Metacognitive beliefs, mood symptoms, and fatigue four years after stroke: An explorative study.

OBJECTIVE: This cross-sectional study investigated the relationship between metacognition and mood symptoms four years post-stroke and examined fatigue as a potential moderator for this relationship. METHODS: A number of 143 participants completed a survey that included the Hospital Anxiety and Depression Scale (HADS), the Metacognition Questionnaire-30 (MCQ-30), the Fatigue Severity Scale (FSS), and the modified Rankin Scale (mRS) (functional status) four years after stroke. Multiple regression analyses adjusting for demographic and stroke-specific covariates were performed with anxiety and depression as dependent variables and fatigue as a moderator. RESULTS: The proportions of participants satisfying the caseness criteria for anxiety and depression were 20% and 19%, respectively, and 35% reported severe fatigue. Analysed separately, all MCQ-30 subscales contributed significantly to anxiety, whereas only three MCQ-30 subscales contributed significantly to depression. In the adjusted analyses, the MCQ-30 subscales 'positive beliefs' (p < 0.05) and 'uncontrollability and danger' (p < 0.001), as well as fatigue (p < 0.001) and functional status at four years (p < 0.05) were significantly associated with anxiety symptoms. Similarly, the MCQ-30 subscales 'cognitive confidence' (p < 0.05) and 'self-consciousness' (p < 0.05), as well as fatigue (p < 0.001), stroke severity at baseline (p < 0.01), and functional status at four years (p < 0.01) were significantly associated with depression symptoms. Fatigue did not significantly moderate the relationship between any MCQ-30 subscale and HADS scores. CONCLUSION: Maladaptive metacognitions were associated with the mood symptoms of anxiety and depression, independent of fatigue, even after controlling for demographic and stroke-specific factors. Future studies should implement longitudinal designs to determine whether metacognitions precede anxiety or depression after a stroke, and more strongly indicate the potential of metacognitive therapy for improving the mental health of individuals after a stroke.

Predicting treatment outcome using kinome activity profiling in HER2+ breast cancer biopsies.

In this study, we measured the kinase activity profiles of 32 pre-treatment tumor biopsies of HER2-positive breast cancer patients. The aim of this study was to assess the prognostic potential of kinase activity levels, to identify potential mechanisms of resistance and to predict treatment success of HER2-targeted therapy combined with chemotherapy. Indeed, our system-wide kinase activity analysis allowed us to link kinase activity to treatment response. Overall, high kinase activity in the HER2-pathway was associated with good treatment outcome. We found eleven kinases differentially regulated between treatment outcome groups, including well-known players in therapy resistance, such as p38a, ERK, and FAK, and an unreported one, namely MARK1. Lastly, we defined an optimal signature of four kinases in a multiple logistic regression diagnostic test for prediction of treatment outcome (AUC = 0.926). This kinase signature showed high sensitivity and specificity, indicating its potential as predictive biomarker for treatment success of HER2-targeted therapy.

Deep (phospho)proteomics profiling of pre- treatment needle biopsies identifies signatures of treatment resistance in HER2+ breast cancer.

Patients with early-stage HER2-overexpressing breast cancer struggle with treatment resistance in 20%-40% of cases. More information is needed to predict HER2 therapy response and resistance in vivo. In this study, we perform (phospho)proteomics analysis of pre-treatment HER2+ needle biopsies of early-stage invasive breast cancer to identify molecular signatures predictive of treatment response to trastuzumab, pertuzumab, and chemotherapy. Our data show that accurate quantification of the estrogen receptor (ER) and HER2 biomarkers, combined with the assessment of associated biological features, has the potential to enable better treatment outcome prediction. In addition, we identify cellular mechanisms that potentially precondition tumors to resist therapy. We find proteins with expression changes that correlate with resistance and constitute to a strong predictive signature for treatment success in our patient cohort. Our results highlight the multifactorial nature of drug resistance in vivo and demonstrate the necessity of deep tumor profiling.

Tumour-educated platelets for breast cancer detection: biological and technical insights.

BACKGROUND: Studies have shown that blood platelets contain tumour-specific mRNA profiles tumour-educated platelets (TEPs). Here, we aim to train a TEP-based breast cancer detection classifier. METHODS: Platelet mRNA was sequenced from 266 women with stage I-IV breast cancer and 212 female controls from 6 hospitals. A particle swarm optimised support vector machine (PSO-SVM) and an elastic net-based classifier (EN) were trained on 71% of the study population. Classifier performance was evaluated in the remainder (29%) of the population, followed by validation in an independent set (37 cases and 36 controls). Potential confounding was assessed in post hoc analyses. RESULTS: Both classifiers reached an area under the curve (AUC) of 0.85 upon internal validation. Reproducibility in the independent validation set was poor with an AUC of 0.55 and 0.54 for the PSO-SVM and EN classifier, respectively. Post hoc analyses indicated that 19% of the variance in gene expression was associated with hospital. Genes related to platelet activity were differentially expressed between hospitals. CONCLUSIONS: We could not validate two TEP-based breast cancer classifiers in an independent validation cohort. The TEP protocol is sensitive to within-protocol variation and revision might be necessary before TEPs can be reconsidered for breast cancer detection.

