Abstract
Background: Chest wall recurrence (CWR) causes much morbidity when not controlled by local measures. Lyso-thermosensitive liposomal doxorubicin (LTLD) provides accelerated release of ...doxorubicin (Dox) at ≥ 39° C, and is being studied for CWR based on the pioneering thermochemotherapy work of Dewhirst and colleagues at Duke. We now report on its tolerance, pharmacology, and preliminary antitumor effects in a dose-escalation study combined with local hyperthermia (LH) for radiation-refractory CWR. LH selectively increases liposomal permeability in tumor microvasculature, and promotes release of Dox from LTLD, and Dox tumor uptake, in addition to LH anti-tumor effects.
Methods: This phase I study entered patients (pts) with CWRs < 3 cm deep failing all standard Tx including surgery, radiation, and chemotherapy: pts received up to 6 LTLD/LH treatments every 21 days at a starting dose of 40 mg/m2 (cohort 1) and escalated to 50 mg/m2 (cohort 2). LTLD was infused IV over 30 minutes (min); followed within 30 min by microwave or ultrasound LH. The thermal dose goal was 40°C-42°C for 60 min. Pharmacokinetic samples for total plasma Dox and doxorubicinol (Doxol) were taken at 0.5, 5, 10 and 24 hours after starting infusion. Left ventricular ejection fraction was monitored every other cycle.
Results: Eleven pts with a median of 4 prior chemotherapy regimens (range 2 — 12) were enrolled; all but one had prior anthracycline (AC). All pts received ≥ 2 cycles. The within subject variability in Dox and Doxol exposure was small with mean Cycle 2 vs Cycle 1 ratios ranging from 0.99 to 1.06.
Cmax/dose (ng/ml)/(mg/m2) Cycle 1 Cycle 2
Dox 499.82 512.00
Doxol 0.46 0.45
AUClast/dose ((ng*hr/ml)/(mg/m2)
Dox 1338.12 1381.82
Doxol 7.96 8.04
Grade 3 and 4 toxicities included reversible neutropenia in 17 (40.5%) and one case (each) of mucositis (grade 1), chest wall thermal burn, and chest wall cellulitis (both grade 4); these occurred in only ≥ 5% of 42 cycles given. No cardiomyopathy or hand-foot toxicity occurred. The rate of clinically-significant (≥ 6 point) QoL improvement on the FACT-B after 2 cycles was 54.5% (95% CI: 25.1%–83.9%), including 1 lasting > 3 months. The local objective response rate was encouraging: 45.5% (95% CI: 16.1%–74.9%), with 1 complete and 4 partial local responses.
Conclusion: LTLD + LH is safe in CWR after prior radiation and doxorubicin. A phase II study is planned for pharmacologic evaluations and to add pts with less or no anthracycline treatment.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-13-01.
The High Altitude Water Cherenkov (HAWC) observatory is a wide field-of-view detector sensitive to gamma rays of 100 GeV to a few hundred TeV. Located in central Mexico at 19degrees North latitude ...and 4100 m above sea level, HAWC will observe gamma rays and cosmic rays with an array of water Cherenkov detectors. The full HAWC array is scheduled to be operational in Spring 2015. In this paper, we study the HAWC sensitivity to the gamma-ray signatures of high-mass (multi-TeV) dark matter annihilation. The HAWC observatory will be sensitive to diverse searches for dark matter annihilation, including annihilation from extended dark matter sources, the diffuse gamma-ray emission from dark matter annihilation, and gamma-ray emission from nonluminous dark matter subhalos. Here we consider the HAWC sensitivity to a subset of these sources, including dwarf galaxies, the M31 galaxy, the Virgo cluster, and the Galactic center. We simulate the HAWC response to gamma rays from these sources in several well-motivated dark matter annihilation channels. If no gamma-ray excess is observed, we show the limits HAWC can place on the dark matter cross section from these sources. In particular, in the case of dark matter annihilation into gauge bosons, HAWC will be able to detect a narrow range of dark matter masses to cross sections below thermal. HAWC should also be sensitive to nonthermal cross sections for masses up to nearly 1000 TeV. The constraints placed by HAWC on the dark matter cross section from known sources should be competitive with current limits in the mass range where HAWC has similar sensitivity. HAWC can additionally explore higher dark matter masses than are currently constrained.
