Validation of inflammatory genetic variants associated with long-term cancer related fatigue in a large breast cancer cohort.

BACKGROUND: Studies to date have reported several associations between single nucleotide polymorphisms (SNPs) and cancer related fatigue (CRF), but have been limited by small sample sizes, missing adjustment for relevant covariates or multiple testing, as well as varying CRF definitions, i.e. time and method of assessment. This study aimed to validate previously reported associations using the largest independent breast cancer sample to date and to evaluate further functional cytokine variants in relation to total CRF and all relevant CRF subdomains (physical, cognitive, and affective CRF). METHOD: 45 candidate SNPs in inflammatory pathway genes were selected based on previous reports (16 SNPs) or regulatory function (29 SNPs). Breast cancer patients recruited between 2002 and 2005 provided information on CRF at first follow-up (FU1) (N = 1389) and second follow-up (FU2) (N = 950), a median of 6.2 years and 11.7 years respectively after diagnosis. SNP associations were assessed using linear regression models on CRF scores separately for FU1 and FU2. Additionally, patients with persistent fatigue (fatigued at both time-points) were compared to those never fatigued using logistic regression models (N = 684). All analyses were adjusted for relevant covariates. Secondary analyses were conducted for CRF subdomains. RESULTS: For total CRF none of the previously reported associations were confirmed after correction for multiple testing. The p-value distribution of all SNPs was not different than the one expected by chance. Analyses of CRF subdomains yielded a significant association between TNF-α rs3093662 and persistent physical CRF (Odds Ratio (OR) = 3.23, 95% Confidence Interval (CI) = 1.71-6.10, p = 0.0003). CONCLUSION: We were unable to confirm previously reported findings, suggesting that individual SNPs are unlikely to be of clinical utility. Further investigations in well powered studies are warranted, which consider genetic heterogeneity according to subdomains of CRF.

Effects of 12-week resistance training during radiotherapy in breast cancer patients.

Exercise is considered to be an effective supportive treatment approach in breast cancer (BC) patients. We conducted a randomized controlled trial to assess the efficacy of a 12-week PRT during radiotherapy. Strength performance was assessed by maximal isokinetic peak torque (MIPT) in two different angular velocities (60°/s and 180°/s) and maximal voluntary isometric contraction for shoulder external and internal rotation, as well as for knee extension and flexion were assessed pre- and post-intervention in 146 patients randomized to PRT or a control group. Statistical analyses were based on analysis of covariance models for the individual changes from baseline to week 13. Intention-to-treat analyses showed significant between-group differences favoring the exercise group (EX) for MIPT in knee flexion and shoulder internal and external rotation (P < 0.05). Subgroup analyses showed borderline significant differences with regard to pretreatment history, revealing that pretreated chemotherapy patients tend to benefit more from PRT than patients without chemotherapy (P = 0.06). Strength gain at the operated arm was significantly higher than at the non-operated arm in EX. PRT was efficacious in increasing upper and lower limb strength in BC patients undergoing adjuvant radiotherapy. Patients with restrictions due to breast cancer-related surgery and pretreated with chemotherapy might benefit the most.

Determining best practices in reconnoitering sites for habitability potential on Mars using a semi-autonomous rover: A GeoHeuristic Operational Strategies Test.

We tested science operations strategies developed for use in remote mobile spacecraft missions, to determine whether reconnoitering a site of potential habitability prior to in-depth study (a walkabout-first strategy) can be a more efficient use of time and resources than the linear approach commonly used by planetary rover missions. Two field teams studied a sedimentary sequence in Utah to assess habitability potential. At each site one team commanded a human "rover" to execute observations and conducted data analysis and made follow-on decisions based solely on those observations. Another team followed the same traverse using traditional terrestrial field methods, and the results of the two teams were compared. Test results indicate that for a mission with goals similar to our field case, the walkabout-first strategy may save time and other mission resources, while improving science return. The approach enabled more informed choices and higher team confidence in choosing where to spend time and other consumable resources. The walkabout strategy may prove most efficient when many close sites must be triaged to a smaller subset for detailed study or sampling. This situation would arise when mission goals include finding, identifying, characterizing or sampling a specific material, feature or type of environment within a certain area.

