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Objective: Risk-reducing therapy with selective estrogen receptor (ER) modulators and aromatase inhibitors reduce breast cancer risk. However, the effects are limited to ER-positive breast cancer. Therefore, new agents with improved toxicity profiles that reduce the risk in ER-negative breast cancers are urgently needed. The aim of this prospective, short-term, prevention study was to evaluate the effect of dasatinib, an inhibitor of the tyrosine kinase Src, on biomarkers in normal (but increased risk) breast tissue and serum of women at high risk for a second, contralateral primary breast cancer. Materials and Methods: Women with a history of unilateral stage I, II, or III ER-negative breast cancer, having no active disease, and who completed all adjuvant therapies were eligible. Patients underwent baseline fine-needle aspiration (FNA) of the contralateral breast and serum collection for biomarker analysis and were randomized to receive either no treatment (control) or dasatinib at 40 or 80 mg/day for three months. After three months, serum collection and breast FNA were repeated. Planned biomarker analysis consisted of changes in cytology and Ki-67 on breast FNA, and changes in serum levels of insulin-like growth factor 1 (IGF-1), IGF-binding protein 1, and IGF-binding protein 3. The primary objective was to evaluate changes in Ki-67 and secondary objective included changes in cytology in breast tissue and IGF-related serum biomarkers. Toxicity was also evaluated. Results: Twenty-three patients started their assigned treatments. Compliance during the study was high, with 86.9% (20/23) of patients completing their assigned doses. Dasatinib was well tolerated and no drug-related grade 3 and 4 adverse events were observed. Since only one patient met the adequacy criteria for the paired FNA sample, we could not evaluate Ki-67 level or cytological changes. No significant change in serum biomarkers was observed among the three groups. Conclusion: Dasatinib was well tolerated but did not induce any significant changes in serum biomarkers. The study could not fulfill its primary objective due to an inadequate number of paired FNA samples. Further, larger studies are needed to evaluate the effectiveness of Src inhibitors in breast cancer prevention. [ABSTRACT FROM AUTHOR]

An important problem in oncology is comparing chemotherapy (chemo) agents in terms of their effects on survival or progression-free survival time. When the goal is to evaluate individual agents, a difficulty commonly encountered with observational data is that many patients receive a chemo combination including two or more agents. Because agents given in combination may interact, quantifying the contribution of each individual agent to the combination's overall effect is problematic. Still, if on average combinations including a particular agent confer longer survival, then that agent may be considered superior to agents whose combinations confer shorter survival. Motivated by this idea, we propose a definition of individual agent effects based on observational survival data from patients treated with many different chemo combinations. We define an individual agent effect as the average of the effects of the chemo combinations that include the agent. Similarly, we define the effect of each pair of agents as the average of the effects of the combinations including the pair. Under a Bayesian regression model for survival time in which the chemo combination effects follow a hierarchical structure, these definitions are used as a basis for estimating the posterior effects and ranks of the individual agents, and of all pairs of agents. The methods are illustrated by a data set arising from 224 pediatric brain tumor patients treated with over 27 different chemo combinations involving seven chemo agents. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background Retinoids have shown antiproliferative and chemopreventive activity. We analyzed data from a randomized, placebo-controlled chemoprevention trial to determine whether a 3-month treatment with either 9-cis-retinoic acid (RA) or 13-cis-RA and α-tocopherol reduced Ki-67, a proliferation biomarker, in the bronchial epithelium. Methods Former smokers (n = 225) were randomly assigned to receive 3 months of daily oral 9-cis-RA (100 mg), 13-cis-RA (1 mg/kg) and α-tocopherol (1200 IU), or placebo. Bronchoscopic biopsy specimens obtained before and after treatment were immunohistochemically assessed for changes in the Ki-67 proliferative index (i.e., percentage of cells with Ki-67-positive nuclear staining) in the basal and parabasal layers of the bronchial epithelium. Per-subject and per-biopsy site analyses were conducted. Multicovariable analyses, including a mixed-effects model and a generalized estimating equations model, were used to investigate the treatment effect (Ki-67 labeling index and percentage of bronchial epithelial biopsy sites with a Ki-67 index ≥ 5%) with adjustment for multiple covariates, such as smoking history and metaplasia. Coefficient estimates and 95% confidence intervals (Cls) were obtained from the models. All statistical tests were two-sided. Results In per-subject analyses, Ki-67 labeling in the basal layer was not changed by any treatment; the percentage of subjects with a high Ki-67 labeling in the parabasal layer dropped statistically significantly after treatment with 13-cis-RA and α-tocopherol treatment (P = .04) compared with placebo, but the drop was not statistically significant after 9-cis-RA treatment (P= .17). A similar effect was observed in the parabasal layer in a per-site analysis; the percentage of sites with high Ki-67 labeling dropped statistically significantly after 9-cis-RA treatment (coefficient estimate = -0.72, 95% CI = -1.24 to -0.20; P= .007) compared with placebo, and after 13-cis-RA and α-tocopherol treatment (coefficient estimate = -0.66, 95% CI = -1.15 to -0.17; P = .008). Conclusions In per-subject analyses, treatment with 13-cis-RA and α-tocopherol, compared with placebo, was statistically significantly associated with reduced bronchial epithelial cell proliferation; treatment with 9-cis-RA was not. In per-site analyses, statistically significant associations were obtained with both treatments. [ABSTRACT FROM AUTHOR]

Ciclosporin is a potent immunomodulator that acts selectively and locally when administered at the ocular surface. 0.05% ciclosporin ophthalmic emulsion has recently been approved by the US FDA for treatment of keratoconjunctivitis sicca (KCS) [dry-eye disease]. After topical application, ciclosporin accumulates at the ocular surface and cornea, achieving concentrations (>/=0.236 microg/g) that are sufficient for immunomodulation. Very little drug penetrates through the ocular surface to intraocular tissues. Ciclosporin is not metabolised in rabbit or dog eyes and may not be prone to metabolism in human eyes. Cultured human corneal endothelial and stromal cells exposed to ciclosporin in vitro exhibited no adverse effects and only minor effects on DNA synthesis. No ocular or systemic toxicity was seen with long-term ocular administration of ciclosporin at concentrations up to 0.4%, given as many as six times daily for 6 months in rabbits and 1 year in dogs. Systemic blood ciclosporin concentration after ocular administration was extremely low or undetectable in rabbits, dogs and humans, obviating concerns about systemic toxicity. In 12-week and 1-year clinical safety studies in dry-eye patients, the most common adverse event associated with the ophthalmic use of ciclosporin emulsion was ocular burning. No serious drug-related adverse events occurred. These data from in vitro, nonclinical and clinical studies indicate effective topical delivery of ciclosporin to desired target tissues along with a favourable safety profile, making 0.05% ciclosporin ophthalmic emulsion a promising treatment for KCS. [ABSTRACT FROM AUTHOR]

The diffusion from the site of intramuscular injection of 900 kDa botulinum neurotoxin–hemagglutinin complex (BoNT/A-complex) and 150 kDa free-botulinum neurotoxin (free-BoNT/A) was compared. Radioiodinated compounds were injected into the gastrocnemius muscle of rats (70 Units (U) 125I-BoNT/A-complex, 67 or 344 U free-125I-BoNT/A, or free-125I-iodide) and the eyelids of rabbits (24 U 125I-BoNT/A-complex or 108 U free-125I-BoNT/A), and measured in various tissues at different time points. There were no detectable systemic effects or generalized botulinum neurotoxin toxicity in either rats or rabbits, indicating that most of the toxin, whether as 125I-BoNT/A-complex or free-125I-BoNT/A, remained at the injection site. In rats, 125I-BoNT/A-complex and free-125I-BoNT/A diffused in a pattern that was grossly similar. Almost no radioactivity was recovered from the brain. Radioactivity recovered from distant tissues (thyroid, skin, and contralateral muscle) was primarily attributable to either low molecular weight 125I-containing peptides or 125I-iodide. After injection into rabbit eyelids, neither 125I-BoNT/A-complex nor free-125I-BoNT/A spread to distant structures, including the eye. The results indicate that most of the neurotoxin does not diffuse from the injection site, whether in free or complexed form, and this may reduce the potential for systemic effects. [Copyright &y& Elsevier]

Talimogene laherparepvec (T-VEC) is an immunotherapy that generates local tumor lysis and systemic antitumor immune response. We studied the efficacy of intratumoral administration of T-VEC as monotherapy for inoperable locoregional recurrence of breast cancer. T-VEC was injected intratumorally at 106 PFU/mL on day 1 (cycle 1), 108 PFU/mL on day 22 (cycle 2), and 108 PFU/mL every 2 weeks thereafter (cycles ≥ 3). Nine patients were enrolled, 6 with only locoregional disease and 3 with both locoregional and distant disease. No patient completed the planned 10 cycles or achieved complete or partial response. The median number of cycles administered was 4 (range, 3–8). Seven patients withdrew prematurely because of uncontrolled disease progression, 1 withdrew after cycle 3 because of fatigue, and 1 withdrew after cycle 4 for reasons unrelated to study treatment. Median progression-free survival and overall survival were 77 days (95% CI, 63–NA) and 361 days (95% CI, 240–NA). Two patients received 8 cycles with clinically stable disease as the best response. The most common grade 2 or higher adverse event was injection site reaction (n = 7, 78%). Future studies could examine whether combining intratumoral T-VEC with concurrent systemic therapy produces better outcomes. [ABSTRACT FROM AUTHOR]