IMPORTANCE: The rapid expansion of virtual health care has caused a surge in patient messages concomitant with more work and burnout among health care professionals. Artificial intelligence (AI) ...assistants could potentially aid in creating answers to patient questions by drafting responses that could be reviewed by clinicians. OBJECTIVE: To evaluate the ability of an AI chatbot assistant (ChatGPT), released in November 2022, to provide quality and empathetic responses to patient questions. DESIGN, SETTING, AND PARTICIPANTS: In this cross-sectional study, a public and nonidentifiable database of questions from a public social media forum (Reddit’s r/AskDocs) was used to randomly draw 195 exchanges from October 2022 where a verified physician responded to a public question. Chatbot responses were generated by entering the original question into a fresh session (without prior questions having been asked in the session) on December 22 and 23, 2022. The original question along with anonymized and randomly ordered physician and chatbot responses were evaluated in triplicate by a team of licensed health care professionals. Evaluators chose “which response was better” and judged both “the quality of information provided” (very poor, poor, acceptable, good, or very good) and “the empathy or bedside manner provided” (not empathetic, slightly empathetic, moderately empathetic, empathetic, and very empathetic). Mean outcomes were ordered on a 1 to 5 scale and compared between chatbot and physicians. RESULTS: Of the 195 questions and responses, evaluators preferred chatbot responses to physician responses in 78.6% (95% CI, 75.0%-81.8%) of the 585 evaluations. Mean (IQR) physician responses were significantly shorter than chatbot responses (52 17-62 words vs 211 168-245 words; t = 25.4; P < .001). Chatbot responses were rated of significantly higher quality than physician responses (t = 13.3; P < .001). The proportion of responses rated as good or very good quality (≥ 4), for instance, was higher for chatbot than physicians (chatbot: 78.5%, 95% CI, 72.3%-84.1%; physicians: 22.1%, 95% CI, 16.4%-28.2%;). This amounted to 3.6 times higher prevalence of good or very good quality responses for the chatbot. Chatbot responses were also rated significantly more empathetic than physician responses (t = 18.9; P < .001). The proportion of responses rated empathetic or very empathetic (≥4) was higher for chatbot than for physicians (physicians: 4.6%, 95% CI, 2.1%-7.7%; chatbot: 45.1%, 95% CI, 38.5%-51.8%; physicians: 4.6%, 95% CI, 2.1%-7.7%). This amounted to 9.8 times higher prevalence of empathetic or very empathetic responses for the chatbot. CONCLUSIONS: In this cross-sectional study, a chatbot generated quality and empathetic responses to patient questions posed in an online forum. Further exploration of this technology is warranted in clinical settings, such as using chatbot to draft responses that physicians could then edit. Randomized trials could assess further if using AI assistants might improve responses, lower clinician burnout, and improve patient outcomes.
Globally, gastric cancer incidence shows remarkable international variation and demonstrates distinct characteristics by the two major topographical subsites, cardia (CGC) and non-cardia (NCGC). ...Because global incidence estimates by subsite are lacking, we aimed to describe the worldwide incidence patterns of CGC and NCGC separately.
Using Cancer Incidence in Five Continents Volume X (CI5X), we ascertained the proportions of CGC and NCGC by country, sex and age group (<65 and ≥65 years). These derived proportions were applied to GLOBOCAN 2012 data to estimate country-specific age-standardised CGC and NCGC incidence rates (ASR). Regional proportions were used to estimate rates for countries not included in CI5X.
According to our estimates, in 2012, there were 260,000 cases of CGC (ASR 3.3 per 100,000) and 691,000 cases of NCGC (ASR 8.8) worldwide. The highest regional rates of both gastric cancer subsites were in Eastern/Southeastern Asia (in men, ASRs: 8.7 and 21.7 for CGC and NCGC, respectively). In most countries NCGC occurred more frequently than CGC with an average ratio of 2:1; however, in some populations where NCGC incidence rates were lower than the global average, CGC rates were similar or higher than NCGC rates. Men had higher rates than women for both subsites but particularly for CGC (male-to-female ratio 3:1).
This study has, for the first time, quantified global incidence patterns of CGC and NCGC providing new insights into the global burden of these cancers. Country-specific estimates are provided; however, these should be interpreted with caution. This work will support future investigations across populations.
This paper reports the first measurement of muon neutrino charged-current interactions without pions in the final state using multiple detectors with correlated energy spectra at T2K. The data was ...collected on hydrocarbon targets using the off-axis T2K near detector (ND280) and the on-axis T2K near detector (INGRID) with neutrino energy spectra peaked at 0.6 GeV and 1.1 GeV respectively. The correlated neutrino flux presents an opportunity to reduce the impact of the flux uncertainty and to study the energy dependence of neutrino interactions. The extracted double-differential cross sections are compared to several Monte Carlo neutrino-nucleus interaction event generators showing the agreement between both detectors individually and with the correlated result.
Promoting Diversity and Social Justice provides theories, perspectives, and strategies that are useful for working with adults from privileged groups—those who are in a more powerful position in any ...given type of oppression. The thoroughly revised edition of this accessible and practical guide offers tools that allow educators to be more reflective and intentional in their work—helping them to consider who they’re working with, what they’re doing, why they’re doing it and how to educate more effectively.
New features include:
A new chapter, "The Joy of Unlearning Privilege/Oppression," highlights specific ways people from privileged groups benefit from unlearning privilege/oppression and from creating greater equity.
A new chapter, "Allies and Action," gives focus and guidance on how people from privileged groups can constructively and appropriately be involved in social change efforts.
Updated Appendix of additional resources.
The theories and approaches discussed can be applied to a range of situations and audiences. This book is an excellent resource for professors, diversity trainers, teachers in classrooms and workshops, counselors, organizers, student affairs personnel, community educators, advocates, group facilitators, and any others involved with educating about diversity and equity.