Efficacy of neoadjuvant treatment with or without pertuzumab in patients with stage II and III HER2-positive breast cancer: a nationwide cohort analysis of pathologic response and 5-year survival.

BACKGROUND: Pathologic complete response (pCR) rates in early stage HER2-positive breast cancer improved after pertuzumab was added to neoadjuvant treatment. However, survival benefit is less-well established and seems mostly limited to node-positive patients. We used national cancer registry data to compare outcomes of patients treated with and without pertuzumab. METHODS: We identified stage II-III HER2-positive breast cancer patients treated with neoadjuvant trastuzumab-based chemotherapy between November 2013 until January 2016 from the Netherlands Cancer Registry. During that period pertuzumab was only available in the 37 hospitals that participated in the TRAIN-2 study. Missing grade and pCR-status were obtained from the Dutch Pathology Registry (PALGA) and cause of death from Statistics Netherlands. We used multiple imputation to impute missing data, multivariable logistic regression to evaluate the association between pertuzumab and pCR (ypT0/is, ypN0) and multivariable Cox regression models for overall survival and breast cancer specific survival (BCSS). RESULTS: We identified 1124 patients of whom 453 received pertuzumab. Baseline characteristics were comparable, although tumor grade was missing more often in patients treated without pertuzumab (12% vs. 2%). Pertuzumab improved pCR rates (41% vs 65%, adjusted odds ratio [aOR] 2.91; 95% CI:2.20-3.94). After a median follow-up of 6.0 years, 5-year BCSS rates were 95% and 98% respectively (adjusted hazard ratio [aHR]: 0.58; 95% CI:0.36-0.95). Younger patients derived more benefit from pertuzumab, but no other significant interactions were found. CONCLUSION: These results support earlier data of a small survival benefit with the addition of pertuzumab to trastuzumab-based neoadjuvant chemotherapy which is most meaningful in younger patients.

The Way of the Future: Personalizing Treatment Plans Through Technology.

Advances in tissue analysis methods, image analysis, high-throughput molecular profiling, and computational tools increasingly allow us to capture and quantify patient-to patient variations that impact cancer risk, prognosis, and treatment response. Statistical models that integrate patient-specific information from multiple sources (e.g., family history, demographics, germline variants, imaging features) can provide individualized cancer risk predictions that can guide screening and prevention strategies. The precision, quality, and standardization of diagnostic imaging are improving through computer-aided solutions, and multigene prognostic and predictive tests improved predictions of prognosis and treatment response in various cancer types. A common theme across many of these advances is that individually moderately informative variables are combined into more accurate multivariable prediction models. Advances in machine learning and the availability of large data sets fuel rapid progress in this field. Molecular dissection of the cancer genome has become a reality in the clinic, and molecular target profiling is now routinely used to select patients for various targeted therapies. These technology-driven increasingly more precise and quantitative estimates of benefit versus risk from a given intervention empower patients and physicians to tailor treatment strategies that match patient values and expectations.

Proteomic profiling of extracellular vesicles allows for human breast cancer subtyping.

Extracellular vesicles (EVs) are a potential source of disease-associated biomarkers for diagnosis. In breast cancer, comprehensive analyses of EVs could yield robust and reliable subtype-specific biomarkers that are still critically needed to improve diagnostic routines and clinical outcome. Here, we show that proteome profiles of EVs secreted by different breast cancer cell lines are highly indicative of their respective molecular subtypes, even more so than the proteome changes within the cancer cells. Moreover, we detected molecular evidence for subtype-specific biological processes and molecular pathways, hyperphosphorylated receptors and kinases in connection with the disease, and compiled a set of protein signatures that closely reflect the associated clinical pathophysiology. These unique features revealed in our work, replicated in clinical material, collectively demonstrate the potential of secreted EVs to differentiate between breast cancer subtypes and show the prospect of their use as non-invasive liquid biopsies for diagnosis and management of breast cancer patients.

Cortical Thickness and Cognitive Performance After Out-of-Hospital Cardiac Arrest.