Purpose: The impact of regional nodal irradiation (RNI) on locoregional recurrence (LRR) and any disease recurrence (DR) in women with node-positive breast cancer who receive neoadjuvant systemic therapy (NAT) is unknown.Methods and Materials: The impact of RNI on LRR and DR was estimated with the cumulative incidence method in 1289 women with stage II to III breast cancer with cytologically confirmed axillary metastases who received NAT between 1989 and 2007. Multicovariate Cox regression analysis was performed to examine the effect of RNI after accounting for other predictive and prognostic variables.Results: The median follow-up after definitive surgery was 10.2 years. Axillary pathologic complete response (pCR) was observed in 368 of 1289 patients (28.5%). On univariate analysis, axillary pCR reduced 10-year LRR risk from 9.7% to 4.8% (P = .006) and DR risk from 43.0% to 17.0% (P < .001). RNI was administered to 1080 of 1289 patients (83.8%). On univariate analysis, RNI did not affect 10-year LRR risk (no RNI, 9.4%; RNI, 8.1%; P = .62) or DR risk (no RNI, 31.3%; RNI, 36.5%; P = .16). On multicovariate analysis, RNI significantly reduced the risk of LRR (hazard ratio, 0.497; 95% confidence interval [CI], 0.279-0.884; P = .02) and DR (hazard ratio, 0.731; 95% CI, 0.541-0.988; P = .04) and showed a particularly strong reduction in risk of DR in patients with HER2+ disease who received trastuzumab (hazard ratio, 0.237; 95% CI, 0.109-0.517; P = .0003). A nomogram to predict 10-year LRR risk with and without RNI has been generated to assist clinicians in individualizing treatment decisions based on patient and disease characteristics and response to NAT.Conclusions: Adjuvant RNI reduces risk of LRR and DR in patients with breast cancer with axillary metastases who receive NAT across subtypes and particularly decreases the risk of DR in HER2+ breast cancer treated with trastuzumab. Enrollment on the National Surgical Adjuvant Breast and Bowel Project B-51/Radiation Therapy Oncology Group 1304 protocol is encouraged to help determine whether RNI can be omitted in patients with axillary pCR to NAT. [ABSTRACT FROM AUTHOR]

Context: Assessment of cancer-related fatigue is currently based on patient-reported outcomes. We asked whether objective assessments, such as muscle strength and nutritional markers, can be used as surrogate measures of cancer-related fatigue.Objective: We examined the association among three fatigue scales, muscle strength, and nutritional markers in patients with advanced cancer.Methods: In this prospective study, we enrolled hospitalized cancer patients who had been seen in palliative care consultation at MD Anderson Cancer Center. We assessed fatigue using three fatigue scales-the Brief Fatigue Inventory (BFI), the Edmonton Symptom Assessment System (ESAS), and the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire 30 (EORTC QLQ-C30)-and determined their association with objective assessments, including handgrip strength, maximal inspiratory pressure, lean body mass, phase angle, and albumin. Spearman's correlation test was used to assess associations.Results: Among 222 patients, the mean age was 55 years; 59% were women. The median overall survival was 106 days. The total BFI score had weak association with handgrip strength (ρ = -0.18, P = 0.007) and no association with the remaining objective measures. ESAS fatigue and EORTC fatigue showed similar findings. Total BFI had moderate-to-strong association with ESAS (ρ = 0.54, P < 0.0001) and EORTC (ρ = 0.60, P < 0.0001) fatigue.Conclusion: Our study showed that subjective assessment of fatigue based on patient-reported outcomes correlates only weakly with muscle strength and nutritional markers; thus, patient-reported outcomes remain the gold standard for fatigue assessment. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this multicenter study was to characterize the association between spirituality, religiosity, spiritual pain, symptom distress, coping, and quality of life (QOL) among Latin American advanced cancer patients. Methods: Three hundred twenty-five advanced cancer patients from palliative care clinics in Chile, Guatemala, and the United States completed validated assessments: Faith, Importance and Influence, Community, and Address (FICA) (spirituality/religiosity), Edmonton Symptom Assessment Scale-Financial/Spiritual (ESAS-FS), including spiritual pain, Penn State Worry Questionnaire-Abbreviated (PSWQ-A), Center for Epidemiologic Studies Depression Scale (CES-D), Brief-coping strategies (COPE) and Brief religious coping (RCOPE) and RCOPE, respectively, and Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being, Expanded version (FACIT-Sp-Ex). Results: Median age: 58 years (range: 19–85); 60% female; and 62% Catholic and 30% Christian, but not Catholic. Three hundred fifteen patients (97%) considered themselves spiritual and 89% religious, with median intensities of 7 (interquartile range [IQR]: 5–10) and 7 (5–9), respectively (0–10 scale, 10 = "very much"). Median importance of spirituality/religiosity was 10 (IQR: 8–10). The frequency and associations between spirituality/religiosity and various items were as follows: helps to cope with illness (98%; r = 0.66303; p < 0.0001), positive effect on physical symptoms (81%; r = 0.42067; p < 0.0001), and emotional symptoms (84%; r = 0.16577; p < 0.0001). One hundred ninety-five patients (60%) reported that their spiritual/religious needs had not been supported by the medical team. Spiritual pain was reported in 162/311 patients (52%), with median intensity of 6 (IQR: 5–8). Spiritual pain was associated with pain (p = 0.0225), depression (p < 0.0001), anxiety (p < 0.0001), worry (p < 0.001), behavioral disengagement (p = 0.0148), FACIT-Sp-Ex score (p = 0.0002), and negative RCOPE (p < 0.0001). Significance of Results: Spirituality and religiosity are frequent, intense, and rarely addressed among Latin American patients. Spirituality/religiosity was associated with positive COPE and higher QOL. Spiritual pain was also frequent and associated with physical and psychosocial distress. These patients need increased spiritual/religious support. [ABSTRACT FROM AUTHOR]

Abstract: The activities of insulin-like growth factors (IGFs) in regulating cell proliferation, differentiation, and apoptosis are modulated by a family of high-affinity specific IGF-binding proteins (IGFBPs), IGFBP-3 being the most abundant in circulation. Down-regulation of IGFBP-3 has been shown to be associated with a shorter disease-specific survival probability in early non-small-cell lung cancer (NSCLC). We examined the prognostic role of IGFBP-3 protein expression loss in 34 squamous cell carcinomas (SCC) of the tongue (stages II–IV) and 30 premalignant lesions of the oral cavity and the larynx. Reduced IGFBP-3 expression was found in 11 (32%) of 34 tongue SCC cases, and was associated with significantly shorter disease-specific and disease-free survival (P=0.0002 and <0.0001 by Log-rank test). In premalignant lesions, IGFBP3 loss was found in 8 (27%) of 30 cases without significant association with cancer-free survival. Therefore, down-regulation of IGFBP-3 is an early event during head and neck carcinogenesis, that bears an adverse prognostic significance in tongue cancer and could serve as both a marker of aggressive disease and target for intervention. [Copyright &y& Elsevier]

Background: Altered cyclin D1 expression in advanced preinvasive lesions of the upper aerodigestive tract (UADT) is associated with an increased risk of developing cancer and histologic progression during and after combination biochemopreventive therapy (13-cis-retinoic acid, alpha-interferon, and alpha-tocopherol). Both alleles of the adenine (A)/guanine (G) cyclin D1 polymorphism located at nucleotide 870 encode two alternatively spliced transcripts, but the A allele preferentially encodes a protein with an extended half-life. We investigated whether the cyclin D1 genotype at nucleotide 870 was associated with baseline levels of cyclin D1 protein, post-treatment modulation of cyclin D1 protein levels, histologic response to treatment, and the outcome for subjects with preinvasive UADT lesions after biochemopreventive therapy.Methods: UADT tissue biopsy samples were obtained before and 6 and 12 months after biochemopreventive treatment from 31 individuals with advanced preinvasive UADT lesions. Tissues were examined for cyclin D1 genotype (by DNA single-strand conformation polymorphism analysis), for cyclin D1 protein expression (by immunohistochemistry), and for cyclin D1 gene copy number (by fluorescence in situ hybridization). Associations of cyclin D1 genotype with histologic response to therapy and time to progression to a higher degree of dysplasia or invasive cancer were investigated. All statistical tests were two-sided.Results: The A allele was associated with increased baseline cyclin D1 expression in the parabasal epithelial layer (16 of 18 AA/AG subjects versus four of nine GG subjects; P =.02), decreased histologic response to biochemopreventive treatment (six of 21 AA/AG subjects versus four of 10 GG subjects; P =.70), decreased favorable modulation of cyclin D1 expression by the treatment (seven of 18 AA/AG subjects versus eight of nine GG subjects; P =.02), and shorter progression-free survival (P =.05).Conclusions: The cyclin D1 A allele was associated with a diminished modulation of normal physiologic and treatment-induced decreased expression of cyclin D1, a decreased likelihood of response to biochemopreventive intervention, and an increased rate of progression to cancer development, findings that require validation in a larger cohort. [ABSTRACT FROM AUTHOR]

Studies the expression of retinoic acid receptor beta and telomerase catalytic subunit in the bronchial epithelium of heavy smokers. Key issues of interest; Analysis of pertinent topics and relevant issues; Implications on oncology.

