Polypharmacy, over-the-counter medications, and aromatase inhibitor adherence in early-stage breast cancer.

PURPOSE: Polypharmacy is associated with negative health outcomes and decreased medication adherence. Polypharmacy is common in cancer populations, but few studies have evaluated the relationship between polypharmacy and aromatase inhibitor (AI) adherence. No studies have evaluated the relationship between over-the-counter (OTC) supplements and AI adherence. Our primary hypothesis was that polypharmacy would be associated with increased risk of premature AI discontinuation. METHODS: This exploratory analysis used data from the Exemestane and Letrozole Pharmacogenetics (ELPh) trial, a prospective, multicenter, randomized controlled trial that enrolled participants from 2005 to 2009. Included patients were female, postmenopausal, with stage 0-III breast cancer, who had completed indicated chemotherapy, surgery, and radiation. Participants were randomized to adjuvant exemestane or letrozole and completed serial clinical examinations and questionnaires for two years. Concomitant medication data were collected prospectively. Cox proportion models were used for statistical analysis of the relationship between polypharmacy, OTCs, medication class, and AI adherence. RESULTS: In the 490 analyzed participants, use of any prescription medications at baseline was associated with decreased risk of premature AI discontinuation (HR 0.56, p = 0.02). Use of selective serotonin reuptake inhibitors (SSRIs) or selective serotonin and norepinephrine reuptake inhibitors (SNRIs) at baseline was associated with decreased risk of premature AI discontinuation (HR 0.67, p = 0.04). Use of any OTCs was not associated with AI discontinuation. CONCLUSION: Baseline use of prescription medications but not OTCs was associated with increased AI persistence. Future research is needed to understand how this can be utilized to promote AI adherence.

Phylogenomic analyses of Sapindales support new family relationships, rapid Mid-Cretaceous Hothouse diversification, and heterogeneous histories of gene duplication.

Sapindales is an angiosperm order of high economic and ecological value comprising nine families, c. 479 genera, and c. 6570 species. However, family and subfamily relationships in Sapindales remain unclear, making reconstruction of the order's spatio-temporal and morphological evolution difficult. In this study, we used Angiosperms353 target capture data to generate the most densely sampled phylogenetic trees of Sapindales to date, with 448 samples and c. 85% of genera represented. The percentage of paralogous loci and allele divergence was characterized across the phylogeny, which was time-calibrated using 29 rigorously assessed fossil calibrations. All families were supported as monophyletic. Two core family clades subdivide the order, the first comprising Kirkiaceae, Burseraceae, and Anacardiaceae, the second comprising Simaroubaceae, Meliaceae, and Rutaceae. Kirkiaceae is sister to Burseraceae and Anacardiaceae, and, contrary to current understanding, Simaroubaceae is sister to Meliaceae and Rutaceae. Sapindaceae is placed with Nitrariaceae and Biebersteiniaceae as sister to the core Sapindales families, but the relationships between these families remain unclear, likely due to their rapid and ancient diversification. Sapindales families emerged in rapid succession, coincident with the climatic change of the Mid-Cretaceous Hothouse event. Subfamily and tribal relationships within the major families need revision, particularly in Sapindaceae, Rutaceae and Meliaceae. Much of the difficulty in reconstructing relationships at this level may be caused by the prevalence of paralogous loci, particularly in Meliaceae and Rutaceae, that are likely indicative of ancient gene duplication events such as hybridization and polyploidization playing a role in the evolutionary history of these families. This study provides key insights into factors that may affect phylogenetic reconstructions in Sapindales across multiple scales, and provides a state-of-the-art phylogenetic framework for further research.

Association between nociplastic pain and premature endocrine therapy discontinuation in breast cancer patients.

PURPOSE: At least 5 years of adjuvant endocrine therapy (ET) is recommended for patients with hormone receptor-positive invasive breast cancer to reduce cancer recurrence risk. Up to half of patients prematurely discontinue ET, often due to musculoskeletal pain. Nociplastic pain is abnormal central nervous system pain processing without evidence of tissue or neuronal damage. This study aimed to evaluate the relationship between baseline nociplastic pain and ET discontinuation. METHODS: This was a retrospective, single center, cohort study. Included patients were female, had stage 0-III invasive breast cancer, did not receive neoadjuvant therapy, and completed quality of life questionnaires prior to breast surgery, including Fibromyalgia Survey for nociplastic pain. Clinical data including duration of ET were abstracted from the medical record. Patient characteristics were analyzed with t-tests and Chi-squared tests, as appropriate. Univariate and multivariable regressions were performed with Cox proportional hazard models. RESULTS: Six hundred eighty-one patients diagnosed between 2012 and 2019 met inclusion criteria; 480 initiated ET and were included in the analysis. Of these 480 patients, 203 (42.3%) prematurely discontinued initial ET therapy. On univariate analysis, tamoxifen use (hazard ratio [HR] 0.70, p = 0.021) and premenopausal status (HR 0.73, p = 0.04) were inversely associated with ET discontinuation, while Fibromyalgia Score was positively associated (HR 1.04, p = 0.043). On multivariable analysis, baseline Fibromyalgia Score remained associated with ET discontinuation. CONCLUSION: Nociplastic pain present prior to surgery was associated with premature ET discontinuation. Fibromyalgia Score screening may be useful for evaluating ET discontinuation risk. Treatments targeting nociplastic pain may be more effective for treating ET-emergent pain.