Randomized, controlled trial of resistance training in breast cancer patients receiving adjuvant radiotherapy: results on cancer-related fatigue and quality of life.

BACKGROUND: Exercise has been reported to decrease cancer-related fatigue and to increase quality of life (QoL) in various breast cancer (BC) populations. However, studies investigating exercise during radiotherapy or resistance training are scarce. We conducted a randomized, controlled trial (BEST study) to assess the efficacy of 12-week resistance training on fatigue beyond possible psychosocial effects of a group-based intervention. PATIENTS AND METHODS: One hundred sixty patients with BC stage 0-III were randomly assigned to a 12-week progressive resistance training (2 times/week) or a 12-week relaxation control (RC, 2 times/week). Both interventions were group-based. The primary end point fatigue was assessed with a 20-item multidimensional questionnaire, QoL with EORTC questionnaires. Statistical analyses were based on analysis of covariance models for the individual changes from baseline to week 13. RESULTS: Adherence to the intervention program as well as the completion rate (97%) for the primary outcome variable fatigue was high. In intention-to-treat analyses for the N = 155 patients, significant between-group mean differences (MD) favoring the exercise group (EX) were observed for general fatigue (P = 0.044), especially for the subscale physical fatigue [MD = -0.8; 95% confidence interval -1.5 to -0.2, P = 0.013], but not for affective (P = 0.91) or cognitive fatigue (P = 0.65). For QoL, significantly larger improvements regarding the role function (P = 0.035) and pain (P = 0.040) were noted among exercisers compared with RCs. Future perspective improved significantly stronger in the RC group compared with the EX group (P = 0.047). CONCLUSIONS: The 12-week resistance training program was a safe, feasible and efficacious strategy to improve cancer-related fatigue and components of QoL in BC patients during adjuvant radiotherapy. As exercise was compared with another group-based intervention, results indicate that resistance training effects on fatigue and QoL go beyond psychosocial benefits, and that the clinically relevant overall benefit of resistance exercise compared with usual care can be assumed to be higher. TRIAL REGISTRATION: ClinicalTrials.gov NCT01468766.

Aqueously altered igneous rocks sampled on the floor of Jezero crater, Mars.

The Perseverance rover landed in Jezero crater, Mars, to investigate ancient lake and river deposits. We report observations of the crater floor, below the crater's sedimentary delta, finding that the floor consists of igneous rocks altered by water. The lowest exposed unit, informally named Séítah, is a coarsely crystalline olivine-rich rock, which accumulated at the base of a magma body. Magnesium-iron carbonates along grain boundaries indicate reactions with carbon dioxide-rich water under water-poor conditions. Overlying Séítah is a unit informally named Máaz, which we interpret as lava flows or the chemical complement to Séítah in a layered igneous body. Voids in these rocks contain sulfates and perchlorates, likely introduced by later near-surface brine evaporation. Core samples of these rocks have been stored aboard Perseverance for potential return to Earth.

An olivine cumulate outcrop on the floor of Jezero crater, Mars.

The geological units on the floor of Jezero crater, Mars, are part of a wider regional stratigraphy of olivine-rich rocks, which extends well beyond the crater. We investigated the petrology of olivine and carbonate-bearing rocks of the Séítah formation in the floor of Jezero. Using multispectral images and x-ray fluorescence data, acquired by the Perseverance rover, we performed a petrographic analysis of the Bastide and Brac outcrops within this unit. We found that these outcrops are composed of igneous rock, moderately altered by aqueous fluid. The igneous rocks are mainly made of coarse-grained olivine, similar to some martian meteorites. We interpret them as an olivine cumulate, formed by settling and enrichment of olivine through multistage cooling of a thick magma body.

Effects and moderators of exercise on sleep in adults with cancer: Individual patient data and aggregated meta-analyses.