Background: There is limited information regarding the true frequency of nonmedical opioid use (NMOU) among patients receiving opioid therapy for cancer pain. Data to guide patient selection for urine drug testing (UDT) as well as the timing and frequency of ordering UDT are insufficient. This study examined the frequency of abnormal UDT among patients with cancer who underwent random UDT and their characteristics. Methods: Demographic and clinical information for patients with cancer who underwent random UDT were retrospectively reviewed and compared with a historical cohort that underwent targeted UDT. Random UDT was ordered regardless of a patient's risk potential for NMOU. Targeted UDT was ordered on the basis of a physician's estimation of a patient's risk for NMOU. Results: In all, 552 of 573 eligible patients (96%) underwent random UDT. Among these patients, 130 (24%) had 1 or more abnormal results; 38 of the 88 patients (43%) who underwent targeted UDT had 1 or more abnormal results. When marijuana was excluded, 15% of the random group and 37% of the targeted group had abnormal UDT findings (P <.001). It took a shorter time from the initial consultation to detect 1 or more abnormalities with the random test than the targeted test (median, 130 vs 274 days; P =.02). Abnormal random UDT was independently associated with younger age (P <.0001), male sex (P =.03), Cut Down, Annoyed, Guilty, and Eye Opener–Adapted to Include Drugs positivity (P =.001), and higher Edmonton Symptom Assessment System anxiety (P =.01). Conclusions: Approximately 1 in 4 patients receiving opioids for cancer pain at a supportive care clinic who underwent random UDT had 1 or more abnormalities. Random UDT detected abnormalities earlier than the targeted test. These findings suggest that random UDT is justified among patients with cancer pain. Approximately 1 in 4 patients receiving opioids for cancer pain at a supportive care center who underwent random urine drug testing had 1 or more abnormalities. Random urine drug testing detected abnormalities earlier than the targeted test. [ABSTRACT FROM AUTHOR]

Purpose. To determine the ocular pharmacokinetics of cyclosporin A after topical ophthalmic administration. Methods. Radiolabled cyclosporin A in either a castor oil-in-water emulsion or a corn oil ointment was applied to the eyes of beagle dogs or albino rabbits using the following paradigms: (i) single doses of 0.2% emulsion to rabbits and dogs, (ii) single doses of 0.05%, 0.2%, or 0.4% emulsion to rabbits, (iii) multiple doses of 0.2% emulsion to dogs, (iv) single and multiple doses of 0.2% ointment to rabbits. The distribution of cyclosporin A was determined by measuring the distribution of radio-activity. Results. After a single dose, cyclosporin A was rapidly absorbed into the conjunctiva (Cmax: dogs, 1490 ng/g; rabbits, 1340 ng/g) and cornea (Cmax: dogs, 311 ng/g; rabbits, 955 ng/g). High concentrations (>300 ng/g) could be detected in the cornea up to 96 hours post-dose. Lower concentrations were found in the intraocular tissues, and systemic absorption was minimal. After multiple doses, there was some accumulation in the cornea, lens, lacrimal gland, and iris-cilliary body, but limited accumulation in the conjunctiva and sclera. Ocular tissue concentrations of cyclosporin A increased with increasing dose concentration; proportionally in lacrimal gland and intraocular tissues; less than proportionally in conjunctiva and cornea. The pharmacokinetic profile of the cyclosporin A corn oil ointment was similar to that of the emulsion. Conclusions. Topical ophthalmic cyclosporin A penetrated into extraocular tissues at concentrations adequate for local immunomodulation while penetration into intraocular tissues was much less and absorption into the blood was minimal. [ABSTRACT FROM AUTHOR]

Data subject to length-biased sampling are frequently encountered in various applications including prevalent cohort studies and are considered as a special case of left-truncated data under the stationarity assumption. Many semiparametric regression methods have been proposed for lengthbiased data to model the association between covariates and the survival outcome of interest. In this paper, we present a brief review of the statistical methodologies established for the analysis of length-biased data under the Cox model, which is the most commonly adopted semiparametric model, and introduce an R package CoxPhLb that implements these methods. Specifically, the package includes features such as fitting the Cox model to explore covariate effects on survival times and checking the proportional hazards model assumptions and the stationarity assumption. We illustrate usage of the package with a simulated data example and a real dataset, the Channing House data, which are publicly available. [ABSTRACT FROM AUTHOR]

Background: Tumor cells with a mesenchymal phenotype and/or cancer stem-like cells (CSCs) are known to contribute to metastasis and drug resistance. Circulating tumor cells (CTCs) undergoing epithelial-mesenchymal transition (EMT) and CTCs reflecting a dedifferentiated CSC phenotype may not be detected using only an anti-EpCAM antibody to capture them. We used an antibody-independent CTC enrichment platform, ApoStream®, which does not rely on any antibody, including anti-EpCAM, to capture EMT- and CSC-CTCs in breast cancer patients who received neoadjuvant chemotherapy and correlated them to pathological complete response (pCR). Methods: Blood samples from newly diagnosed breast cancer patients were prospectively collected before neoadjuvant chemotherapy (T0), after chemotherapy but before surgery (T1), and after surgery (T2) and processed using ApoStream. CTCs detected were stained with additional markers to define 3 CTC subsets with the following phenotypes: epithelial CTCs (CK+, EpCAM+ or E-cadherin+), EMT-CTCs (β-catenin+ or vimentin+), and CSC-CTCs (CD44+ and CD24low). Results: We enrolled 55 patients, 47 of which had data for analysis. EMT-CTCs were detected in 57%, 62%, and 72% and CSC-CTCs in 9%, 22%, and 19% at the T0, T1, and T2 time points, respectively. Counts of epithelial (P = 0.225) and EMT (P = 0.522) phenotypes of CTCs at T0 did not significantly predict pCR. Moreover, no correlation between CTC count change and pCR was demonstrated. Conclusions: ApoStream was successful in detecting EMT-CTCs among patients after neoadjuvant chemotherapy. However, EMT-/CSC-CTC counts did not correlate with pCR. Due to the small sample size and heterogeneity of this patient population, further study in a larger cohort of molecularly homogeneous patients is warranted. [ABSTRACT FROM AUTHOR]

Context: Multiple studies have demonstrated that adults do not store prescription opioids safely. Increased prescription opioid rates have led to an increased incidence of opioid poisonings in children and adolescents.Objectives: We investigated whether parents practiced safe storage, use, and disposal techniques of opioids that were prescribed to their child with cancer-related pain.Methods: We conducted a prospective cross-sectional survey of parents whose children were prescribed opioids and asked them about their patterns of storage, use, and disposal of prescription opioids.Results: Virtually, all parents (106 of 109; 97%) completed the survey. Most parents (95 of 106; 90%) did not store opioids safely. Six of 106 parents (6%) gave their child's opioid pain medication to someone else with pain, and three of 106 parents (3%) personally took some of their child's opioid. Parents who personally took their child's opioid (P = 0.01) or gave it to another person (P < 0.001) were more likely to use opioids unsafely with their child. A minority of parents (22 of 106; 21%) did not use opioids safely in their child. A small number of parents (3 of 22; 14%) did not dispose of opioids safely.Conclusion: Universal education about the safe use and disposal of opioids should be adopted when prescribing opioids. Pediatricians need to maintain vigilance about the nonmedical use of prescription opioid use by parents of children. [ABSTRACT FROM AUTHOR]

