The first high-quality clinical trial to support ultrahypofractionated whole-breast irradiation (ultra-HF-WBI) for invasive early-stage breast cancer (ESBC) was published in April 2020, coinciding ...with the beginning of the COVID-19 pandemic. We analyzed adoption of ultra-HF-WBI for ductal carcinoma in situ (DCIS) and ESBC at our institution after primary trial publication.
We evaluated radiation fractionation prescriptions for all patients with DCIS or ESBC treated with WBI from March 2020 to May 2021 at our main campus and regional campuses. Demographic and clinical characteristics were extracted from the electronic medical record. Treating physician characteristics were collected from licensure data. Hierarchical logistic regression models identified factors correlated with adoption of ultra-HF-WBI (26 Gy in 5 daily factions UK-FAST-FORWARD or 28.5 Gy in 5 weekly fractions UK-FAST).
Of 665 included patients, the median age was 61.5 years, and 478 patients (71.9%) had invasive, hormone-receptor-positive breast cancer. Twenty-one physicians treated the included patients. In total, 249 patients (37.4%) received ultra-HF-WBI, increasing from 4.3% (2 of 46) in March-April 2020 to a high of 45.5% (45 of 99) in July-August 2020 (P < .001). Patient factors associated with increased use of ultra-HF-WBI included older age (≥50 years old), low-grade WBI without inclusion of the low axilla, no radiation boost, and farther travel distance (P < .03). Physician variation accounted for 21.7% of variance in the outcome, with rate of use of ultra-HF-WBI by the treating physicians ranging from 0% to 75.6%. No measured physician characteristics were associated with use of ultra-HF-WBI.
Adoption of ultra-HF-WBI at our institution increased substantially after the publication of randomized evidence supporting its use. Ultra-HF-WBI was preferentially used in patients with lower risk disease, suggesting careful selection for this new approach while long-term data are maturing. Substantial physician-level variation may reflect a lack of consensus on the evidentiary standards required to change practice.
The goals of this study were: (1) to determine the effects of acute systemic or local application of ethanol (ETOH) on the response of cerebellar Purkinje cells (P-cells) to iontophoretically applied ...γ-aminobutyric acid (GABA) and (2) to characterize the effects of Ro15-4513, a putative antagonist of ETOH-GABA interactions, on ETOH-induced changes in GABA responsiveness. Male Sprague-Dawley rats (230–370 g) were anesthetized with halothane and implanted with intraperitoneal catheters for administration of ETOH (1.0–2.0 g/kg), before the recording session. Extracellular activity of single P-cells was recorded with the central barrel of a five-barrel micropipette, the other barrels of which were used for microiontophoresis of GABA and electro-osmosis of ETOH at the recording site. Spontaneous discharge and response of P-cells to GABA were monitored during a pre-ETOH control and for 1–1.5 h after systemic or electro-osmotic administration of ETOH. Transient suppression of spontaneous P-cell discharge was usually observed within 4–8 min of systemic ETOH injection. This effect lasted 2–4 min in 10 out of 19 rats tested. GABA-mediated inhibitory responses of cerebellar P-cells were increased by 45–50% relative to pre-ETOH values at 10 and 90 min post-ETOH injection. Prior administration of the imidazobenzodiazepine Ro15-4513 (4–6 mg/kg) failed to antagonize either the ETOH-induced enhancement of GABA-mediated inhibition o r the transient inhibition of spontaneous P-cell activity rat cerebellar P-cell produced by ETOH. In these studies, electro-osmotically applied ETOH produced a potent suppression of spontaneous P-cell activity which precluded further augmentation of unit responses to GABA. These results show that doses of systemically administered ETOH which are mildly intoxicating in the awake, behaving animal, enhance the inhibitory action of GABA on cerebellar P-cell discharge.
