in Latin America, physician expertise has been cited as a possible contributor to inferior oncologic outcomes in some cancers. As two-dimensional radiotherapy rapidly evolved to intensity-modulated radiation therapy in Latin America, adequate contouring education is an actionable target to improving physician knowledge and clinical outcomes. Yet, topics of interest to Latin American radiation oncologists are underreported. We assessed Latin American interest in a virtual platform for case discussion and identified the educational topics of most interest to them.MATERIALS AND METHODSA Spanish-language online survey was designed by a team of Latin American educators. The questions assessed professional nationality, desire for an online educational platform for case presentation, career length, and topics of interest. Educational topics included head and neck (H&N), CNS, GI, lung, gynecologic, breast, and pediatric cancers, lymphoma, sarcoma, stereotactic body radiotherapy (SBRT), brachytherapy, and medical physics.RESULTSOne hundred thirty-three surveys were included for analysis. Overall, 127 respondents (98%) affirmed interest in participating in a virtual platform for case discussion and treatment advances. The most popular educational themes were H&N cancers (24%), SBRT (14%), and CNS cancers (13%). Of countries with > 10 respondents, the most popular educational topic remained H&N cancers for Argentina, Chile, and Mexico, but the most popular topic among Peruvian respondents was CNS cancer (27%).CONCLUSIONWith international collaboration and a large sample size, we present the first survey results describing Latin American radiation oncology educational interests. Participants were overwhelmingly interested in a virtual platform, and most were specifically interested in H&N cancer education. These results can be used for focused didactic preparation in Latin America. Future efforts should expand on improving representation and outreach among Central American radiation oncologists.

BackgroundCyclin-dependent kinase 4/6 inhibitors are a standard treatment for patients with hormone receptor−positive (HR+)/human epidermal growth factor receptor 2−negative (HER2−) metastatic breast cancer (MBC). However, real-world data on effectiveness in patients with liver or lung metastatic disease is limited. This study compared outcomes of palbociclib plus letrozole versus letrozole alone in patients with HR+/HER2− MBC with lung or liver metastasis treated in routine clinical practice in the United States.MethodsThis retrospective analysis used Flatiron Health’s database of electronic health records. Women with HR+/HER2− MBC and liver or lung metastasis received first-line palbociclib plus letrozole or letrozole alone between February 2015 and February 2019. Real-world progression-free survival (rwPFS) was defined as time from start of treatment to death or disease progression. Stabilized inverse probability treatment weighting (sIPTW) was used to balance baseline demographic and clinical characteristics between palbociclib plus letrozole versus letrozole cohorts. Cox proportional-hazards models were used to estimate the effectiveness of palbociclib plus letrozole versus letrozole alone in rwPFS and overall survival (OS).ResultsThe study included 353 patients with lung metastasis, 123 with liver metastasis, and 75 with both. After sIPTW, palbociclib plus letrozole versus letrozole alone was significantlly associated with prolonged rwPFS (hazard ratio (HR), 0.56) and OS (HR, 0.58) (both p

Purpose: Despite the call to increase the number of radiation oncologists in Latin America, the quality, similarity, and number of residency training programs are unknown. We seek to describe the current state of residency programs in radiation oncology in Latin America. Methods and Materials: Latin American Residents in Radiation Oncology performed a cross-sectional analysis of universities and training centers for radiation oncologists in Latin America. Latin American Residents in Radiation Oncology members identified and contacted current residents and specialists at each center to obtain information and documents that described their training curricula. Results: As of 2020, 13 of 23 (56.5%) Latin American countries have radiation oncology training. Seventy-three training centers were identified (59 active and 14 inactive), associated with 28 universities. On average, each active center trains 2.6 new residents per year, and in total, 156 residents are trained annually. The average length of training programs is 3.6 years. Brazil and Mexico comprise 31 (52.5%) and 7 (11.9%) of active programs, respectively, and 64 (41.8%) and 50 (32.7%) residents, respectively. Training is available in 38 cities in 13 countries, and outside Brazil and Mexico, only 13 cities in 11 countries (9 capitals and 4 noncapital cities). Individualized curriculum documents were provided by 20 (83.3%) of 24 non-Brazilian programs, while 1 standardized guideline was provided for Brazilian training programs. These demonstrated variation between subjects taught, their devoted time, outside specialty rotations, and experiences in modern techniques. Seventy-five percent include volumetric modulated arc therapy, 70% stereotactic radiosurgery, and 55% stereotactic body radiation therapy training. One-hundred percent include gynecologic brachytherapy education and