Background: Radium‐223 dichloride (Ra‐223) is a targeted alpha therapy that induces localized cytotoxicity in bone metastases. We evaluated the efficacy and safety of Ra‐223 plus hormonal therapy in hormone receptor‐positive (HR+), bone‐dominant metastatic breast cancer. Methods: In this single‐center phase II study, 36 patients received Ra‐223 (55 kBq/kg intravenously every 4 weeks) up to 6 cycles with endocrine therapy. The primary objective was to determine the clinical disease control rate at 9 months. Secondary objectives were to determine (a) tumor response rate at 6 months, (b) progression‐free survival (PFS) durations, and (c) safety. Results: The median number of prior systemic treatments for metastatic disease was 1 (range, 0‐4). The disease control rate at 9 months was 49%. The tumor response rate at 6 months was 54% (complete response, 21%; partial, 32%). The median PFS was 7.4 months (95% CI, 4.8‐not reached [NR]). The median bone‐PFS was 16 months (95% CI, 7.3‐NR). There were no grade 3/4 adverse events. Conclusions: Ra‐223 with hormonal therapy showed possible efficacy in HR+ bone‐dominant breast cancer metastasis, and adverse events were tolerable. We plan to further investigate the clinical application of Ra‐223 in these patients. (NCT02366130). [ABSTRACT FROM AUTHOR]

Background: The concurrent use of opioids with benzodiazepines (BZD) or nonbenzodiazepine sedatives (S) recently was found to be associated with an increased risk of overdose death compared with the use of opioids alone. In the current study, the authors examined the frequency and trend of concurrent opioid/BZD-S use and its associated risk factors among patients with cancer.Methods: Data regarding the frequency and trend of concurrent opioid/BZD-S use were extracted for 1500 randomly selected patients referred to the outpatient palliative care clinic at The University of Texas MD Anderson Cancer Center between the calendar years of 2011 and 2016. To explore associated risk factors, the authors compared the demographic and clinical predictors of 418 patients each in the concurrent opioid/BZD-S group and opioids-only group.Results: In 2011, at the time of referral to the palliative care clinic, 96 of 221 patients with cancer (43%) were prescribed concurrent opioids/BZD-S. This rate progressively declined to 67 of 217 patients (31%) by 2016 (P = .0008). Patients in the concurrent opioid/BZD-S group had a higher percentage of females (233 individuals; 55% [P = .007]) and whites (323 individuals; 77% [P = .002]), and patients reported higher scores regarding depression (P = .0001), anxiety (P ≤ .0001), drowsiness (P = .048), and worst feeling of well-being (P = .001). The morphine equivalent daily dose was significantly higher in concurrent opioid/BZD-S group (median of 67.5 mg/day [interquartile range (IQR), 30-135 mg/day] vs 60 mg/day [IQR, 30-105 mg/day]; P = .034). Multivariate analysis demonstrated that anxiety (P ≤ .0001), white race (P = .0092), and poor Eastern Cooperative Oncology Group performance status (P = .0017) were significantly associated with concurrent use.Conclusions: The concurrent use of opioids with BZD-S has declined but continues to be frequent among patients with cancer. Anxiety, white race, and poor Eastern Cooperative Oncology Group performance status were associated with its use. More research is needed to explore which medications can replace these agents. [ABSTRACT FROM AUTHOR]

PURPOSE: The primary aim of this study was to determine the attitudes and beliefs of hematology and medical oncology (HMO) fellows regarding palliative care (PC) after they completed a 4-week mandatory PC rotation. METHODS: The PC rotation included a 4-week standardized curriculum covering all PC domains. HMO fellows were provided educational materials and attended all didactic sessions. All had clinical rotation in an acute PC unit and an outpatient clinic. All HMO fellows from 2004 to 2017 were asked to complete a 32-item survey on oncology trainee perception of PC. RESULTS: Of 105 HMO fellows, 77 (73%) completed the survey. HMO fellows reported that PC rotation improved assessment and management of symptoms (98%); opioid prescription (89%), opioid rotation (78%), and identification of opioid adverse effects (87%); communication with patients and families (91%), including advance care planning discussion (88%) and do-not-resuscitate discussion (88%); and they reported comfort with discussing ethical issues (74%). Participants reported improvement in knowledge of symptom assessment and management (n = 76; 98%) as compared with efficacy in ethics (n = 57 [74%]; P =.0001) and for coping with stress of terminal illness (n = 45 [58%]; P =.0001). The PC rotation educational experience was considered either far better or better (53%) or the same (45%) as other oncology rotations. Most respondents (98%) would recommend PC rotations to other HMO fellows, and 95% felt rotation should be mandatory. CONCLUSION: HMO fellows reported PC rotation improved their attitudes and knowledge in all PC domains. PC rotation was considered better than other oncology rotations and should be mandatory. [ABSTRACT FROM AUTHOR]

Context: Psychology services utilization in cancer patients remains low due to barriers such as patient/caregiver acceptance of counseling.Objective: We aimed to determine if the manner of introducing psychology services impacted patients' acceptance of services and to identify factors associated with acceptance and barriers to psychology utilization.Methods: In this double-blind randomized cross-over trial, cancer patients with no prior psychology services observed two video vignettes: (a) physician introducing counselor and psychology services to the patient (PI) and (b) counselor introducing psychology services alone (CI). A counterbalanced design was used to control for order effects. After viewing both videos, patients completed a survey regarding preference, attitudes, and barriers for psychology services. Patients and investigators were blinded to the purpose of the study and content and order of videos, respectively. We hypothesized that patients would prefer physician introduction of counselor.Results: One hundred patients participated: 40 (40%) expressed no difference, 34 (34%) preferred PI, and 26 (26%) preferred CI (P > .2). Younger patients (less than 40 years) either preferred PI (86%) or had no preference (14%, P = .01). Most reported awareness of available psychology services (N = 63), and half (N = 50) were offered psychology services by their physician. Only 40 (40%) and 43 (43%) patients felt psychology services would be helpful for them and their family/caregivers, respectively. Patients who perceived psychology as helpful for self or family had higher anxiety (P = .01 and P = .006, respectively).Conclusions: No significant difference was found in patient preference of introducing psychology services except in patients less than 40 years old who preferred PI. [ABSTRACT FROM AUTHOR]

Context: Current guidelines recommend early referral to palliative care for patients with advanced cancer; however, no studies have examined the optimal timing of referral from the patients' perspective.Objectives: To examine patients' perceptions of timeliness of referral and its association with survival among patients with advanced cancer referred to an outpatient supportive care (SC) clinic.Methods: This cross-sectional prospective study in an SC clinic at a comprehensive cancer center included patients aged 18 years or older with locally advanced, recurrent, or metastatic cancer. Patients were asked to complete an anonymous survey regarding the timeliness and perceived usefulness of SC referral within four weeks of their first SC consultation.Results: Of 253 eligible patients, 209 (83%) enrolled in the study and 200 completed the survey. Median survival was 10.3 months. Most patients (72%) perceived that referral occurred "just in time," whereas 21% felt it was "late," and 7% felt "early." A majority (83%) found the referral useful, and 88% would recommend it to other patients with cancer. The perception of being referred early was associated with lower reported levels of pain (P = 0.043), fatigue (P = 0.004), drowsiness (P = 0.005), appetite loss (P = 0.041), poor well-being (P = 0.041), and lower physical (P = 0.001) and overall symptom distress (P = 0.001). No other associations were found between perceived timeliness and usefulness and patients' baseline characteristics.Conclusion: Most patients with a median survival of 10 months perceived that SC referral was timely and useful. Patient care needs rather than the timing of advanced cancer diagnosis drove this perception of referral timing. Lower symptom burden was associated with the perception of being referred to early. [ABSTRACT FROM AUTHOR]

Context: Psychologists can provide unique contributions to interdisciplinary palliative care. Despite research indicating high distress in palliative care cancer patients, little has been reported regarding the feasibility and practice of psychology in this setting.Objectives: To review the integration of clinical psychology practice in a palliative care department at a major comprehensive cancer center.Methods: Retrospective chart review of 1940 unique cancer patients (6451 total patient contacts) referred for psychology services provided by clinical psychologists in palliative care from September 1, 2013 to February 29, 2016.Results: Psychologists provided services to 1644 inpatients (24% of palliative care inpatients) and 296 outpatients (19% of palliative care outpatients). Most of them (85%) received services in the inpatient setting. Most patients were females (57%) and white (68%) with a variety of cancer diagnoses. Adjustment disorders were the most prevalent in both settings with significant differences in other Diagnostic and Statistical Manual of Mental Disorders (5th Edition) diagnoses by service location (P < 0.0001). Psychological assessment (86%) and supportive expressive counseling (79%) were the most frequent services provided in the initial consult. Duration of initial visit was significantly longer in outpatient (median 60 minutes) compared with inpatient setting (median 40 minutes) (P < 0.0001). No significant differences were noted between settings regarding the median number of counseling sessions per patient; however, most (70%) only received one or two sessions. Over time, total patient encounters increased in the inpatient setting (P < 0.0001), whereas session lengths in both settings significantly decreased (P < 0.0001).Conclusion: Palliative care psychology services successfully integrated into an interdisciplinary palliative care department and rapidly grew in both inpatient and outpatient settings. [ABSTRACT FROM AUTHOR]