Patient and practitioner perspectives on the design of a simulated affective touch device to reduce procedural anxiety associated with radiotherapy: a qualitative study.

OBJECTIVE: The aim of this study was to elicit the views of relevant stakeholders on the design of a device using simulated affective touch to reduce procedural anxiety surrounding radiotherapy and imaging. DESIGN: This qualitative study collected data from focus groups which were then analysed using inductive thematic analysis in line with Braun and Clarke's methods. PARTICIPANTS AND SETTING: Twenty patients and carers were recruited, as well as 10 healthcare practitioners involved in either delivering radiotherapy or imaging procedures. RESULTS: Patients, carers and healthcare practitioners agreed on some aspects of the device design, such as ensuring the device is warm and flexible in where it can be used on the body. However, patient and healthcare practitioner cohorts had at times differing viewpoints. For example, healthcare practitioners provided professional perspectives and required easy cleaning of the device. Meanwhile patients focused on anxiety-relieving factors, such as the tactile sensation of the device being either a vibration or pulsation. There was no consensus on who should control the device. CONCLUSIONS: The desired features of a simulated affective touch device have been investigated. Different priorities of patients and their carers and healthcare practitioners were evident. Any design must incorporate such features as to appease both groups. Areas where no consensus was reached could be further explored, alongside including further patient and public involvement in the form of a project advisory group.

Not as simple as "fear of the unknown": A qualitative study exploring anxiety in the radiotherapy department.

OBJECTIVE: Little is understood about the anxiety experienced by cancer patients undergoing radiotherapy or investigative imaging. Our aim was to identify sources of anxiety, the points along the cancer journey where anxiety occurred and methods to alleviate it. METHODS: Six focus groups were conducted with cancer patients (n = 17), caregivers (n = 3) and healthcare practitioners (HCPs; n = 10) in the radiotherapy department. Patients described specific elements in the care pathway which induced anxiety, while HCPs focused on their perception of the patient experience. Thematic analysis was used to analyse data. RESULTS: Three broad themes emerged: The Environment, The Individual and The Unknown. The physical environment of the hospital, inside the scanner for example, emerged as a key source of anxiety. The impact of cancer on patients' individual lives was significant, with many feeling isolated. The majority of participants described anxiety associated with the unknown. HCPs reported difficulty in identifying the anxious patient. CONCLUSIONS: Anxiety is experienced throughout the cancer pathway. Common sources include the physical environment and the uncertainty associated with having cancer. Identifying both anxiety-inducing factors, and the anxious patients themselves, is crucial to enable targeted interventions to alleviate anxiety.

HybPhaser: A workflow for the detection and phasing of hybrids in target capture data sets.

PREMISE: Hybrids contain divergent alleles that can confound phylogenetic analyses but can provide insights into reticulated evolution when identified and phased. We developed a workflow to detect hybrids in target capture data sets and phase reads into parental lineages using a similarity and phylogenetic framework. METHODS: We used Angiosperms353 target capture data for Nepenthes, including known hybrids to test the novel workflow. Reference mapping was used to assess heterozygous sites across the data set and to detect hybrid accessions and paralogous genes. Hybrid samples were phased by mapping reads to multiple references and sorting reads according to similarity. Phased accessions were included in the phylogenetic framework. RESULTS: All known Nepenthes hybrids and nine additional samples had high levels of heterozygous sites, had reads associated with multiple divergent clades, and were phased into accessions resembling divergent haplotypes. Phylogenetic analysis including phased accessions increased clade support and confirmed parental lineages of hybrids. DISCUSSION: HybPhaser provides a novel approach to detect and phase hybrids in target capture data sets, which can provide insights into reticulations by revealing origins of hybrids and reduce conflicting signal, leading to more robust phylogenetic analyses.

Safety of fluoroscopically guided pain procedures in patients receiving cytotoxic chemotherapy: a retrospective analysis.