The goal of the present study was to determine the effect of acute ethanol (ETOH), administered intraperitoneally or electro-osmotically, on norepinephrine (NE) induced increases in γ-aminobutyric ...acid (GABA) mediated inhibition of single cerebellar Purkinje neurons (P-cells). Male Sprague-Dawley rats (230–370 g) were anesthetized with halothane and implanted with an intraperitoneal catheter for systemic administration of ETOH (1.0–1.5 g/kg) prior to the recording session. Extracellular activity of single P-cells was recorded before and after iontophoresis of GABA and NE using five-barrel glass micropipettes. GABA was administered at the recording site by microiontophoretic pulses before, during and after continuous iontophoretic application of NE. Spontaneous discharge, GABA responses and NE-GABA interactions in P-cells were monitored for each experiment before and 1–1.5 h following systemic administration of ETOH. As in our previous reports administration of NE, at low ejection currents (10–60 nA), augmented GABA mediated suppression of P-cell spontaneous discharge. Between 10 and 60 min after injection of ETOH, this NE induced augmentation of GABA inhibition was further potentiated. This potentiation involved increases in both the magnitude and the duration of the GABA inhibition observed after NE alone. NE-induced augmentation of GABA inhibition persisted for 2–13 min longer after ETOH administration than in the pre-ETOH control period. Local electro-osmotic application of ETOH, which resulted in strong depression of spontaneous activity and caused small increases in GABA-mediated inhibition, did not directly potentiate NE-induced augmentation of GABA action. These results indicate that NE-mediated augmentation of GABA inhibition of P-cell activity is potentiated following systemic, but not local, ETOH administration.
To determine the frequency of emergency department (ED) visits for nonurgent and urgent ocular conditions and risk factors associated with ED use for nonurgent and urgent ocular problems.
...Retrospective, longitudinal cohort analysis.
All enrollees aged 21 years or older in a United States managed care network during 2001-2014.
We identified all enrollees visiting an ED for ocular conditions identified by International Classification of Diseases, billing codes. Diagnosis is well-described as urgent, nonurgent, or other. We assessed the frequency of ED visits for urgent and nonurgent ocular conditions and how they changed over time. Next, we performed multivariable Cox regression modeling to determine factors associated with visiting an ED for urgent or nonurgent ocular conditions.
Hazard ratios (HRs) with 95% confidence intervals (CIs) of visiting an ED for urgent or nonurgent ocular conditions.
Of the 11 160 833 enrollees eligible for this study, 376 680 (3.4%) had 1 or more ED visit for an eye-related problem over a mean ± standard deviation of 5.4±3.3 years' follow-up. Among these enrolled, 86 473 (23.0%) had 1 or more ED visits with a nonurgent ocular condition and 25 289 (6.7%) had at least 1 ED visit with an urgent ocular condition. Use of the ED for nonurgent ocular problems was associated with younger age (P < 0.0001 for all comparisons), black race or Latino ethnicity (P < 0.0001 for both), male sex (P < 0.0001), lower income (P < 0.0001 for all comparisons), and those who frequently sought treatment at an ED for nonophthalmologic medical problems in a given year (P < 0.0001). Enrollees with established eye care professionals had a 10% reduced hazard of visiting the ED for nonurgent ocular conditions (adjusted HR, 0.90; 95% CI, 0.88-0.92; P < 0.0001).
Nearly one-quarter of enrollees who visited the ED for an ocular problem received a diagnosis of a nonurgent condition. Better educating and incentivizing patients to seek care for nonurgent ocular diseases in an office-based setting could yield considerable cost savings without adversely affecting health outcomes and could allow EDs to better serve patients with more severe conditions.
Abstract
There is an unmet need for improved methods of rapidly identifying responses to targeted therapies. Liquid biopsy approaches have potential as early biomarkers of response based on ...noninvasive, real-time monitoring of disease burden. We have used the ultrasensitive targeted error correction sequencing (TEC-Seq) approach to analyze 58 cancer driver genes in patients with metastatic non-small cell lung cancer undergoing treatment with targeted tyrosine kinase inhibitors. As a proof-of-principle study, liquid biopsies were obtained from sixteen patients immediately prior to treatment, 6-22 days after treatment, and at serial timepoints until disease progression. Tumor derived alterations and copy number changes were directly detected in plasma and tracked over timepoints analyzed. Based on the dynamics of cell-free circulating tumor DNA (ctDNA) mutations identified, we developed a noninvasive measure of cell-free clonal tumor load (cfTL) to evaluate real-time response to treatment. These analyses revealed that patients with a radiographic response to therapy had a significant drop in cfTL from an average mutant allele fraction of 3.59% to 0.13% within 6-22 days (P < 0.05) as well as in the number of detectable mutations and aneuploidy scores, while radiographic non-responders had limited to no changes. Analyses of residual cfTL 6-22 days after treatment stratified patients into ctDNA responders and ctDNA non-responders. ctDNA responders had improved progression-free survival (12.4 vs 1.7 months, P < 0.001), which was detected on average 38 days earlier and was as predictive as CT imaging. These analyses provide an approach for rapid evaluation of response to targeted therapies and have important clinical implications for the management of cancer patients.