Context There is limited literature regarding outpatient palliative care and factors associated with unscheduled clinic visits. Objectives To compare characteristics of patients with unscheduled vs. scheduled outpatient palliative care clinic visits. Methods Medical records of 183 unscheduled cancer new outpatients and 104 unscheduled follow-up (FU) patients were compared with random samples of 361 and 314 scheduled new patients and FU patients, respectively. We gathered data on demographics, symptoms, daily opioid usage, and performance status. Results Compared with scheduled new patients, unscheduled new patients had worse Edmonton Symptom Assessment Scale subscores for pain ( P < 0.001), fatigue ( P = 0.002), nausea ( P = 0.016), depression ( P = 0.003), anxiety ( P = 0.038), drowsiness ( P = 0.002), sleep ( P < 0.001), and overall feeling of well-being ( P = 0.001); had a higher morphine equivalent daily dose of opioids (median of 45 mg for unscheduled vs. 30 mg for scheduled; P < 0.001); and were more likely to be from outside the greater Houston area ( P < 0.001). Most unscheduled and scheduled new and FU visits were for uncontrolled physical symptoms. Unscheduled FU patients, compared with scheduled FU patients, had worse Edmonton Symptom Assessment Scale subscores for pain ( P < 0.001), fatigue ( P < 0.001), depression ( P = 0.002), anxiety ( P = 0.004), drowsiness ( P = 0.010), appetite ( P = 0.023), sleep ( P = 0.022), overall feeling of well-being ( P < 0.001), and higher morphine equivalent daily dose of opioid (median of 58 mg for unscheduled FU visits vs. 40 mg for scheduled FU visits; P = 0.054). Conclusion Unscheduled new FU patients have higher levels of physical and psychosocial distress and higher opioid intake. Outpatient palliative care centers should consider providing opportunities for walk-in visits for timely management and close monitoring of such patients. [ABSTRACT FROM AUTHOR]

Background: Understanding patients' decision control preferences is important in providing quality cancer care. Patients' decisional control preference can be either active (patients prefer to make decisions themselves), shared (collaborative between patient, their physician, and/or family), or passive (patients prefer that the decisions are made by either the physician and/or their family). Aim: To determine the frequency and predictors of passive decision control preferences among advanced cancer patients. We also determined the concordance between actual decision-making and decision control preferences and its association with patient satisfaction. Design: In this cross-sectional survey of advanced cancer patients referred to palliative care across 11 countries, we evaluated sociodemographic variables, Control Preference Scale, and satisfaction with the decisions and care. Results: A total of 1490 participants were evaluable. Shared, active, and passive decision control preferences were 33%, 44%, and 23%, respectively. Passive decision control preferences (odds ratio, p value) was more frequent in India (4.34, <0.001), Jordan (3.41, <0.001), and France (3.27, <0.001). Concordance between the actual decision-making and decision control preferences was highest in the United States (k = 0.74) and lowest in Brazil (0.34). Passive decision control preference was significantly associated with (odds ratio per point, p value) better performance status (0.99/point, 0.017), higher education (0.64, 0.001), and country of origin (Brazil (0.26, <0.0001), Singapore (0.25, 0.0003), South Africa (0.32, 0.0002), and Jordan (2.33, 0.0037)). Conclusion: Passive decision control preferences were less common (23%) than shared and active decision control preference even among developing countries. Significant predictors of passive decision control preferences were performance status, education, and country of origin. [ABSTRACT FROM AUTHOR]

Context: Low-income patients face barriers to palliative care access, which might negatively influence symptom management and advanced care planning.Objective: Our aim was to compare time of referral and characteristics (level of symptom distress) among uninsured (indigent), low-insured (Medicaid), and insured patients presenting to our supportive care center (SCC).Methods: We conducted a retrospective review of randomly selected 100 indigent, 100 Medicaid, and 300 insured outpatients referred during the same five-year period. We reviewed demographic and clinical characteristics including date of diagnosis of advanced cancer and of first visit to SCC, symptom assessment (Edmonton Symptom Assessment System), type and dose of opioid medication, number of total outpatient visits, and date of last contact with palliative care team.Results: Among 482 evaluable patients, indigent, Medicaid, and insured patients, respectively, had mean (SD) ages of 48 (11), 50 (12), and 63 (13) years (P < 0.001); Edmonton Symptom Assessment System pain scores at first visit of 6.7 (2.5), 5.6 (3.2), and 4.9 (3.2) (P < 0.001); nonwhite race in 60%, 49%, and 25% of cases (P < 0.001); unmarried status in 68%, 64%, and 33% of cases (P < 0.001), while 63%, 87%, and 54% of patients (P < 0.001) were on opioids with median number of encounters per month of 0.6, 0.8, and 0.5 (P = 0.001). Median survival (95% CI) from first visit to last contact was 4.6 (2.8-6.2), 5.4 (3.5-7), and 5.6 (4.7-7.3) months (P = 0.036).Conclusion: Patients with limited or no insurance had significantly higher pain and were more frequently on opioids, younger, nonwhite, and not married. They required higher number of SCC follow-up visits. Insurance status did not affect timing of SCC referral or follow-ups at our cancer center. [ABSTRACT FROM AUTHOR]

Context: Cranial electrotherapy stimulation (CES) is a safe modulation of brain activity for treating depression, anxiety, insomnia, and pain. However, there are no published studies in patients with advanced cancer (ACPs).Objectives: The aim of the study was to determine the feasibility and preliminary efficacy of a four-week CES intervention on depression, anxiety, sleep disturbance, and pain scores. Concurrent salivary biomarker studies were conducted.Methods: In this one group open label pre- and post-intervention study with a four-week CES intervention, ACPs with one or more of four moderate intensity (≥3/10) Edmonton Symptom Assessment Scale (ESAS) symptoms (depression, anxiety, sleep disturbance, and pain) were eligible. Adherence (0%-100%), satisfaction rates (0-10), and safety were assessed. ESAS, Hospital Anxiety and Depression Scale (HADS), Pittsburgh Sleep Quality Index, Brief Pain Inventory, and salivary levels (cortisol, alpha amylase, C-reactive protein, and interleukin-1β, and interleukin-6) were assessed from baseline to Week 4.Results: Thirty-three of 36 patients (92%) completed the CES. Median (interquartile range) adherence CES use and satisfaction scores were 93% (89-100) and 10% (9-10), respectively, and the adherence criteria was met in the study. CES use was safe (no Grade 3 or higher adverse events). HADS anxiety (P < 0.001), HADS depression (P = 0.024), ESAS anxiety (P = 0.001), ESAS depression (P = 0.025), Brief Pain Inventory pain (P = 0.013), Pittsburgh Sleep Quality Index daytime dysfunction (P = 0.002), and medication use (P = 0.006) scores improved after four-week CES treatment.Conclusion: In this preliminary study, we found that the use of CES was safe and feasible in ACP. The use of CES was associated with significant improvement of depression, anxiety, pain, and sleep scores. These findings support further studies of CES in ACP for symptom control. [ABSTRACT FROM AUTHOR]

Introduction: In the United States, opioid regulations have become increasingly stringent in recent years. Increased regulatory scrutiny, in part, is related to heightened awareness through literature and a recent media blitz on the opioid prescription epidemic. These regulations have the potential to impact prescription trends by health care providers. Our objective was to evaluate changes in the type and dose of opioid prescriptions among patients who are referred by oncologists to an outpatient palliative care clinic. Materials and Methods: We reviewed the electronic health records of 750 patients who were seen as new consultations at MD Anderson Cancer Center's outpatient palliative care clinic between January 1 and April 30 each year from 2010 through 2015. Data collected included demographics, cancer type and stage, symptom assessment, performance status, opioid type, and opioid dose defined as the morphine equivalent daily dose (MEDD). Results: Median age was 59 years (interquartile range [IQR], 51 to 67), 383 (51%) were female, 529 (70%) were white, and 654 (87%)of patients had advanced cancer. In 2010, median MEDD before referral was 78 mg/d (IQR, 30 to 150); however, by 2015, the MEDD had progressively decreased to 40 mg/d (IQR, 19 to 80; P = .001). Hydrocodone was the most common opioid prescribed between 2010 and 2015; however, after its reclassification as a schedule II opioid in October 2014, the use of tramadol, a schedule IV opioid, increased (P < .001). Conclusion: During the past several years, the MEDD prescribed by referring oncologists has decreased. After hydrocodone reclassification, the use of tramadol with less stringent prescription limits has increased. [ABSTRACT FROM AUTHOR]

