Everolimus with exemestane (EVE+EXE) was FDA-approved to treat metastatic hormone receptor-positive breast cancer (mHRBC) based on BOLERO-2. However, none of those patients received prior CDK4/6 ...inhibitors. The purpose of this study is to evaluate the efficacy of EVE+EXE in mHRBC after CDK4/6 inhibitors.
A retrospective review of patients ≥18 years old with mHRBC treated with EVE+EXE, for ≥30 days, at our institution from January 1, 2012, to April 1, 2020 was conducted. Primary objective was to compare progression free survival (PFS) for EVE+EXE between patients with and without prior exposure to CDK4/6 inhibitors. Secondary outcomes included overall survival and safety.
192 patients were included in the study (n = 79, prior CDK4/6 inhibitor use; n = 113, no prior CDK4/6 inhibitor use). Baseline patient characteristics were similar between groups. Greater number of prior therapies before EVE+EXE use increased risk of disease progression (P = .017). Patients with prior CDK4/6 inhibitor use had a lower median PFS of 3.8 months (95% CI: 3.4-4.7) vs. 5.4 months (95% CI: 3.9-6.2) for patients without prior CDK4/6 inhibitor use, with a HR for progression of 1.46 (95% CI: 1.08 to 1.97, P = .013). Overall survival between groups was not significantly different.
Patients who received a prior CDK4/6 inhibitor had a lower median PFS benefit from EVE+EXE compared to those who did not, without differences in overall survival. Although PFS is expected to decrease with subsequent lines of therapy, it is reasonable to use EVE+EXE after CDK4/6 inhibitors in selected patients, recognizing that additional benefit is modest.
This retrospective study (n = 192 patients) identified that patients who received everolimus + exemestane with prior CDK4/6 inhibitor use had a significantly decreased progression free survival of 3.8 months vs. 5.4 months compared to those who did not use prior CDK4/6 inhibitors. It is reasonable to use this combination after CDK4/6 inhibitors in selected patients, recognizing that additional benefit is modest.
Abstract Background Postmenopausal women with breast cancer receiving adjuvant aromatase inhibitors (AIs) are at risk for accelerated bone loss and subsequent fractures. The ongoing Zometa-Femara ...Adjuvant Synergy Trial (Z-FAST) is evaluating the efficacy and safety of zoledronic acid in preventing such bone loss. Patients and Methods In this multicenter study, postmenopausal women with early hormone receptor–positive breast cancer receiving adjuvant letrozole were randomized to receive up-front or delayed-start zoledronic acid (ZA; 4 mg intravenously every 6 months) for 5 years. Delayed-start ZA was administered if the lumbar spine (LS) or total hip (TH) T score fell below −2.0 or a nontraumatic fracture occurred. The primary endpoint was to compare the change from baseline in LS bone mineral density (BMD) between groups at month 12; secondary endpoints, measured at other predetermined timepoints, included comparing changes in TH BMD, LS BMD, and markers of bone turnover, fracture incidence, and time to disease recurrence. Herein, we report the results of the 36-month interim analysis. Results Overall, 301 patients were randomized to each group. At month 36, the absolute difference in mean LS and TH BMDs between the up-front and delayed groups was 6.7% and 5.2%, respectively ( P < .0001 for both). Although this study was not designed to show antifracture efficacy, the incidence of fractures was slightly higher in the delayed group (up-front, 17 5.7% vs. delayed, 19 6.3%) but not statistically significant ( P = .8638). Pyrexia (27 9% vs. 6 2%; P = .0002) and bone pain (39 13% vs. 20 6.7%; P = .01) were more common in up-front patients; cough (13 4.3% vs. 27 9%; P = .03) was more common in delayed patients. No severe renal dysfunction or confirmed cases of osteonecrosis of the jaw were reported. Disease recurrence was reported in 9 up-front (3.0%) and 16 delayed (5.3%) patients (Kaplan-Meier analysis, P = .127), with an absolute decrease of 2.3%. Conclusion Up-front ZA more effectively prevents AI-associated bone loss in postmenopausal women with early breast cancer than delaying therapy until substantial bone loss or fracture occurs.
Purpose
Persistent fatigue and cognitive dysfunction are poorly understood potential long-term effects of adjuvant chemotherapy. In this pilot study, we assessed the value of electroencephalogram ...(EEG) power measurements as a means to evaluate physical and mental fatigue associated with chemotherapy.
Patients and methods
Women planning to undergo adjuvant chemotherapy for breast cancer and healthy controls underwent neurophysiologic assessments at baseline, during the time of chemotherapy treatment, and at 1 year. Repeated measures analysis of variance was used to analyze the data.