Citation Format: Jillian A. Phallen, Alessandro Leal, Brian D. Woodward, Patrick M. Forde, Jarushka Naidoo, Kristen Marrone, Julie Brahmer, Jacob Fiksel, Doreen N. Palsgrove, Stephen Cristiano, Daniel Bruhm, Elizabeth Weihe, Vilmos Adleff, Parissa Keshavarzian, Valsamo Anagnostou, Robert B. Scharpf, Victor E. Velculescu, Hatim Husain. Early noninvasive prediction of response to targeted therapy in non-small cell lung cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4596.
The therapeutic utility of cyclooxygenase (CO) inhibitors, such as ketorolac, in reducing the inflammatory events associated with allergic conjunctivitis is not unexpected since prostanoids (PG) ...elicit conjunctival redness (PGD2, PGE2, PGF2 alpha), edema (PGD2, TxA2), eosinophil infiltration (PGD2, PGJ2) and mucous cell discharge (PGD2, PGJ2, TxA2). Recently, topically administered ketorolac has also been reported to alleviate the itching associated with allergic conjunctivitis. This was viewed as intriguing since CO inhibitors are not regarded as useful for treating itching dermatoses and PGs do not elicit itching when applied to the skin. In order to investigate the antipruritic activity of ketorolac, we developed a model for reproducibly measuring ocular surface itch responses. The model involves itch-scratch responses to pruritogens applied locally to the ocular surface. Painful and foreign body stimuli do not produce an itch-scratch response. Unlike reported skin studies, PGE2 was a potent itch-producing substances in the conjunctiva. PGD2 was weakly pruritogenic but PGF2 alpha and the TxA2-mimetic U-46619 were inactive. The PG precursor arachidonic acid was also a potent pruritogen and its effects were inhibited by ketorolac pretreatment. Ketorolac also dose-dependently inhibited the itching associated with experimental allergic conjunctivitis. It appears that PGs are potent itch-producing substances in the conjunctiva and the anti-itch efficacy of ketorolac in allergic conjunctivitis appears to involve inhibition of conjunctival PG biosynthesis from arachidonic acid.
One benefit of hyaluronic acid fillers is the ability to dissolve them using hyaluronidase. With the increasing number of fillers entering the market, it is crucial to understand each of these ...fillers' responsiveness to hyaluronidase.
Twenty-one hyaluronic acid fillers of 0.2 mL aliquots each were placed on slides. Twenty units of recombinant human hyaluronidase were injected into the aliquots every 30 minutes for a total of 120 units recombinant human hyaluronidase injected over 3 hours. With each injection, videos and photographs were taken from bird's eye and lateral views to measure aliquot height. Stirring videos were graded by three oculoplastic surgeons, and these grades were used to categorize each filler's responsiveness.
Restylane Lyft, Restylane-L/Eyelight, and Resilient Hyaluronic Acid (RHA) 1/Redensity were the least resistant. The moderately resistant group comprised of Restylane Silk, Juvéderm Volbella, Revanesse Versa/Lips, and Belotero Balance on the less resistant side to Juvéderm Vollure, RHA 2, Restylane Contour, Juvéderm Ultra, Restylane Refyne, Belotero Intense, Restylane Kysse, RHA 3, Juvéderm Ultra Plus, and Restylane Defyne on the more resistant side. The most resistant were RHA 4, Juvéderm Voluma, Belotero Volume, and Juvéderm Volux. The most resistant fillers required 120 units of hyaluronidase per 0.2 mL filler to dissolve.
With the increasing popularity of fillers comes the increasing need to dissolve them for both ischemic and nonischemic complications. The majority of hyaluronic acid fillers available on the market are very resistant to hyaluronidase, which must be considered when determining the amount of hyaluronidase to dissolve a particular filler.
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