Background: There is limited research in advanced cancer patients (ACP) regarding association between objectively measured daytime activity and sleep (as measured by actigraphy), patient characteristics, and cancer symptoms (fatigue, sleep, anxiety, depression, cachexia, and symptom distress scores [SDSs]). Objectives: Our aim of the study was to determine the association between mean daytime activity (MDTA) and the following items: fatigue (FACIT-F), SDSs (Edmonton Symptom Assessment Scale [ESAS]), sleep quality (Pittsburg Sleep Quality Index [PSQI]), objective sleep variables (OSV) (sleep onset, sleep efficacy, wake after sleep onset, total sleep time), anxiety and depression (Hospital Anxiety and Depression Scale [HADS]), body composition scores, and overall survival (OS). We also examined the association between sleep [PSQI and OSV scores] and FACIT-F, HADS, and ESAS. Methods: Secondary analysis of a recent clinical trial of cancer-related fatigue in advanced cancer (NCT00424099). Association between MDTA and OSV (measured by actigraphy) during the first week of the study and patient characteristics, symptoms (FACIT-F, ESAS, HADS, and PSQI), and OS were analyzed. Results: Seventy-nine eligible patients were evaluable. The median age was 57 years. Median MDTA was 248.43 counts/minute. Multivariate analysis shows that low MDTA was significantly associated with age, gender, Functional Assessment of Cancer Therapy (FACT)-Functional Well-Being (FWB), ESAS dyspnea, HADS-anxiety, and total sleep time. MDTA was not associated with FACIT-F ( p = 0.997) and OS ( p = 0.18). Sleep quality (PSQI) was significantly associated with FACIT-F, HADS, ESAS anxiety, and depression, but none of these variables was associated with OSV. Conclusion: In ACP, lower MDTA was significantly associated with age, gender, FACT-FWB, ESAS dyspnea, HADS-anxiety, and total sleep time. Both sleep quality and cancer-related fatigue scores were strongly associated with depression and anxiety. More research is needed. [ABSTRACT FROM AUTHOR]

Purpose Checklists are used in many different settings for the purpose of standardization and reduction of preventable errors in practice. Our group sought to determine whether a palliative care checklist (PCC) would improve the clinical documentation of key patient information. Methods An initial review of 110 randomly selected medical records dictated by 10 physicians was performed. The authors identified portions of the dictated medical records that were included regularly, as well as those that were frequently missed. A PCC was drafted after final approval was obtained from the 13 faculty members. Dictations from 13 clinical faculties in the supportive care center were reviewed. A χ౪ test or Fisher's exact test was applied to assess the difference in overall checked rates before and after checklist use. A paired t test was used to examine the difference in the average complete rate and checked rates before and after checklist use. Results There were improvements in the documentation before and after the checklist for scores on the Cut-down, Annoyed, Guilty, Eye-opener questionnaire for alcoholism (79% v 94%; P ≤ .0001), psychosocial history (69% v 95%; P ≤ .0001), Eastern Cooperative Oncology Group performance status (38% v 81%; P ≤ .0001), advance care planning (28% v 41%; P = .0008), and overall (78% v 95%; P ≤ .0001). There was no significant improvement in the documentation for opioid-induced neurotoxicity (37% v 37%; P = .9492) or the Edmonton Symptom Assessment Scale (98% v 99%; P = .4511). Conclusion Our study showed that the use of a PCC improved the quality of the documentation of a patient visit in an outpatient clinical setting. [ABSTRACT FROM AUTHOR]

Purpose To test, in a single-arm, prospective, phase 2 trial, whether adding the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib to concurrent chemoradiotherapy for previously untreated, locally advanced, inoperable non-small cell lung cancer would improve survival and disease control without increasing toxicity. Methods and Materials Forty-eight patients with previously untreated non-small cell lung cancer received intensity modulated radiation therapy (63 Gy/35 fractions) on Monday through Friday, with chemotherapy (paclitaxel 45 mg/m², carboplatin area under the curve [AUC] = 2) on Mondays, for 7 weeks. All patients also received the EGFR tyrosine kinase inhibitor erlotinib (150 mg orally 1/d) on Tuesday-Sunday for 7 weeks, followed by consolidation paclitaxel–carboplatin. The primary endpoint was time to progression; secondary endpoints were overall survival (OS), toxicity, response, and disease control and whether any endpoint differed by EGFR mutation status. Results Of 46 patients evaluable for response, 40 were former or never-smokers, and 41 were evaluable for EGFR mutations (37 wild-type [WT] and 4 mutated [all adenocarcinoma]). Median time to progression was 14.0 months and did not differ by EGFR status. Toxicity was acceptable (no grade 5, 1 grade 4, 11 grade 3). Twelve patients (26%) had complete responses (10 WT, 2 mutated), 27 (59%) partial (21 WT, 2 mutated, 4 unknown), and 7 (15%) none (6 WT, 2 mutated, 1 unknown) ( P =.610). At 37.0 months' follow-up (range, 3.6-76.5 months) for all patients, median OS time was 36.5 months, and 1-, 2-, and 5-year OS rates were 82.6%, 67.4%, and 35.9%, respectively; none differed by mutation status. Twelve patients had no progression, and 34 had local and/or distant failure. Eleven of 27 distant failures were in the brain (7 WT, 3 mutated, 1 unknown). Conclusions Toxicity and OS were promising, but time to progression did not meet expectations. The prevalence of distant failures underscores the need for effective systemic therapy. [ABSTRACT FROM AUTHOR]

Lung cancer is often refractory to radiotherapy, but molecular mechanisms of tumor resistance remain poorly defined. Here we show that the receptor tyrosine kinase EphA5 is specifically overexpressed in lung cancer and is involved in regulating cellular responses to genotoxic insult. In the absence of EphA5, lung cancer cells displayed a defective G1/S cell cycle checkpoint, were unable to resolve DNA damage, and became radiosensitive. Upon irradiation, EphA5 was transported into the nucleus where it interacted with activated ATM (ataxia-telangiectasia mutated) at sites of DNA repair. Finally, we demonstrate that a new monoclonal antibody against human EphA5 sensitized lung cancer cells and human lung cancer xenografts to radiotherapy and significantly prolonged survival, thus suggesting the likelihood of translational applications. [ABSTRACT FROM AUTHOR]

Study Objective: To assess the effect of perioperative beta blockers on recurrence and overall survival after non-small cell lung cancer surgery. Design: Retrospective study. Setting: Academic medical center. Measurements: The medical records of patients with stage 1, 2, and 3a non-small cell lung cancer were divided into three different groups: those patients who never received beta blockers perioperatively, those receiving nonselective beta blockers within 60 days of surgery, and those taking selective beta blockers within 60 days of surgery. Recurrence-free survival and overall survival were the main clinical endpoints. Univariate log-rank tests and multivariate Cox proportional hazards models were used to assess the effects of selective beta blockers, nonselective beta blockers, or no beta blockers on recurrence-free survival and overall survival. Main Results: The analysis included records of 435 patients. Univariate analyses showed that the use of both selective and nonselective beta blockers was associated with decreased recurrence-free survival (P = 0.014) and overall survival (P = 0.009). However, these findings were not sustained after adjusting for possible confounding variables in the multivariate analysis. The hazard ratios for recurrence-free survival (selective beta blockers vs no beta blocker use were: 1.304; 95% confidence intervals [CI] 0.973 - 1.747; P = 0.075; for nonselective beta blockers vs no beta blockers: 0.989; 95% CI 0.639 - 1.532; P = 0.962. The hazard ratios for overall survival were: selective beta blocker use vs no beta blockers: 1.335; 95% CI 0.966 - 1.846; P = 0.080; nonselective beta blocker use vs no beta blocker use: 1.108; 95% CI 0.678 - 1.812; P = 0.682. Conclusion: Administration of beta blockers during the perioperative period did not improve recurrence-free or overall survival in patients undergoing resection of non-small cell lung cancer. [ABSTRACT FROM AUTHOR]

Study Objective: To determine whether postoperative epidural analgesia is associated with better recurrence-free survival and overall survival after lung cancer surgery. Design: Retrospective study. Setting: Academic hospital. Measurements: Data of patients with stage 1, stage 2, and stage 3 nonsmall cell lung cancer, who underwent tumor resection surgery, were studied. Patient data were grouped into three different postoperative pain management interventions: intravenous patient-controlled analgesia, patient-controlled epidural analgesia, and their combination. Univariate and multicovariate Cox proportional hazards models were applied to assess the effects of covariates of interest on overall survival and recurrence-free survival. Main Results: The type of postoperative analgesia used for patients who underwent surgery for nonsmall cell lung cancer did not affect recurrence-free survival or overall survival. However, certain variables, including age = 65 years, male gender, body mass index = 25 kg/m², ASA physical status 4, and the need for preoperative blood transfusions, pneumonectomy, and postoperative radiation, were associated with decreased recurrence-free survival and overall survival. Conclusions: The type of postoperative analgesia used after surgery for nonsmall cell lung cancer is not associated with better 2-year or 5-year recurrence-free survival or overall survival rates. [ABSTRACT FROM AUTHOR]