BACKGROUND: Cognitive impairment is common in long-term survivors of out-of-hospital cardiac arrest (OHCA) but corresponding neuroimaging data are lacking. OBJECTIVES: This study explored the relationship among the cortical brain structure, cognitive performance, and clinical variables after OHCA. METHODS: Three months after resuscitation, 13 OHCA survivors who had recovered from a coma to living independently and 19 healthy controls were assessed by cerebral magnetic resonance imaging and neuropsychological tests quantifying memory, fine-motor coordination, and attention/executive functions. Cortical thickness (Cth) and surface area (SA) were compared between groups and analyzed for relationships with cognitive performance as well as the clinical variables of coma duration and the time to return of spontaneous circulation (ROSC). All analyses were controlled for age and sex. RESULTS: Analyses of SA revealed no significant differences. Compared with controls, survivors had significantly reduced memory and fine-motor coordination and significantly thinner cortex in large clusters in the frontal, parietal, and inferior temporal cortices, with additional regions in the left occipital lobe and the left temporal lobe. Widespread thinner cortical regions were significantly associated with decreased memory performance in survivors when compared with those in controls and were significantly associated with an increased time to ROSC and increased coma duration in the OHCA group. Increased coma duration, but not increased time to ROSC, was significantly correlated with cognitive test performance. CONCLUSIONS: The results suggest that widespread Cth reductions correspond to the cognitive impairments observed after OHCA. Neuroimaging studies of long-term OHCA survivors are warranted to guide the development of diagnostics and treatment options.

The relation of hippocampal subfield volumes to verbal episodic memory measured by the California Verbal Learning Test II in healthy adults.

Total hippocampal volume has previously been shown to correlate with performance on tests for verbal episodic memory. However, there are sparse evidence on how hippocampal subfield volumes are related to verbal episodic memory in healthy adults. The present study investigated the association between volumes of separate hippocampal subfields and verbal episodic memory performance in healthy volunteers. Forty-seven participants (31 females) between 20-71 years age underwent testing with the California Verbal Learning Test II (CVLT II), and the Wechsler Abbreviated Scale of Intelligence (WASI) to obtain an estimate of cognitive functioning. T1-weighted MR images were obtained after cognitive testing, and volumetric estimates adjusted for age and estimated total intracranial volume were calculated in the FreeSurfer 6.0 software suite for cerebral -and hippocampal structures. The sample performed within the statistical normal range on both CVLT II and WASI. Significant correlations adjusted for multiple testing were found between CVLT II subtests of total learning, free immediate recall and free delayed recall and volumes of the left Cornu Ammonis (CA) 1-4 subfields. There were no significant correlations between right hippocampal subfields and CVLT II performance, and no significant correlation between WASI results and hippocampal subfields. The present results suggest that better verbal episodic memory measured by the CVLT II is associated with relative larger volumes of specific left CA hippocampal subfields in healthy adults. Due to the small sample size and large age-span of the participants, the present findings are preliminary and should be confirmed in larger samples.

Memory performance, global cerebral volumes and hippocampal subfield volumes in long-term survivors of Out-of-Hospital Cardiac Arrest.

AIM: We explored the associations between global brain volumes, hippocampal subfield volumes and verbal memory performance in long-term survivors of out-of-hospital cardiac arrest (OHCA). METHODS: Three months after OHCA, survivors and healthy, age-matched controls were assessed with cerebral MRI and the California Verbal Learning Test-II (CVLT-II). Volumetric brain segmentation was performed automatically by FreeSurfer. RESULTS: Twenty-six OHCA survivors who were living independently in regular homes at the time of assessment and 19 controls participated in the study. Thirteen of the survivors had been conscious upon arrival to the emergency department. The other 13 survivors had 0.5-7 days of inpatient coma before recovery. Memory was poorer in the OHCA group that had been comatose beyond initial hospital admission compared to both other groups. Total cortical volumes, total hippocampus volumes and several hippocampal subfield volumes were significantly smaller in the OHCA group comatose beyond initial hospital admission compared to controls. No significant differences between the OHCA group conscious upon emergency department arrival and the other two groups were found for brain volumes. No significant differences were observed between any groups for white matter or total subcortical volumes. In OHCA survivors with recovery from inpatient coma, the various CVLT-II trials were significantly, but differentially, correlated to total gray matter volume, cortical volume and the hippocampal subfield subiculum. CONCLUSION: In this small, single-site study, both hippocampal volume and cortical volume were smaller in good outcome OHCA survivors 3 months after resuscitation in comparison to healthy controls. Smaller cerebral volumes were correlated with poorer memory performance.

Vitamin D and C-Reactive Protein: A Mendelian Randomization Study.