OBJECTIVES: To evaluate the effects of exercise interventions on sleep disturbances and sleep quality in patients with mixed cancer diagnoses, and identify demographic, clinical, and intervention-related moderators of these effects. METHODS: Individual patient data (IPD) and aggregated meta-analyses of randomized controlled trials (RCTs). Using data from the Predicting OptimaL cAncer RehabIlitation and Supportive care project, IPD of 2173 adults (mean age = 54.8) with cancer from 17 RCTs were analyzed. A complementary systematic search was conducted (until November 2018) to study the overall effects and test the representativeness of analyzed IPD. Effect sizes of exercise effects on self-reported sleep outcomes were calculated for all included RCTs. Linear mixed-effect models were used to evaluate the effects of exercise on post-intervention outcome values, adjusting for baseline values. Moderator effects were studied by testing interactions for demographic, clinical and intervention-related characteristics. RESULTS: For all 27 eligible RCTs from the updated search, exercise interventions significantly decreased sleep disturbances in adults with cancer (g = -0.09, 95% CI [-0.16; -0.02]). No significant effect was obtained for sleep quality. RCTs included in IPD analyses constituted a representative sample of the published literature. The intervention effects on sleep disturbances were not significantly moderated by any demographic, clinical, or intervention-related factor, nor by sleep disturbances. CONCLUSIONS: This meta-analysis provides some evidence that, compared to control conditions, exercise interventions may improve sleep disturbances, but not sleep quality, in cancer patients, although this effect is of a small magnitude. Among the investigated variables, none was found to significantly moderate the effect of exercise interventions on sleep disturbances.

Prostate cancer tissue is masked by bicalutamide: a case report.

Prostate cancer is the most common malignant tumor in men. Recently, a slightly decreased frequency of margin positivity following neoadjuvant bicalutamide treatment due to tumor shrinkage was reported. Trials investigating other anti-androgens in the past also reported lower frequencies of surgical margin positivity, but patients outcome has not improved. In this case, local recurrence was confirmed by needle biopsy in a patient five years following radical prostatectomy for prostate adenocarcinoma. After therapy with 50 mg bicalutamide for a month, the tumour was resected. Despite of detailed histological work-up and immunohistochemistry cancer suspicious lesions were not found. We think that bicalutamide may be capable of masking prostate cancer cells.

Redox stratification of an ancient lake in Gale crater, Mars.

In 2012, NASA's Curiosity rover landed on Mars to assess its potential as a habitat for past life and investigate the paleoclimate record preserved by sedimentary rocks inside the ~150-kilometer-diameter Gale impact crater. Geological reconstructions from Curiosity rover data have revealed an ancient, habitable lake environment fed by rivers draining into the crater. We synthesize geochemical and mineralogical data from lake-bed mudstones collected during the first 1300 martian solar days of rover operations in Gale. We present evidence for lake redox stratification, established by depth-dependent variations in atmospheric oxidant and dissolved-solute concentrations. Paleoclimate proxy data indicate that a transition from colder to warmer climate conditions is preserved in the stratigraphy. Finally, a late phase of geochemical modification by saline fluids is recognized.

Aggressive angiomyxoma of the prostate mimicking benign prostatic hyperplasia.

Aggressive angiomyxoma (AAM) is a locally invasive soft tissue tumor with a high risk of local recurrence but without metastatic spread. The mesenchymal tumor is relatively site-specific and has a peak incidence in females in their 2nd or 4th decade. Only few cases in males have been reported in the literature. We describe what we think is the first case of an aggressive angiomyxoma arising in the prostate presenting with classical symptoms of benign prostatic hyperplasia.

Statistical methods for the validation of questionnaires--discrepancy between theory and practice.