Results
Compared with controls, patients reported more subjective fatigue at baseline that increased during chemotherapy and did not entirely resolve by 1 year. Performance on endurance testing was similar in patients versus controls at all time points; however, values of EEG power increased after a physical task in patients during chemotherapy but not controls. Compared with controls, subjective mental fatigue was similar for patients at baseline and 1 year but worsened during chemotherapy. Patients performed similarly to controls on formal cognitive testing at all time points, but EEG activity after the cognitive task was increased in patients only during chemotherapy.
Conclusion
EEG power measurement has the potential to provide a sensitive neurophysiologic correlate of cancer treatment-related fatigue and cognitive dysfunction.
The purpose of the study was to identify key sensory attributes that influence consumer liking for frozen and fresh red raspberries using preference mapping. Sensory profiling of different raspberry ...cultivars and selections from the Washington State Univ. and Oregon State Univ. breeding programs was carried out using a trained panel (frozen, n = 12 and fresh, n = 10). In addition, a subset of frozen and fresh raspberries of each cultivar was assessed by consumers for sensory acceptability (n = 105 and n = 100, respectively). Based on overall hedonic ratings, cluster analysis identified 3 clusters of frozen raspberry consumers from day 1 (41% “nondistinguishers,” 34% “likers,” and 25% “nonlikers”) and day 2 (41% “group 1 likers,” 26% “nonlikers,” and 34% and 33% group 2 likers”). For fresh raspberry consumers, 2 clusters were detected from day 1 (54% “likers” and 46% nondistinguishers”) and day 2 (54% “group 1 likers” and 46% “group 2 likers”). Preference mapping was applied on the descriptive sensory and acceptability of clustered consumer data. Partial least squares regression results showed that liking of frozen raspberries was driven by high raspberry flavor, firmness, and sweetness. Conversely, disliking of frozen raspberries was related to high sour and aftertaste intensity. In the case of fresh raspberries, high color uniformity, raspberry aroma, raspberry flavor, floral aroma, green flavor, bitter, astringency, and aftertaste increased the acceptability, whereas high color intensity and green aroma were associated with negative drivers of liking. The information obtained in this study can be a useful guide for breeders in the selection of characteristics for growing superior quality raspberries.
Practical Application
The study provides insight into the sensory characteristics that influence consumer preference of raspberries. Identification of the sensory properties that increase or decrease liking of consumers may assist in breeding and production of new raspberry varieties. The development of new varieties with desirable sensory characteristics may focus not only to increase consumption of the “likers” but also to encourage the “nondistinguishers” and “nonlikers” group of consumers, thus increasing market success.
Automatic taps use solenoid valves (SVs) which incorporate a rubber (typically EPDM) diaphragm to control water flow. Contaminated SVs can be reservoirs of opportunistic pathogens such as Pseudomonas ...aeruginosa; an important cause of healthcare-associated infection.
To investigate the attachment and biofilm formation of P. aeruginosa on EPDM and relevant alternative rubbers to assess the impact on water hygiene in a laboratory model.
Biofilm formation on EPDM, silicone and nitrile rubber coupons was investigated using a CDC biofilm reactor. SVs incorporating EPDM or nitrile rubber diaphragms were installed on to an experimental water distribution system (EWDS) and inoculated with P. aeruginosa. P. aeruginosa water levels were monitored for 12-weeks. SVs incorporating diaphragms (EPDM, silicone or silver ion-impregnated silicone rubber), pre-colonized with P. aeruginosa, were installed and the effect of flushing as a control measure was investigated. The concentration of P. aeruginosa in the water was assessed by culture and biofilm assessed by culture and microscopy.
Bacterial attachment was significantly higher on nitrile (6.2 × 105 cfu/coupon) and silicone (5.4 × 105 cfu/coupon) rubber than on EPDM (2.9 ×105 cfu/coupon) (P<0.05, N = 17). Results obtained in vitro did not translate to the EWDS where, after 12-weeks in situ, there was no significant difference in P. aeruginosa water levels or biofilm levels. Flushing caused a superficial reduction in bacterial counts after <5 min of stagnation.
This study did not provide evidence to support replacement of EPDM with (currently available) alternative rubbers and indicated the first sample of water dispensed from a tap should be avoided for use in healthcare settings.