BackgroundCombination axitinib plus pembrolizumab is a standard of care in the first-line treatment of patients with advanced clear cell renal cell carcinoma (RCC). This analysis describes the clinical characteristics, treatment management and outcomes of patients receiving first-line (1L) axitinib plus pembrolizumab in a real-world US setting.MethodsElectronic health record (EHR)-derived data from the Flatiron Health Database, which includes ~280 cancer clinics across 800 sites in the US, were used. Patients had confirmed Stage IV or metastatic RCC and initiated 1L axitinib plus pembrolizumab on or after 1/1/2018 to 3/31/2021. Outcomes were best overall response rate; real-world progression-free survival (rwPFS) and overall survival (OS) at landmark time periods (3, 6, 9, and 12 months). Therapy management (TM) included dose hold, dose change and discontinuation. Data are reported as medians (IQR) unless otherwise noted.Results355 patients received 1L axitinib plus pembrolizumab, with median follow-up of 9.7 (0.1–24.3) months. IMDC Risk Score was favorable, intermediate, and poor in 27 (7.6%), 126 (35.5%), and 76 (21.4%) patients, respectively (23.4% intermediate/poor, 12.1% unknown). 270 patients (76.1%) received only 1L axitinib plus pembrolizumab and 85 patients (24.3%) received ≥1 subsequent line of treatment; cabozantinib was the most frequent subsequent line of treatment (47.9%). rwPFS at 3 months and 1 year was 77.2% and 39.3%, respectively. OS ranged from 90.8% at 3 months to 73.5% at 1 year. Best overall response rate was 47.9%. Toxicity was the most common reason for first TM events of dose hold, change and discontinuation at, 58.6%, 58.5%, and 45.8%, respectively. Over 80% of patients with TM were able to continue with 1L axitinib plus pembrolizumab.ConclusionsIn a real-world setting, axitinib plus pembrolizumab was effective as a 1L treatment for patients with advanced RCC. Dose holds, changes and discontinuation were driven by treatment-related toxicity. Dose holds may represent an effective TM strategy to toxicity.

BackgroundContinuing medical education in stereotactic technology are scarcely accessible in developing countries. We report the results of upscaling a longitudinal telehealth training course on stereotactic body radiation therapy (SBRT) and stereotactic radiosurgery (SRS), after successfully developing a pilot course in Latin America.MethodsLongitudinal training on SBRT and SRS was provided to radiation oncology practitioners in Peru and Colombia at no cost. The program included sixteen weekly 1-hour live conferencing sessions with interactive didactics and a cloud-based platform for case-based learning. Participant-reported confidence was measured in 16 SBRT/SRS practical domains, based on a 1-to-5 Likert scale. Pre- and post-curriculum exams were required for participation credit. Knowledge-baseline, pre- and post-curriculum surveys, overall and single professional-group confidence changes, and exam results were assessed.ResultsOne hundred and seventy-three radiotherapy professionals participated. An average of 56 (SD ±18) attendees per session were registered. Fifty (29.7%) participants completed the pre- and post-curriculum surveys, of which 30% were radiation oncologists (RO), 26% radiation therapists (RTT), 20% residents, 18% medical physicists and 6% neurosurgeons. Significant improvements were found across all 16 domains with overall mean +0.55 (SD ±0.17, p