BACKGROUND: Germline TP53 mutations predispose to early onset breast cancer in women and are associated with Li-Fraumeni syndrome. Published data on the pathological characteristics of breast cancer among women with TP53 mutations is limited. METHODS: We retrospectively reviewed the clinical records of women who underwent genetic testing for suspected germline TP53 mutations and who were diagnosed with breast cancer between 2000 and 2011. The pathological characteristics of the breast tumors from patients testing positive for a mutation (cases) were compared with those testing negative (controls). RESULTS: Patients who tested positive for germline TP53 mutations (n = 30) were compared with controls (n = 79). Human epidermal growth factor receptor 2 (HER2) amplification and/or overexpression was found in 67% of the tumors from the cases, compared with 25% for the controls ( P = .0001). Among patients with a mutation, 70% had estrogen receptor- and/or progesterone receptor-positive tumors, compared with 68% in the control group ( P = .87). After adjusting for age at breast cancer diagnosis, having a HER2-positive tumor increased the odds of testing positive for a germline TP53 mutation (odds ratio, 6.9; 95% confidence interval, 2.6-18.2). For each yearly increment in age at breast cancer diagnosis, there was decreased likelihood of having a TP53 mutation of 5% (odds ratio, 0.95; 95% confidence interval0.91-0.99). CONCLUSIONS: This study suggests an association between germline TP53 mutations and early onset HER2-positive breast cancer. If confirmed in a larger cohort, these results could guide genetic testing strategies, lead to chemoprevention trials incorporating HER2-targeted therapies, and elucidate some of the molecular pathways involved in breast cancer. Cancer 2012;. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

Abstract: Background: Determining the differential diagnosis between typical (TCs) and atypical carcinoid tumors (ACs) is imperative, as the distinction between TCs and ACs is currently based on histologic criteria that are not always correlated with the unfavorable clinical outcomes. Patients and methods: We conducted a retrospective study of patients who were diagnosed with carcinoid tumors between 1990 and 2005 at M. D. Anderson Cancer Center. We reviewed the slides for the following pathologic features: infiltrative growth; pleural, blood, or lymphatic vessel invasion; tumor stroma; presence of active fibroblastic proliferation; chromatin pattern; presence of nucleolus; and nuclear pleomorphism. We also evaluated the necrotic patterns. Finally, we evaluated three methods for calculating the number of mitoses: randomly selected, the most mitotically active in 10 high-power fields (HPFs), or overall mean mitotic count. Results: Our cohort consisted of 80 patients (68 with TCs and 12 with ACs). Older age (P =0.002), pathologic stage III or IV disease (P =0.04), active fibroblastic proliferation (P =0.041), and comedo-like necrosis (P =0.001) were significantly associated with tumor recurrence or patient''s death. Among the three mitotic counting methods, the overall mean number of mitoses was significantly correlated with recurrence-free survival (P <0.0001). Our criteria for distinguishing AC from TC included the presence of comedo-like necrosis and/or an overall mean number of mitoses ≥0.2/HPF. Conclusions: Using an overall mean number in counting mitoses and detecting comedo-like necrosis is important for classifying lung carcinoid tumors. [Copyright &y& Elsevier]

Background: Bevacizumab has recently been demonstrated to prolong overall survival when added to carboplatin and paclitaxel for chemotherapy-naïve patients with nonsquamous nonsmall-cell lung cancer (NSCLC). However, the effects of combining bevacizumab with other standard, front-line, platinum-based doublets have not been extensively explored. We designed this single treatment arm, phase 2 trial to determine whether the combination of carboplatin, docetaxel, and bevacizumab is tolerable and prolongs progression-free survival of chemotherapy-naïve patients with advanced, nonsquamous NSCLC.Methods: Forty patients were treated with up to 6 cycles of carboplatin (AUC 6), docetaxel (75 mg/m(2)), and bevacizumab (15 mg/kg) on Day 1 every 21 days. Patients with an objective response or stable disease received maintenance bevacizumab (15 mg/kg) every 21 days until disease progression. The primary endpoint was median progression-free survival. Secondary endpoints included safety, response rates, and overall survival.Results: The median number of chemotherapy and maintenance bevacizumab cycles/patient was 6 and 2, respectively. Grades 3-5 adverse events included febrile granulocytopenia (10%), infections (13%), bleeding (13%), thrombotic events (13%), hypertension (5%), bowel perforation (5%), and proteinuria (3%). Median progression-free survival was 7.9 months and median overall survival was 16.5 months. Partial responses were observed in 21 patients (53%), and stable disease >or=6 weeks occurred in another 17 patients (43%), for a disease control rate of 95%.Conclusions: Carboplatin, docetaxel, and bevacizumab were feasible and effective for front-line treatment of advanced, nonsquamous NSCLC. These data provide further evidence that bevacizumab may be used in combination with multiple standard, platinum-based doublets in this setting. [ABSTRACT FROM AUTHOR]

The article discusses a study which determines the effectiveness of the combined carboplatin, bevacizumab and docetaxel in the treatment of patients with nonsquamous nonsmall-cell lung cancer (NSCLC). The study uses 40 patients who were treated with 6 cycles of carboplatin, bevacizumab and docetaxel every 21 days. The results demonstrate that the combination of carboplatin, bevacizumab and docetaxel is an effective and a feasible treatment for patients with advanced, squamous NSCLC.

Background: Non-small cell lung cancer (NSCLC) is the foremost cause of cancer-related death in Western countries, which is due partly to the propensity of NSCLC cells to metastasize. The biologic basis for NSCLC metastasis is not well understood. Methodology/Principal Findings: Here we addressed this deficiency by transcriptionally profiling tumors from a genetic mouse model of human lung adenocarcinoma that develops metastatic disease owing to the expression of K-rasG12D and p53R172H. We identified 2,209 genes that were differentially expressed in distant metastases relative to matched lung tumors. Mining of publicly available data bases revealed this expression signature in a subset of NSCLC patients who had a poorer prognosis than those without the signature. Conclusions/Significance: These findings provide evidence that K-rasG12D; p53R172H mice recapitulate features of human NSCLC metastasis and will provide a useful platform on which to study the biologic basis for lung adenocarcinoma metastasis and its prevention by novel agents. [ABSTRACT FROM AUTHOR]

The article focuses on a study which examined the long-term safety of avoiding completion axillary dissection (CLND) in selected patients with positive sentinel lymph nodes (SLN). The respondents of the study are patients with invasive breast cancer who underwent SLN biopsy. The locoregional failure rate was low without CLND in selected patients who had positive SLN.

Oral tazarotene, an acetylenic retinoid, is in clinical development for the treatment of psoriasis. The disposition and biotransformation of tazarotene were investigated in six healthy male volunteers, following a single oral administration of a 6 mg (100 µCi) dose of [14C]tazarotene, in a gelatin capsule. Blood levels of radioactivity peaked 2 h postdose and then rapidly declined. Total recovery of radioactivity was 89.2 ± 8.0% of the administered dose, with 26.1 ± 4.2% in urine and 63.0 ± 7.0% in feces, within 7 days of dosing. Only tazarotenic acid, the principle active metabolite formed via esterase hydrolysis of tazarotene, was detected in blood. One major urinary oxidative metabolite, tazarotenic acid sulfoxide, accounted for 19.2 ± 3.0% of the dose. The majority of radioactivity recovered in the feces was attributed to tazarotenic acid representing 46.9 ± 9.9% of the dose and only 5.82 ± 3.84% of dose was excreted as unchanged tazarotene. Thus following oral administration, tazarotene was rapidly absorbed and underwent extensive hydrolysis to tazarotenic acid, the major circulating species in the blood that was then excreted unchanged in feces. A smaller fraction of tazarotenic acid was further metabolized to an inactive sulfoxide that was excreted in the urine. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:2246–2255, 2005 [ABSTRACT FROM AUTHOR]

Objective: To evaluate the safety and pharmacokinetics of tazarotene cream 0.1% under standard (face only) or exaggerated (15% body surface area, including the face) application conditions after a single dose and after repeat topical applications once daily to patients with acne vulgaris or photodamaged skin. Methods: Two separate, randomised, single-centre, nonblinded, parallel-group pharmacokinetic studies were conducted. In one study, tazarotene cream 0.1% was applied either to the face of eight female patients with moderate acne or to 15% body surface area of ten female patients with severe acne. In the other study, tazarotene cream 0.1% was applied either to the face (six females, two males) or to 15% body surface area (8 females. 8 males) of patients with photodamaged skin. In both studies, tazarotene cream 0.1% was applied once daily (except on days 1 and 2) for 30 days. Blood was drawn for measurement of plasma concentrations of tazarotenic acid at defined time intervals after applicat ion of the cream. Plasma tazarotenic acid concentrations were determined by a validated gas chromatography-tandem mass spectrometry method with a lower limit of quantification of 0.005 μg/L. Results: At exaggerated application rates in patients with acne vulgaris, the maximum average peak concentration (C[submax]) and 24-hour area under the concentration-time curve (AUC) values of tazarotenic acid were (mean ± SD) 1.20 ± 0.41 μg/L (n = 10) and 17.0 ±6.1 μg · h/L (n = 10), respectively, and occurred on day 15. The single highest C[submax] was 1.91 μg/L. At standard application rates in patients with acne vulgaris, the maximum average C[submax] and AUC values of tazarotenic acid were 0.10 ± 0.06 μg/L (n = 8) and 1.54 ± 1.01 μg · h/L (n = 8), respectively, and occurred on day 15. At exaggerated application rates in patients with photodamaged skin, the maximum average C[submax] and AUC values of tazarotenic acid were (mean ± SD) 1.75 ± 0.53 μg/L (n = 16) and 23.8 ± 7.0 μg • h/L (n = 16), respectively, and occurred on day 22. The single highest C[submax] was 3.43 μg/L on day 29. At standard application rates in patients with photodamaged skin, the maximum average C[submax] and AUC values of tazarotenic acid were 0.236 ± 0.255 μg/L (n = 8) and 2.44 ± 1.38 μg · h/L (n = 8), respectively, and occurred on day 15. Gender had no influence on the systemic exposure of tazarotenic acid. The most common treatment-related adverse events were signs and symptoms of local irritation, of mild or moderate severity. Conclusions: The pharmacokinetics of tazarotene cream 0.1% in patients with acne vulgaris or photodamaged skin are similar. The maximum average plasma concentrations of tazarotenic acid after topical application of tazarotene cream 0.1% to the face were less than 0.25 μg/L. The maximum average plasma concentrations of tazarotenic acid following application to an exaggerated body surface area (15%) were less than 1.8 μg/L. [ABSTRACT FROM AUTHOR]