PURPOSE: To examine the incidence of bleeding and infectious adverse events (AEs) in patients undergoing interventional, fluoroscopic-guided axial spine procedures to modulate pain. METHODS: Retrospective data of patients undergoing fluoroscopically guided axial spine injections at a single tertiary care medical center Cancer Rehabilitation program in the USA were reviewed. AEs, type of chemotherapy, type of tumor, age, platelet and absolute neutrophil counts (ANC) prior to the procedure, and relevant past medical history were collected. Descriptive statistical analyses were performed. RESULTS: Sixty-three separately identifiable procedures across 28 patients met inclusion criteria. Zero AEs were recorded. Platelet and ANC were generally above the recommended safety threshold, but granulocyte colony stimulating factor was administered prior to four procedures to boost ANC levels. Multiple myeloma was the most common cancer diagnosis (64.3%). Various solid tumors made up the remaining cancer diagnoses. Epidural steroid injections (n=23) and medial branch blocks (n=23) were the most common procedures performed and lumbar (n=35) was the most common location of procedures. Three patients died within 30 days of the procedures but their deaths were not directly attributable to the injections. CONCLUSION: This provides preliminary data to support the safety of injections in patients receiving cytotoxic chemotherapy. Larger, multicenter studies are required before firm conclusions can be drawn.

Interventional and Non-interventional Medical Rehabilitation Approaches to Axial Spine Pain in Vertebral Metastatic Disease.

As targeted therapies help patients with advanced cancer live longer, interventions for management of axial spine pain will become more common. Unfortunately, the indications for and safety of these procedures have been relatively unexplored compared with non-cancer adults. This review focuses on the following aspects of axial spine pain management in patients with vertebral metastatic disease: (1) pathophysiology and symptoms of cancer- and non-cancer-related spine pain; (2) safety and efficacy of non-interventional rehabilitation approaches to treat this pain; (3) considerations for interventional pain approaches to acute and chronic pain in patients with vertebral metastatic disease. This review also summarizes gaps in the literature and describes specific cases in which the described interventions have been applied.

Quantification of conjunctival TNF-α in aqueous-deficient dry eye.

PURPOSE: This study aimed to quantify and compare conjunctival epithelial tumor necrosis factor (NF) α mRNA expression in Sjögren syndrome (SS), non-Sjögren syndrome aqueous-deficient dry eye (non-SS DE), and non-dry eye (NDE) control subjects. METHODS: A total of 76 subjects were recruited for this study: 25 SS (confirmed via American-European Consensus Criteria 2002), 25 non-SS DE (confirmed by symptoms and Schirmer scores ≤ 10 mm), and 26 NDE. Superior and temporal bulbar conjunctival epithelial cells were collected via impression cytology. Epithelial RNA was extracted, and TNF-α mRNA expression was quantified by real-time quantitative polymerase chain reaction. RESULTS: The expression of TNF-α mRNA was found to be significantly higher in the SS group (2.48 ± 1.79) compared to both non-SS DE (0.95 ± 1.18; p < 0.05) and NDE (0.84 ± 0.51; p < 0.05) groups. No difference in TNF-α mRNA expression was found between the non-SS DE and NDE groups (p = 0.67). CONCLUSIONS: These results demonstrate that SS-associated aqueous-deficient dry eye is associated with a significant upregulation of conjunctival epithelial TNF-α mRNA relative to both non-SS DE and control groups. The degree to which TNF-α mRNA is upregulated in SS may contribute to the severe ocular surface damage observed in these patients.

MUC1 expression in Sjogren's syndrome, KCS, and control subjects.

PURPOSE: To quantify and compare human mucin 1 (MUC1) protein and mRNA expression in tears and conjunctival epithelial cells collected from Sjogren's syndrome (SS), non-Sjogren's keratoconjunctivitus sicca (KCS) and non-dry eyed (NDE) control subjects. METHODS: Seventy-six subjects were recruited for this study: 25 SS (confirmed via American-European Consensus Criteria 2002), 25 KCS (confirmed by symptoms and Schirmer scores < or = 10 mm) and 26 NDE. Tears were collected using an eye-wash technique. Impression cytology was used to gather protein and mRNA from conjunctival epithelial cells. Soluble and membrane bound MUC1 were quantified via western blotting and MUC1 mRNA was quantified by real time qPCR. RESULTS: The SS group demonstrated significantly higher concentrations of soluble MUC1 (0.12 +/- 0.11 [SS]; 0.013 +/- 0.02 [KCS; p=0.001]; 0.0023 +/- 0.0024 [NDE; p<0.001]) and MUC1 mRNA (3.18 +/- 1.44 [SS]; 1.79 +/- 1.18 [KCS; p<0.05]; 1.60 +/- 0.74 [NDE; p<0.05]) compared to both KCS and NDE groups. Soluble MUC1 expression was also higher in the KCS group compared to the NDE group (p=0.02), where as MUC1 mRNA expression was similar in both KCS and NDE groups. Membrane bound MUC1 expression differed only between the SS and NDE groups (0.005 +/- -0.003 [SS]; 0.003 +/- 0.002 [NDE; p=0.002]). CONCLUSIONS: These results demonstrate that SS subjects express greater quantities of MUC1 protein and mRNA compared to both KCS and control subjects. Increased soluble MUC1 expression was also found in KCS subjects compared to controls. Membrane bound MUC1 was present in higher concentration in SS versus NDE only. These significant changes in MUC1 expression may represent compensatory or protective responses to chronic insult to the ocular surface.