PURPOSEOur objective was to demonstrate the efficacy of a telehealth training course on high-dose-rate (HDR) brachytherapy for gynecologic cancer treatment for clinicians in low- and middle-income countries (LMICs)METHODSA 12-week course consisting of 16 live video sessions was offered to 10 cancer centers in the Middle East, Africa, and Nepal. A total of 46 participants joined the course, and 22 participants, on average, attended each session. Radiation oncologists and medical physicists from 11 US and international institutions prepared and provided lectures for each topic covered in the course. Confidence surveys of 15 practical competencies were administered to participants before and after the course. Competencies focused on HDR commissioning, shielding, treatment planning, radiobiology, and applicators. Pre- and post-program surveys of provider confidence, measured by 5-point Likert scale, were administered and compared.RESULTSForty-six participants, including seven chief medical physicists, 16 senior medical physicists, five radiation oncologists, and three dosimetrists, representing nine countries attended education sessions. Reported confidence scores, both aggregate and paired, demonstrated increases in confidence in all 15 competencies. Post-curriculum score improvement was statistically significant (P < .05) for paired respondents in 11 of 15 domains. Absolute improvements were largest for confidence in applicator commissioning (2.3 to 3.8, P = .009), treatment planning system commissioning (2.2 to 3.9, P = .0055), and commissioning an HDR machine (2.2 to 4.0, P = .0031). Overall confidence in providing HDR brachytherapy services safely and teaching other providers increased from 3.1 to 3.8 and 3.0 to 3.5, respectively.CONCLUSIONA 12-week, low-cost telehealth training program on HDR brachytherapy improved confidence in treatment delivery and teaching for clinicians in 10 participating LMICs.

Abstract Introduction In the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT; ClinicalTrials.gov number NCT01994889), tafamidis reduced the risk of all-cause mortality in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) by 30% versus placebo. Median overall survival was not achieved in either treatment arm (57.1 and 70.5% of patients in the placebo and tafamidis groups, respectively, survived at 30 months), limiting assessment of the potential survival benefits of treatment. Methods A survival extrapolation analysis was conducted following technical support guidelines from the National Institute for Health and Care Excellence. Multiple models (i.e., exponential, Weibull, gamma, log-logistic, log-normal, Gompertz, generalized gamma, and generalized F) were applied to systematically fit different candidate curves to existing patient-level data from the 30-month treatment period in ATTR-ACT. The relative goodness-of-fit for each candidate curve was then tested by Akaike’s and Bayesian information criteria to select a single model that was fitted to the placebo and pooled tafamidis treatment arms. Results A gamma distribution was selected as best fitting model and fitted to both treatment arms. The resulting estimated median overall survival was 35.16 months for placebo and 52.64 months for tafamidis (difference 17.48 months). Conclusions This extrapolation of survival data from ATTR-ACT further supports the efficacy of tafamidis in patients with ATTR-CM. Owing to the limitations of this analysis, these survival estimates should be interpreted with caution; however, they are consistent with recently presented findings from a combined analysis of data from ATTR-ACT and interim data from an ongoing long-term extension study (median follow-up 36 months; ClinicalTrials.gov number NCT02791230). Trial Registration ClinicalTrials.gov: NCT01994889.