Diane J. Goodman , Ed.D., is a trainer, college teacher, author, speaker, and consultant on diversity and social justice issues. For more information, see her website: http://www.dianegoodman.com.
"This new edition improves upon what was already an indispensable tool for educators, trainers, and activists. Written in an accessible and sympathetic voice, with concrete strategies and support, this is a text I find myself turning to again and again. If you are committed to dismantling privilege and oppression, you need this book!"
--Abby L. Ferber, Director of the Matrix Center for the Advancement of Social Equity and Inclusion, Professor of Sociology, and Women's and Ethnic Studies, University of Colorado at Colorado Springs
"Updating and extending her foundational work for a newly emerging social climate in a clear, personable, accessible, and yes, joyous style, Diane J. Goodman maintains a laser focus upon members of socially privileged groups. By so doing, she provides readers the tools they need to envision not only the concept, but most importantly, the reality of social justice."
--Warren J. Blumenfeld, Associate Professor, Department of Curriculum and Instruction, Iowa State University
Between 1975 and 1989, 896 patients were treated for endometrial carcinoma at the Massachusetts General Hospital. Thirty patients were identified from the tumor registry as having uterine papillary ...serous carcinomas. The survival for all patients and for groups of patients stratified on clinical and pathological parameters was examined in the Kaplan–Meier survival curves. Curves for the different strata were compared using the logrank test. The 5-year survival for the 30 patients was 30% ± 9%. Patients with surgical stage I and II tumors had a 5-year survival rate of 79% ± 14% compared to 25% ± 10% in patients with stage III and IV tumors (P= 0.02). Clinical stage, depth of myometrial invasion, lymph–vascular space invasion, tumor grade, and DNA aneuploidy were not found to significantly impact on survival. However, a survival advantage was seen in patients diagnosed with early surgical stage tumors, reinforcing the need for thorough staging at the time of laparotomy.
We recently described the characterization and cloning of Drosophila neuroglian, a member of the immunoglobulin superfamily. Neuroglian contains six immunoglobulin-like domains and five fibronectin ...type III domains and shows strong sequence homology to the mouse neural cell adhesion molecule L1. Here we show that the neuroglian gene generates at least two different protein products by tissue-specific alternative splicing. The two protein forms differ in their cytoplasmic domains. The long form is restricted to the surface of neurons in the CNS and neurons and some support cells in the PNS; in contrast, the short form is expressed on a wide range of other cells and tissues. Thus, whereas the mouse L1 gene appears to encode only one protein that functions largely as a neural cell adhesion molecule, its Drosophila homolog, the neuroglian gene, encodes at least two protein forms that may play two different roles, one as a neural cell adhesion molecule and the other as a more general cell adhesion molecule involved in other tissues and imaginal disc morphogenesis.
To compare the safety and efficacy of rofecoxib* to naproxen for the treatment of juvenile rheumatoid arthritis (JRA).
This was a 12-week, multicenter, randomized, double-blind, double-dummy, active ...comparator-controlled, non-inferiority study with a prespecified 52-week open-label active comparator-controlled extension. Children (ages 2-11 yrs) and adolescents (ages 12-17 yrs) received lower-dose (LD)-rofecoxib 0.3 mg/kg/day up to 12.5 mg/day (base study only); or higher-dose (HD)-rofecoxib (0.6 mg/kg/day up to 25 mg/day) or naproxen 15 mg/kg/day as oral suspensions. Adolescents received daily rofecoxib (LD) 12.5 (base study only) or (HD) 25 mg, or naproxen 15 mg/kg/day (maximum 1,000 mg/day) as tablets. The primary endpoint was the time-weighted average proportion of patients meeting the American College of Rheumatology Pediatric-30 (ACR Pedi 30) response criteria. A prespecified bound for the 95% confidence interval for the ratio of the percentage of ACR Pedi 30 responders was used to assess non-inferiority of treatment response between groups. Safety was assessed throughout the study.
A total of 310 patients ages 2-17 years (181 (3/4) age 11) were randomized to receive LD-rofecoxib (N=109), HD-rofecoxib (N=100), or naproxen (N=101). The ACR Pedi 30 response rates following 12 weeks of treatment were 46.2%, 54.5%, and 55.1%, respectively. The relative rates of response compared to naproxen were 0.81 (95% CI 0.61, 1.07) and 0.98 (95% CI 0.76, 1.26) for LD- and HD-rofecoxib, respectively. Both rofecoxib doses were not inferior to naproxen. Patients (N=227) entering the extension received HD-rofecoxib or naproxen with efficacy maintained during the extension. All treatments were generally well tolerated throughout the study.
Daily treatment of JRA patients with rofecoxib up to 12.5 or 25 mg was well tolerated, providing sustained clinical effectiveness comparable to naproxen 15 mg/kg. *On September 30, 2004, Merck & Co., Inc. announced the voluntary worldwide withdrawal of rofecoxib from the market.
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