Vitamin D deficiency is widely prevalent and has been associated with many diseases. It has been suggested that vitamin D has effects on the immune system and inhibits inflammation. The aim of our study was to investigate whether vitamin D has an inhibitory effect on systemic inflammation by assessing the association between serum levels of vitamin D and C-reactive protein. We studied the association between serum 25-hydroxyvitamin D and C-reactive protein through linear regression in 9,649 participants of the Rotterdam Study, an observational, prospective population-based cohort study. We used genetic variants related to vitamin D and CRP to compute a genetic risk score and perform bi-directional Mendelian randomization analysis. In linear regression adjusted for age, sex, cohort and other confounders, natural log-transformed CRP decreased with 0.06 (95% CI: -0.08, -0.03) unit per standard deviation increase in 25-hydroxyvitamin D. Bi-directional Mendelian randomization analyses showed no association between the vitamin D genetic risk score and lnCRP (Beta per SD = -0.018; p = 0.082) or the CRP genetic risk score and 25-hydroxyvitamin D (Beta per SD = 0.001; p = 0.998). In conclusion, higher levels of Vitamin D are associated with lower levels of C-reactive protein. In this study we did not find evidence for this to be the result of a causal relationship.

Stapes surgery in relation to age.

This prospective study aims to evaluate the efficacy of stapedotomy in relation to age. Eighty-four ears of 82 consecutive patients who underwent stapedotomy were studied. Patients were divided into five groups according to their age. In each patient, we evaluated the pre- and postoperative auditory thresholds, according to the Committee on Hearing and Equilibrium of the American Academy of Otolaryngology - Head and Neck Surgery guidelines. Statistically significant (P < 0.05) differences between the pre- and postoperative air conduction thresholds were observed in all groups. Statistically significant reductions of air-bone gap were observed at lower-medium frequencies (250, 500 and 1000 Hz) in the elderly as well as in the younger patients. We did not find a higher susceptibility of the inner ear to surgical trauma in the elderly in comparison to the younger patients. Our data show that stapedotomy results in older adults are comparable to those obtained in the younger, without an increased incidence of complications.

Dysphonia and cervical hyperostosis: a case report.

We report a case of a 77-year-old man with a 3-year-history of progressive dysphonia, without dysphagia. His voice sounded breathy; the pitch and the loudness were low. He complained of a few episodes of voice breaking. At laryngostroboscopy the adduction motion of the left true vocal cord was slower than the contralateral one. A cervical spine X-ray demonstrated a generalized vertebral osteophytosis and a 3-centimeter-long anterior osteophytic spur, originating from C6. Evaluation with barium swallow showed a dislocation of the inferior cervico-oesophagus to the right, with a preservation of its lumen. Cervical-thoracic computed tomography showed a mild pressure produced by the osteophyte on the thyroid cartilage and the presence of the radiological criteria for Forestier's disease. Therefore, the presence of dysphonia in older adults without any primary laryngeal cause, indicates a radiological study of the cervical-thoracic region, in order to discover cervical osteophytosis.

Papanicolaou smear abnormalities in ambulatory care sites for women infected with the human immunodeficiency virus.

OBJECTIVE: We attempted to determine the prevalence of cervical dysplasia in human immunodeficiency virus-infected women in ambulatory care settings and to correlate Papanicolaou smears with demographic and clinical variables. STUDY DESIGN: Papanicolaou smears of 135 women attending three ambulatory care clinics were reviewed. Chart review identified demographic and clinical variables, including CD4 count. Prevalence of abnormal smears was compared with baseline community rates. Demographic and clinical variables were correlated with Papanicolaou results with the chi 2 test. RESULTS: Fivefold to eightfold increased rates of abnormal smears in human immunodeficiency virus-infected women were observed. Prevalence of abnormal smears increased from 21% in women with CD4 counts greater than 600/mm3 to 45% in women with CD4 counts less than 400/mm3. Age, ethnicity, or mode of human immunodeficiency virus transmission was not significantly correlated with Papanicolaou smear findings. CONCLUSION: Increased rates of abnormal Papanicolaou smears and significant correlation with CD4 counts were observed in human immunodeficiency virus-infected women at ambulatory care sites. We recommend comprehensive gynecologic care, including semiannual Papanicolaou smears, for all human immunodeficiency virus-infected women.

HIV infection in women: presentations and protocols.

In the 11th year of the AIDS epidemic in the United States, it is clear that more and more women are becoming infected with HIV. Genital infections by other pathogens may be the first clue to the diagnosis. With progressive immunodeficiency, such infections may follow a protracted course or become recurrent, often requiring maintenance therapy.