Introduction: Diagnostic testing is important in determining appropriate treatment for individuals with lung cancer. In 2018, testing of five biomarkers (EGFR, ALK, ROS1, BRAF, programmed cell death-ligand 1 [PD-L1]) was approved in Japan. Information is lacking regarding real-world testing patterns. Methods: This descriptive, retrospective observational study used the Japan Medical Data Vision Co., Ltd. (MDV), database (June 2017–November 2018) and covered data for EGFR, ALK, ROS1, and PD-L1; records on BRAF testing were not yet available. Adults diagnosed with having lung cancer (International Classification of Diseases-10 C34) with record of any biomarker test ordered were included. Results: Of 8323 patients with any biomarker test, 83.2% were tested for EGFR, 55.3% for ALK, 32.2% ROS1, and 77.2% PD-L1. Combinations of EGFR with other biomarkers accounted for approximately 80% of the testing patterns; 1427 patients (17.1%) had combination testing ordered for EGFR/ALK/ROS1/PD-L1, but some biomarker combinations were tested in less than 1% of the cases. Median time from first testing order to treatment order was 22 (range: 2–525) days overall and increased with number of testing instances: 21 (2–509) days for patients with one, 28 (3–525) days for patients with two, and 30 (9–502) days for patients with three. A 7-day pattern of peaks was observed in the test order date and time to treatment. Conclusions: This real-world evidence revealed variations in diagnostic testing patterns, which could affect time to treatment in Japan. Variations are likely influenced by individual biomarker prioritization considering limited tissue samples in clinical practice.

The present research examines how perceptions of e-scooter mobile apps (i.e., a communication technology) influence intent to use e-scooters (i.e., a transportation technology) while considering other perceptions specific to e-scooters (ease of use, usefulness, safety, environmental impact, and enjoyment), context of use (geographic landscape), and demographic factors (age and sex). Results suggest mobile app perceived ease of use is associated with e-scooter use intent and this effect is mediated by e-scooter perceived usefulness, even when controlling for e-scooter perceived ease of use as well as other influential elements of e-scooter use. In addition to illustrating the importance of user experiences with mobile apps within the e-scooter context, this interdisciplinary research furthers a fundamental argument that media technologies are an integral factor in the adoption of transportation technologies.

ObjectiveTo assess the safety (ie, risk of bleeding) and effectiveness (ie, risk of stroke/systemic embolism (SE)) separately for four non-vitamin K oral anticoagulants (NOACs; apixaban, dabigatran, edoxaban and rivaroxaban) versus warfarin in Japanese patients with non-valvular atrial fibrillation (NVAF), including those at high risk of bleeding and treated with reduced doses of NOACs.MethodsWe conducted a retrospective analysis of electronic health records and claims data from 372 acute care hospitals in Japan for patients with NVAF newly initiated on NOACs or warfarin. Baseline characteristics were balanced using inverse probability of treatment weighting with stabilised weights (s-IPTW). Bleeding risk and stroke/SE risk were expressed as HRs with 95% CIs. Two sensitivity analyses were conducted.ResultsA total of 73 989 patients were eligible for analysis. Notably, 52.8%–81.9% of patients received reduced doses of NOACs. After applying s-IPTW, patient characteristics were well balanced across warfarin/NOAC cohorts. The mean within-cohort age, CHADS2 score and CHA2DS2-VASc score were 76 years, 2.2–2.3 and 3.8, respectively. In all age categories, the majority of the HRs for major bleeding, any bleeding and stroke/SE were equal to or below 1 for all NOACs versus warfarin. Apixaban was the only NOAC associated with a significantly lower risk of any bleeding. There was a trend towards increased risk reduction with NOACs versus warfarin in patients with body weight ≥60 kg. In patients with renal disease, the HRs for apixaban versus warfarin were below 1 for major bleeding, any bleeding and stroke/SE, with statistical significance observed for the risk reduction in stroke/SE versus warfarin. In the sensitivity analysis, there were no large differences in HRs between the two observational periods.ConclusionsIn patients with NVAF primarily treated with reduced-dose NOACs, the risks of stroke/SE and major bleeding were significantly lower with NOACs versus warfarin.