OBJECTIVES: Questionnaires used in epidemiological studies should be validated. However, unclarity exists about the appropriate statistical methods and interpretation of validation studies. Thus, we investigated the theory and practice of statistical evaluation approaches. METHODS: Using three platforms, a literature review, own simulations, and a validation study performed by ourselves, we worked out relevant limitations, advantages, and new important aspects of evaluation methods. RESULTS: Our systematic literature review, based on physical activity questionnaires, revealed that correlation coefficients are still the common approach in validation studies, found in 41 of 46 reviewed publications (89.1%). This practice has been criticized in the theoretically oriented literature for more than 20 years. Appropriate evaluation methods as recommended by Bland and Altman were found in only ten publications (21.7%). We showed that serious bias in questionnaires can be revealed by Bland-Altman plots but may remain undetected by correlation coefficients. With our simulations we refuted the argument that correlation coefficients properly investigate whether a questionnaire ranks the subjects sufficiently well. Further, with Bland-Altman analyses we could evaluate differential errors with respect to case-control status in our validation study. Yet, this was not possible with correlation coefficients, because they generally do not identify systematic bias. In addition, we show a potential pitfall in the interpretation of Bland-Altman plots that might occur in specific rare instances. CONCLUSIONS: The commonly used correlation approach can yield misleading conclusions in validation studies. A more frequent and proper use of the Bland-Altman methods would be desirable to improve epidemiological data quality.

The effects of prolonged lithium exposure on the immune system of normal control subjects: serial serum soluble interleukin-2 receptor and antithyroid antibody measurements.

The purpose of this study was to begin evaluating the effects of lithium carbonate on in vivo immune function in normal controls. We postulated that lithium carbonate would stimulate lymphocytes but would not affect the production of antithyroid antibodies. Twenty-seven normal controls had blood samples drawn for measurements of serum soluble interleukin-2 receptors (SIL-2Rs), antithyroglobulin antibodies, and antimicrosomal antibodies prior to and after approximately 1 and 4 weeks of treatment with lithium carbonate at therapeutic blood levels. Subjects had a small but statistically significant increase in serum SIL-2Rs after 4 weeks of lithium treatment (446.3 +/- 177.2 U/ml versus 497.6 +/- 232.3 U/ml, p = 0.033). There was no increase in the prevalence of antithyroglobulin or antimicrosomal antibodies with lithium treatment nor did lithium act as an adjuvant to increase the titers in subjects with preexisting antithyroid antibodies.

Regional brain glucose metabolism after acute alpha 2-blockade by idazoxan.

BACKGROUND: Several classes of antidepressant drugs act on alpha 2-adrenergic receptors. Studies of patients with disorders responsive to treatment with these drugs report group differences in ex vivo measures of alpha 2-binding and in vivo responses mediated by alpha 2-receptors. Measurement of regional brain metabolic response to an alpha 2-antagonist may be a useful method for further definition of the role alpha 2-receptor regulation plays in the treatment of neuropsychiatric disorders. METHODS: Regional brain glucose metabolism was measured before and after infusion with 200 micrograms/kg idazoxan with use of 18F-fluoro-2-deoxyglucose positron emission tomography in 13 healthy men. Arterial drug concentration, behavioral responses, and cardiovascular responses were also measured. RESULTS: The absolute and normalized glucose metabolic rate significantly increased in primary visual cortex. Significant increases and decreases occurred in normalized metabolic rates in prefrontal cortical regions. Measurement of metabolic effects occurred during the peak cardiovascular response. CONCLUSIONS: Our findings are consistent with regionally specific effects of alpha 2-blockade. This method may be useful for the study of alpha 2-receptor function in humans.

Brain kinetics of paroxetine and fluoxetine on the third day of placebo substitution: a fluorine MRS study.