"Some guys have all the luck": mate preference influences paced-mating behavior in female rats.

In the present study, mating behavior was observed in female rats that were given the opportunity to mate with two males simultaneously. Three groups of females were tested: 1) sexually naïve, naturally cycling rats in proestrous; 2) sexually naïve, hormone-primed, ovariectomized (OVX) rats; and 3) hormone-primed, OVX rats tested 1 week after sexual receptivity testing. One male rat was determined to be the preferred male for each female, if she spent more time with him during a mating test. Independent of sexual experience, female rats were less likely to leave their preferred male than their non-preferred male following intromissions. However, when they left their preferred male, they returned to him faster than to their non-preferred male. This effect of preference was slightly more robust in the OVX rats. When female rats from Group 2 were tested with the same pair of males for 3 additional tests, each female's preference for a particular male was stable. That is, a female rat preferred the same male in approximately 3 out of the 4 tests, which is more likely than would be expected by chance. In a final experiment, pairs of male rats were tested with different females once weekly to determine if different females would prefer particular males consistently. Although no male rat was preferred by all females, females consistently preferred the same male from each pair during approximately 70% of the tests. In conclusion, female mate preference may have adaptive significance for the reproductive success of rats.

Subconjunctival cyst-like formations following impression cytology.

PURPOSE: To report a case of an unusual adverse event subsequent to undertaking Conjunctival Impression Cytology (CIC). METHODS: CIC was undertaken on a 54-year-old healthy Caucasian female, using a 10 mm Millipore membrane on the bulbar conjunctiva. Prior to the CIC procedure, two drops of topical proparacaine (Alcaine were instilled and following the procedure two drops of artificial tears (GenTeal were administered. RESULTS: The subject reported excessive bulbar conjunctival hyperaemia in the left eye 5 min postprocedure, with no marked pain or discomfort. Slitlamp biomicroscopic evaluation revealed several "bubbles" or cystic formations trapped underneath the conjunctival tissue, in association with moderate to severe bulbar conjunctival redness. These cysts began to regress fairly rapidly and completely disappeared within 1h. CONCLUSION: CIC is a useful tool for studying the ocular surface; however, care should be taken while performing this mildly invasive procedure. This is the first report of bubble formation in the conjunctiva following CIC. Subjects should be advised about the short term redness and discomfort that could occur following CIC.

Role of eIF5A in TNF-alpha-mediated apoptosis of lamina cribrosa cells.

PURPOSE: To determine the role of eukaryotic translation initiation factor 5A (eIF5A) in TNF-alpha-induced apoptosis of lamina cribrosa (LC) cells. METHODS: LC cells were isolated from optic nerve heads of eyes of two human donors. The cells were treated with TNF-alpha and camptothecin, a TNF synergist, and the incidence of apoptosis was scored by Hoechst staining. Expression of eIF5A protein in response to camptothecin or a combination of camptothecin and TNF-alpha was determined by Western blot analysis. The ability of small inhibitory (si)RNAs directed against eIF5A to protect LC cells from TNF-alpha-induced apoptosis was determined by Hoechst and TUNEL staining of transfected LC cells. RESULTS: TNF-alpha and camptothecin synergized to induce greater than two times more apoptosis in LC cells than when the cells were treated with TNF-alpha or camptothecin separately. Expression of eIF5A protein increased significantly after 8 hours of exposure to TNF-alpha and camptothecin, but not in response to camptothecin alone. siRNAs directed against eIF5A reduced apoptosis of LC cells in response to TNF-alpha and camptothecin by between 35% and 69%, as determined by Hoechst staining. An siRNA against glyceraldehyde-3-phosphate dehydrogenase (GAPDH) also reduced apoptosis of LC cells by 42%. TUNEL of transfected LC cells treated with TNF-alpha and camptothecin revealed an 80% reduction in apoptosis with siRNA against eIF5A. CONCLUSIONS: TNF-alpha, in synergy with camptothecin, induces apoptosis in human LC cells. eIF5A is upregulated by LC cells in response to TNF-alpha, and siRNAs against eIF5A protect LC cells from apoptosis. Thus, eIF5A appears to be a novel proapoptotic protein in the TNF pathway and a possible target for treatment of glaucoma.