Various factors and challenges are involved in efficiently delivering drugs using nasal sprays to the olfactory region to treat central nervous system diseases. In this study, computational fluid dynamics was used to simulate nasal drug delivery to (1) examine effects on drug deposition when various external magnetic fields are applied to charged particles, (2) comprehensively study effects of multiple parameters (i.e., particle aerodynamic diameter; injection velocity magnitude, angle, and position; magnetic force strength and direction), and (3) determine how to achieve the optimal delivery efficiency to the olfactory epithelium. The Reynolds-averaged Navier–Stokes equations governed airflow, with a realistic inhalation waveform implemented at the nostrils. Particle trajectories were modeled using the one-way coupled Euler–Lagrange model. A current-carrying wire generated a magnetic field to apply force on charged particles and direct them to the olfactory region. Once drug particles reached the olfactory region, their diffusion through mucus to the epithelium was calculated analytically. Particle aerodynamic diameter, injection position, and magnetic field strength were found to be interconnected in their effects on delivery efficiency. Specific combinations of these parameters achieved over 65-fold higher drug delivery efficiency compared with uniform injections with no magnetic fields. The insight gained suggests how to integrate these factors to achieve the optimal efficiency.

The current study reveals the clinicopathological association of PD-L1 in Hong Kong esophageal squamous cell carcinoma (ESCC) patients and the differential regulation of PD-L1 by standard first-line chemotherapy in ESCC. Immunohistochemical analysis of tissue microarray data from 84 Hong Kong ESCC patients shows that PD-L1 was expressed in 21% of the tumors. Positive PD-L1 staining was significantly associated with later disease stage (stages III and IV) (P value = .0379) and lymph node metastasis (P value = .0466) in the Hong Kong cohort. Furthermore, PD-L1 expression was significantly induced in ESCC cell lines after standard chemotherapy treatments, along with EGFR and ERK activation in both in vitro studies and the in vivo esophageal orthotopic model. The endogenous expression of PD-L1 was reduced by treatment with an EGFR inhibitor (erlotinib) or by the knockdown of EGFR. Moreover, the upregulation of PD-L1 by chemotherapy was also attenuated by the treatment with erlotinib and a MAPK/MEK inhibitor (AZD6244), suggesting that PD-L1 is regulated by the EGFR/ERK pathway in ESCC. The regulation of PD-L1 by the EGFR pathway was further supported by the correlation of PD-L1 and EGFR expression observed in the commercially available tissue microarray set (P value = .028). Taken together, the current study was the first to demonstrate the upregulation of PD-L1 by chemotherapy in ESCC and its regulation through the EGFR/ERK pathway. The results suggest the potential usefulness of combined conventional chemotherapy together with anti–PD-L1 immunotherapy to achieve better treatment outcome.

Abstract: Thrombotic thrombocytopenic purpura (TTP), a potentially fatal blood clot disorder, is primarily caused by severe deficiency of plasma ADAMTS13 activity resulting from acquired autoantibodies. Plasma exchange is the only effective initial therapy. However, the high mortality rate and the complications associated with plasma exchange therapy remain a major concern. To address unmet clinical needs, therapeutic efficacies of anfibatide, a snake venom-derived platelet glycoprotein Ib antagonist, in murine models of spontaneous thrombocytopenia and shigatoxin-induced TTP were determined. A light scattering platelet aggregometry, microfluidic shear-based assay, and murine models of TTP were used in the study. We showed that purified anfibatide inhibits ristocetin- or botrocetin-induced human or murine platelet agglutination in the presence of von Willebrand factor in a concentration-dependent manner. Anfibatide could also dramatically inhibit the adhesion and aggregation of murine and human platelets on a collagen surface under arterial shear stress, in the presence or absence of plasma ADAMTS13 activity. Most importantly, we demonstrated that an intraperitoneal administration of anfibatide at the dose of 60 ng/g body weight twice daily mitigated spontaneous thrombocytopenia and prevented shigatoxin-induced TTP in Adamts13−/− and disease-susceptible mice (CAST/Ei strain). Thus, we conclude that anfibatide, when administered at the optimal dosage, route, and interval, is efficacious in treating spontaneous and bacterial shigatoxin-induced TTP in the murine models. Our findings may provide the basis for further development of anfibatide for the treatment of acute TTP in humans.