OBJECTIVE: This study tested whether a relationship exists between concentration and response following discontinuation of selective serotonin reuptake inhibitors. METHOD: Eight patients with remitted major depression who were taking 20 mg/day of either fluoxetine or paroxetine underwent placebo substitution for 3 days. Serum drug and brain fluorine levels were obtained before and after placebo substitution. RESULTS: With placebo substitution, a mean of 88% (SD=13%) of brain fluorine signal from fluoxetine (plus fluorinated metabolites) remained, compared with a mean of 38% (SD=17%) of the brain fluorine signal from paroxetine (plus fluorinated metabolites). Among patients taking paroxetine, adverse events during placebo substitution correlated highly with steady-state brain drug levels. CONCLUSIONS: The correlation of clinical effects with brain drug levels in the paroxetine group suggests that relationships between drug response and brain drug concentrations merit further investigation.

Gender differences in brain metabolic and plasma catecholamine responses to alpha 2-adrenoceptor blockade.

alpha 2-Adrenergic receptors modulate the release of several neurotransmitters implicated in the treatment and pathophysiology of mood and anxiety disorders. Significant sex differences occur in the prevalence of both disorders. To test whether gender affects alpha 2 function, the plasma catecholamine and brain metabolic responses to alpha 2 blockade were measured in male and female volunteers. Ten female and thirteen male volunteers underwent [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) scans before and after infusion of idazoxan (200 micrograms/kg). Measures of plasma catecholamines, blood pressure, and anxiety were obtained. Norepinephrine responses were larger in males. Women showed global increases in metabolism, whereas males had no global changes and some regional decreases in FDG uptake following idazoxan administration. The differences in norepinephrine increases are consistent with previously reported effects of gender on sympathetic activation. The PET data suggest gender differences in responses to alpha 2-receptor blockade in brain as well.

Cerebral glucose metabolism during pharmacologic studies: test-retest under placebo conditions.

UNLABELLED: The reliability of serial [18F]fluorodeoxyglucose (FDG) PET scans for psychopharmacologic studies was tested by using placebo infusions. METHODS: FDG scans were obtained before and after a 30 min placebo infusion (n = 10; Group 1) or after each of two bolus infusions with placebo (n = 8; Group 2). Subjects performed a continuous performance task (CPT) during each scan. Cardiovascular measures and ratings of anxiety were obtained in all subjects. Samples for determination of plasma norepinephrine (NE) were taken at multiple time points in Group 1. RESULTS: A slight increase in apparent global metabolism occurred between scans in both Groups 1 and 2. A few regions significantly increased in both groups. While an apparent increase in sympathetic activity occurred during the placebo infusion, neither NE levels, anxiety ratings nor cardiovascular measures correlated with global or regional FD6 uptake. CONCLUSION: Test-retest differences of global and regional glucose metabolism were highly consistent across two experimental designs. While increases in cerebral glucose metabolism appeared to occur during the second scan, differences between scans were small. This method may offer advantages for selected psychopharmacologic studies.

Responses to alpha 2-adrenoceptor blockade by idazoxan in healthy male and female volunteers.

Seven male and five female volunteers underwent double-blind infusions of the alpha 2-adrenoceptor antagonist idazoxan (100 and 200 micrograms/mg) and placebo in random order. Blood pressure, plasma norepinephrine, growth hormone and subjective responses were measured. The higher dose of idazoxan produced increases in blood pressure, norepinephrine and growth hormone and slight increases in anxiety. Both subject age and sex appeared to influence the magnitude of responses.

The efficacy and safety of a new enteric-coated formulation of fluoxetine given once weekly during the continuation treatment of major depressive disorder.