The advancement of neuroscience depends on continued improvement in methods and models. Here, we present novel techniques for the use of awake functional magnetic resonance imaging (fMRI) in the ...prairie vole (Microtus ochrogaster) — an important step forward in minimally-invasive measurement of neural activity in a non-traditional animal model. Imaging neural responses in prairie voles, a species studied for its propensity to form strong and selective social bonds, is expected to greatly advance our mechanistic understanding of complex social and affective processes. The use of ultra-high-field fMRI allows for recording changes in region-specific activity throughout the entire brain simultaneously and with high temporal and spatial resolutions. By imaging neural responses in awake animals, with minimal invasiveness, we are able to avoid the confound of anesthesia, broaden the scope of possible stimuli, and potentially make use of repeated scans from the same animals. These methods are made possible by the development of an annotated and segmented 3D vole brain atlas and software for image analysis. The use of these methods in the prairie vole provides an opportunity to broaden neuroscientific investigation of behavior via a comparative approach, which highlights the ethological relevance of pro-social behaviors shared between voles and humans, such as communal breeding, selective social bonds, social buffering of stress, and caregiving behaviors. Results using these methods show that fMRI in the prairie vole is capable of yielding robust blood oxygen level dependent (BOLD) signal changes in response to hypercapnic challenge (inhaled 5% CO2), region-specific physical challenge (unilateral whisker stimulation), and presentation of a set of novel odors. Complementary analyses of repeated restraint sessions in the imaging hardware suggest that voles do not require acclimation to this procedure. Taken together, awake vole fMRI represents a new arena of neurobiological study outside the realm of traditional rodent models.
•Neural activation can be imaged in awake prairie voles without the use of anesthesia.•BOLD signal was assessed in 115 regions at 260μm2 in-plane resolution every 6s.•The stress of the procedure does not prevent meaningful inferences but should be considered.•Novel odor presentation in the magnet produced activation in predicted and unpredicted areas.
Chemotherapy-induced peripheral neuropathy (CIPN) can interfere with daily function and quality of life, and there are no known preventive approaches. In a cohort of breast cancer patients receiving ...paclitaxel as part of a clinical trial (SWOG 0221), we examined the use of dietary supplements both before diagnosis and during treatment in relation to CIPN.
At registration to S0221, 1225 breast cancer patients completed questionnaires regarding the use of multivitamins and supplements before and at diagnosis. A second questionnaire at six months queried use during treatment. Supplement use was evaluated in relation to CIPN, assessed via the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v. 3.0) and the self-reported Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity (FACT/GOG-Ntx) subscale. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed with logistic regression for the CTCAE analyses and ordinal regression for the FACT/GOG-Ntx analyses.
Multivitamin use before diagnosis was associated with reduced symptoms of CIPN (CTCAE-adjusted OR = 0.60, 95% CI = 0.42 to 0.87; FACT/GOG-Ntx-adjusted OR = 0.78, 95% CI = 0.61 to 1.00). Use during treatment was marginally inversely associated with CIPN (CTCAE-adjusted OR = 0.73, 95% CI = 0.49 to 1.08; FACT/GOG-Ntx-adjusted OR = 0.77, 95% CI = 0.60 to 0.99). Other supplement use, either before diagnosis or during treatment, was not statistically significantly associated with CIPN.
Multivitamin use may be associated with reduced risk of CIPN, although individual dietary supplement use did not appreciably affect risk. Multivitamin use could be a surrogate for other related behaviors that are the actual drivers of the association with reduced CIPN. Without prospective randomized trials of vitamin supplementation, recommendations for use or changes to clinical practice are clearly not warranted.
Retinitis pigmentosa (RP), the commonest form of inherited retinal dystrophies is a clinically and genetically heterogeneous disorder. It is characterized by progressive degeneration of the ...peripheral retina leading to night blindness and loss of peripheral visual field. RP is inherited either in an autosomal dominant, autosomal recessive or X-linked mode. A locus (RP18) for autosomal dominant RP was previously mapped by linkage analysis in two large pedigrees to chromosome 1p13-q21. The human HPRP3 gene, the orthologue of the yeast pre-mRNA splicing factor (PRP3), localizes within the RP18 disease interval. The recent identification of mutations in human splicing factors, PRPF31 and PRPC8, led us to screen HPRP3 as a candidate in three chromosome 1q-linked families. So far, two different missense mutations in two English, a Danish family and in three RP individuals have been identified. Both mutations are clustered within a two-codon stretch in the 11th exon of the HPRP3 gene. Interestingly, one of the mutations (T494M) is seen repeatedly in apparently unlinked families raising the possibility of a mutation hot spot. This has been confirmed by haplotype analysis using SNPs spanning the HPRP3 gene region supporting multiple origins of the mutation. The altered HPRP3 amino acids, which are highly conserved in all known HPRP3 orthologues, indicate a major function of that domain in the splicing process. The identification of mutations in a third pre-mRNA splicing factor gene further highlights a novel mechanism of photoreceptor degeneration due to defects in the splicing process.
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