Previous studies demonstrated the positive effects of smiling on interpersonal outcomes. The present research examined if enhancing one's smile in a virtual environment could lead to a more positive communication experience. In the current study, participants' facial expressions were tracked and mapped on a digital avatar during a real-time dyadic conversation. The avatar's smile was rendered such that it was either a slightly enhanced version or a veridical version of the participant's actual smile. Linguistic analyses using the Linguistic Inquiry Word Count (LIWC) revealed that participants who communicated with each other via avatars that exhibited enhanced smiles used more positive words to describe their interaction experience compared to those who communicated via avatars that displayed smiling behavior reflecting the participants' actual smiles. In addition, self-report measures showed that participants in the 'enhanced smile' condition felt more positive affect after the conversation and experienced stronger social presence compared to the 'normal smile' condition. These results are particularly striking when considering the fact that most participants (>90%) were unable to detect the smiling manipulation. This is the first study to demonstrate the positive effects of transforming unacquainted individuals' actual smiling behavior during a real-time avatar-networked conversation.

The replacement of small-diameter arteries remains an unmet clinical need. Here we investigated the cellular remodeling of fibrotic conduits as vascular grafts. The formation of fibrotic conduit around subcutaneously implanted mandrels involved not only fibroblasts but also the trans-differentiation of inflammatory cells such as macrophages into fibroblastic cells, as shown by genetic lineage tracing. When fibrotic conduits were implanted as vascular grafts, the patency was low, and many fibrotic cells were found in neointima. Decellularization and anti-thrombogenic coating of fibrotic conduits produced highly patent autografts that remodeled into neoarteries, offering an effective approach to obtain autografts for clinical therapy. While autografts recruited mostly anti-inflammatory macrophages for constructive remodeling, allogenic DFCs had more T cells and pro-inflammatory macrophages and lower patency. Endothelial progenitors and endothelial migration were observed during endothelialization. Cell infiltration into DFCs was more efficient than decellularized arteries, and infiltrated cells remodeled the matrix and differentiated into smooth muscle cells (SMCs). This work provides insight into the remodeling of fibrotic conduits, autologous DFCs and allogenic DFCs, and will have broad impact on using fibrotic matrix for regenerative engineering.

Small-diameter synthetic vascular grafts have high failure rate due to primarily surface thrombogenicity, and effective surface chemical modification is critical to maintain the patency of the grafts. In this study, we engineered a small-diameter, elastic synthetic vascular graft with off-the-shelf availability and anti-thrombogenic activity. Polycarbonate-urethane (PCU), was electrospun to produce nanofibrous grafts that closely mimicked a native blood vessel in terms of structural and mechanical strength. To overcome the difficulty of adding functional groups to PCU, we explored various surface modification methods, and determined that plasma treatment was the most effective method to modify the graft surface with functional amine groups, which were subsequently employed to conjugate heparin via end-point immobilization. In addition, we confirmed in vitro that the combination of plasma treatment and end-point immobilization of heparin exhibited the highest surface density and correspondingly the highest anti-thrombogenic activity of heparin molecules. Furthermore, from an in vivo study using a rat common carotid artery anastomosis model, we showed that plasma-heparin grafts had higher patency rate at 2weeks and 4weeks compared to plasma-control (untreated) grafts. More importantly, we observed a more complete endothelialization of the luminal surface with an aligned, well-organized monolayer of endothelial cells, as well as more extensive graft integration in terms of vascularization and cell infiltration from the surrounding tissue. This work demonstrates the feasibility of electrospinning PCU as synthetic elastic material to fabricate nanofibrous vascular grafts, as well as the potential to endow desired functionalization to the graft surface via plasma treatment for the conjugation of heparin or other bioactive molecules.Statement of significanceVascular occlusion remains the leading cause of death all over the world, despite advances made in balloon angioplasty and conventional surgical intervention. Currently, autografts are the gold-standard grafts used to treat vascular occlusive disease. However, many patients with vascular occlusive disease do not have autologous vascular graft available. Therefore, there is a widely recognized need for a readily available, functional, small-diameter vascular graft (inner diameter of