BACKGROUND: A simple, once-weekly dosing regimen could be a convenient alternative for many patients during long-term treatment of depression. Such a strategy might also be effective for improving medication compliance and the outcome of continuation treatment. The safety and effectiveness of a new formulation of enteric-coated fluoxetine (90 mg) given once weekly was tested during the continuation treatment of major depressive disorder. METHOD: Patients meeting DSM-IV criteria for major depressive disorder with modified 17-item Hamilton Rating Scale for Depression (HAM-D-17) scores > or = 18 and Clinical Global Impressions-Severity of Illness scale (CGI-S) scores > or = 4 were treated 13 weeks with open-label 20 mg/day of fluoxetine in a multicenter U.S. study. Responders (N = 501) were randomly assigned to receive 20 mg of fluoxetine daily, placebo, or 90 mg of enteric-coated fluoxetine weekly for 25 weeks of double-blind continuation treatment. The primary efficacy measure was the percentage of patients who relapsed. Time to relapse was tested over the 25-week continuation period using log-rank analyses of the Kaplan-Meier estimates of relapse rates. Additional analyses of efficacy included comparison of change from baseline to endpoint for the HAM-D-17, CGI-S, and HAM-D-28 subscales by last observation carried forward (LOCF). Safety measures included comparison of treatment-emergent adverse events, both spontaneous and solicited (using the Association for Methodology of Documentation in Psychiatry-Module 5), vital signs, and laboratory measures. RESULTS: Relapse rates for patients assigned to fluoxetine, either 20 mg daily or 90 mg weekly, were significantly lower than for placebo by log-rank analysis and LOCF analyses of secondary efficacy measures. Efficacy did not significantly differ between the 2 active drug groups by these measures. Enteric-coated fluoxetine at a once-weekly dose of 90 mg was well tolerated, and its safety profile was similar to that of daily 20 mg of fluoxetine. CONCLUSION: The formulation of enteric-coated fluoxetine taken once weekly is effective, safe, and well tolerated for continuation treatment of depression in patients who responded to acute treatment with 20 mg/day of fluoxetine. Monitoring during long-term treatment for evidence of sustained remission is important regardless of dosing regimen.

Patient compliance to a new enteric-coated weekly formulation of fluoxetine during continuation treatment of major depressive disorder.

BACKGROUND: A new formulation of enteric-coated fluoxetine given once weekly could be a useful option for the long-term treatment of depression, but compliance to once-weekly fluoxetine treatment has not been assessed. METHOD: Patients were adults from the United Kingdom who had responded to fluoxetine treatment for a current episode of depression (DSM-IV criteria). In the baseline assessment phase, all patients (N = 117) were continued on 20 mg of open-label fluoxetine once daily for 4 weeks. In the follow-up phase, patients (N = 109) were randomly assigned to once-weekly or once-daily fluoxetine for 3 months. Patient compliance was monitored by electronic devices during both phases of the study. RESULTS: Compliance to once-weekly fluoxetine treatment was higher than compliance to once-daily fluoxetine (85.9% vs. 79.4%, respectively). CONCLUSION: Once-weekly fluoxetine treatment allows for new flexibility for both the clinician and the patient, and this study alleviates the concern that patients will forget weekly doses.

Aspergillus and endobronchial abnormalities in lung transplant recipients.

STUDY OBJECTIVE: To determine the relationship between aspergillus recovery from the airways of lung transplant recipients and the development of endobronchial abnormalities. DESIGN: Retrospective case series. SETTING: Tertiary-care hospital. PATIENTS: All patients who underwent lung transplantation between December 1991 and June 1999. MEASUREMENTS AND RESULTS: The study cohort included 38 patients. The primary end point was the bronchoscopic identification of an endobronchial abnormality. Aspergillus was isolated from the lungs of nine patients (23.7%). Most of these isolates occurred early after transplantation (mean, 8 weeks). Endobronchial abnormalities arose in seven of the patients (18.4%) and manifested as either exuberant granulation tissue or stricture formation. Six of the 9 (66.6%) patients with aspergillus developed airway lesions, compared to 1 of the 29 patients (3.4%) without aspergillus (p = 0.0002). Endobronchial abnormalities were 19.3 times more likely to occur in patients in whom aspergillus had previously been isolated. As a screening test for the subsequent diagnosis of an airway complication, the recovery of aspergillus had a sensitivity and specificity of 85.7% and 90.3%, respectively. These aspergillus-related endobronchial abnormalities were clinically relevant as evidenced by a mean increase of 25.9% in the FEV(1) after bronchoscopic intervention. CONCLUSION: The early isolation of aspergillus from the airways of lung transplant recipients identifies patients at increased risk for the development of clinically significant endobronchial abnormalities.