Background: Loss of retinoic acid receptor beta (RAR-beta) expression in the bronchial epithelium is considered a biomarker of preneoplasia. Retinoids can restore expression of this receptor and, presumably, halt the progression of carcinogenesis. This study was designed to investigate whether either of two retinoid-based regimens, 9-cis-retinoic acid (RA) or 13-cis-RA plus alpha-tocopherol (AT), could reverse RAR-beta expression loss in former smokers after 3 months of treatment.Methods: Individuals (n = 226) who had smoked at least 20 pack-years and had ceased smoking for at least 12 months were randomly assigned to receive 3 months of daily oral 9-cis-RA (100 mg), 13-cis-RA (1 mg/kg) + AT (1200 IU), or placebo. Bronchoscopy and biopsy at six predetermined sites of the bronchial tree were performed before treatment and at 3 and 6 months thereafter. Specimens were evaluated for squamous metaplasia, dysplasia, and RAR-beta expression. McNemar's test was used to test changes in RAR-beta expression and squamous metaplasia within each treatment group, and a generalized estimating equations model was applied to model the treatment effect, adjusting for covariates. All statistical tests were two-sided.Results: A total of 177 assessable subjects completed at least 3 months of therapy and underwent at least the baseline and 3-month bronchoscopic evaluations with biopsies. RAR-beta was detected in 69.7% of all baseline biopsy samples, and metaplasia was evident in 6.9% of all baseline samples from 240 subjects. Restoration of RAR-beta expression (P =.03) and reduction of metaplasia (P =.01) were found in the 9-cis-RA group. After adjustment for years of smoking, packs/day smoked, and metaplasia, treatment with 9-cis-RA, but not with 13-cis-RA + AT, led to a statistically significant increase in RAR-beta expression compared with placebo (P =.03).Conclusion: 9-cis-RA treatment can restore RAR-beta expression in the bronchial epithelium of former smokers, raising the possibility that this retinoid has potential chemopreventive properties in former smokers. [ABSTRACT FROM AUTHOR]

Investigates whether treatment of former smokers with 9-cis-retinoic acid reverses loss of retinoic acid receptor-beta (RAR-beta) expression in the bronchial epithelium. Performance of bronchoscopy and biopsy of the bronchial tree; Evaluation of specimens for squamous metaplasia, dysplasia and RAR-beta expression; Potential of the retinoid for chemoprevention in former smokers.

To quantify blood cyclosporin A (CsA) concentrations during treatment with CsA topical ophthalmic emulsions, blood was collected from 128 patients enrolled in a Phase 3, multicenter, double-masked, randomized, parallel-group study of CsA eyedrops for treatment of moderate to severe dry eye disease. Patients received 0.05% CsA, 0.1% CsA, or vehicle b.i.d. for 6 months; vehicle-treated patients then crossed over to 0.1% CsA b.i.d. for 6 months. CsA concentrations were measured using a validated LC/MS-MS assay (quantitation limit = 0.1 ng/mL). No patient receiving 0.05% CsA had any quantifiable CsA in the blood (n = 96 samples). All but 7 of 128 (5.5%) trough blood samples from the 0.1% CsA group were below the quantitation limit for CsA; none exceeded 0.3 ng/mL. CsA was also below the limit of quantitation in 205 of 208 (98.6%) of serial postdose blood samples collected from 26 patients during 1 dosing interval between months 9 and 12. The highest C[sub max] measured, 0.105 ng/mL at 3 hours postdose, occurred in a 0.1% CsA-treated patient. These results indicate that long-term use of topical CsA ophthalmic emulsions at doses that are clinically efficacious for treating dry eye will not cause any system-wide effects. [ABSTRACT FROM AUTHOR]

Motivation: Nonlinear dose-response models are primary tools for estimating the potency [e.g. half-maximum inhibitory concentration (IC) known as IC50] of anti-cancer drugs. We present drexplorer software, which enables biologists to evaluate replicate reproducibility, detect outlier data points, fit different models, select the best model, estimate IC values at different percentiles and assess drug-drug interactions. drexplorer serves as a computation engine within the R environment and a graphical interface for users who do not have programming backgrounds. [ABSTRACT FROM AUTHOR]

Presents information on a study that assessed the corneal and scleral permeabilities of natural prostaglandins as well as their prodrugs and analogs through human cornea and sclera in vitro. Information on glaucoma; Materials and methods used in the study; Discussion on corneal and scleral penetration.

Context: Palliative care (PC) physicians are vulnerable for burnout given the nature of practice. The burnout frequency may be variable and reported between 24% and 38% across different countries.Objective: The main objective of our study was to determine the frequency of burnout among PC physicians participating in PC continuing medical education course.Methods: A survey including the Maslach Burnout Inventory-General along with 41 custom questions were administered to determine the frequency of burnout among physicians attending the 2018 Hospice and Palliative Medicine Board review course.Results: Of 110 physicians, 91 (83%) completed the survey. The median age was 48 years with 65% being females, 81% married, 46% in community practice, 38% in practice for 6-15 years. PC was practiced ≥50% of the time by 62%, and 76% were doing clinical work. About 73 (80%) reported that PC is appreciated at their work, 58 (64%) reported insurance to be a burden, and 58 (64%) reported that the electronic medical record was a burden. About 82 (90%) felt optimistic about continuing PC in future. Maslach Burnout Inventory results suggest that 35 (38%) participants reported at least one symptom of burnout. Only being single/separated showed trend toward significance with burnout (P = 0.056).Conclusion: Burnout among PC physicians who attended a board review course was 38%. Being single/separated showed trend toward association with burnout. Physicians who choose to attend continuing medical education may have unique motivating characteristics allowing them to better cope with stress and avoid burnout. [ABSTRACT FROM AUTHOR]

Context: There is limited literature regarding outpatient palliative care and factors associated with unscheduled clinic visits.Objectives: To compare characteristics of patients with unscheduled vs. scheduled outpatient palliative care clinic visits.Methods: Medical records of 183 unscheduled cancer new outpatients and 104 unscheduled follow-up (FU) patients were compared with random samples of 361 and 314 scheduled new patients and FU patients, respectively. We gathered data on demographics, symptoms, daily opioid usage, and performance status.Results: Compared with scheduled new patients, unscheduled new patients had worse Edmonton Symptom Assessment Scale subscores for pain (P < 0.001), fatigue (P = 0.002), nausea (P = 0.016), depression (P = 0.003), anxiety (P = 0.038), drowsiness (P = 0.002), sleep (P < 0.001), and overall feeling of well-being (P = 0.001); had a higher morphine equivalent daily dose of opioids (median of 45 mg for unscheduled vs. 30 mg for scheduled; P < 0.001); and were more likely to be from outside the greater Houston area (P < 0.001). Most unscheduled and scheduled new and FU visits were for uncontrolled physical symptoms. Unscheduled FU patients, compared with scheduled FU patients, had worse Edmonton Symptom Assessment Scale subscores for pain (P < 0.001), fatigue (P < 0.001), depression (P = 0.002), anxiety (P = 0.004), drowsiness (P = 0.010), appetite (P = 0.023), sleep (P = 0.022), overall feeling of well-being (P < 0.001), and higher morphine equivalent daily dose of opioid (median of 58 mg for unscheduled FU visits vs. 40 mg for scheduled FU visits; P = 0.054).Conclusion: Unscheduled new FU patients have higher levels of physical and psychosocial distress and higher opioid intake. Outpatient palliative care centers should consider providing opportunities for walk-in visits for timely management and close monitoring of such patients. [ABSTRACT FROM AUTHOR]