The Role of HE4 in Ovarian Cancer Follow-up: A Review.

Objective: The aim of this review was to analyze the state of the art about HE4 and follow-up in patients treated for ovarian cancer. Methods: A literature search was conducted in the MEDLINE database using the key words "HE4" and "ovarian cancer" and "recurrence" or "relapse" or "follow up." Results: Seven of 28 clinical studies were selected. Four studies were prospective, and all of them were based on a small number of patients (8Y73 women). A failure of HE4 levels to normalize at completion of standard therapy may indicate a poor prognosis, thus suggesting the need of a closer follow-up. Moreover, HE4 showed better sensibility and specificity in the diagnosis of ovarian cancer recurrence with respect to CA-125, being also an earlier indicator of the relapse with a lead time of 5 to 8 months. HE4 showed a better performance in this setting if performed in association with other markers (CA-125, CA-72.4). HE4 seems to be an independent predictive factor for the surgical outcome at secondary cytoreductive surgery and to maintain its prognostic role even after the recurrence. Conclusions: These preliminary data start to suggest a superiority of HE4 over CA-125 in the detection of ovarian cancer recurrence. Moreover, the prognostic role of HE4 could help clinicians to personalize the follow-up program, whereas its predictive role could be useful to plan the treatment of the relapse. The role of HE4 in ovarian cancer follow-up deserves to be further investigated in prospective randomized multicentric studies

A new index to assess turning quality and postural stability in patients with Parkinson's disease

Parkinson's disease is a neuro-degenerative disorder characterized by the progressive death of dopamine neurons. This leads to delayed and uncoordinated movements, and impacts on the patients’ motor performance with reduced movement intensity, increased axial rigidity and impaired cadence regulation. Turning provides privileged insights in postural instability and fall prediction, as it is regularly performed during daily activities, requires multi-limb coordination. The objective of this work was to define a Quality of Movement (QoM) index, inferred from inertial data related to turns, and strictly correlated with the patient's motor conditions, postural stability, and stage of the disease. Such a concise representation finds its main application in the remote monitoring of patients during daily activities at home. We have recorded and analyzed 180° turns in 72 patients, using inertial sensors embedded in the smartphone. We have set up an algorithm for binary classification of patients: mild vs. moderate/severe conditions, according to the Hoehn and Yahr scale of disease progression and disability degree. Our QoM index is defined as the a posteriori probability output by this binary classifier. It exhibits high correlation (r = 0.73) with the clinical score of postural stability, as well as with the average of four clinical scores related to movement impairment (r = 0.75). These results, together with the widespread smartphone use, provide a step in the direction of a practical, objective and reliable tool for PD patients remote monitoring in domestic environment

Machine learning applied to ambulatory blood pressure monitoring: a new tool to diagnose autonomic failure?

BACKGROUND: Autonomic failure (AF) complicates Parkinson’s disease (PD) in one-third of cases, resulting in complex blood pressure (BP) abnormalities. While autonomic testing represents the diagnostic gold standard for AF, accessibility to this examination remains limited to a few tertiary referral centers. OBJECTIVE: The present study sought to investigate the accuracy of a machine learning algorithm applied to 24-h ambulatory BP monitoring (ABPM) as a tool to facilitate the diagnosis of AF in patients with PD. METHODS: Consecutive PD patients naïve to vasoactive medications underwent 24 h-ABPM and autonomic testing. The diagnostic accuracy of a Linear Discriminant Analysis (LDA) model exploiting ABPM parameters was compared to autonomic testing (as per a modified version of the Composite Autonomic Symptom Score not including the sudomotor score) in the diagnosis of AF. RESULTS: The study population consisted of n = 80 PD patients (33% female) with a mean age of 64 ± 10 years old and disease duration of 6.2 ± 4 years. The prevalence of AF at the autonomic testing was 36%. The LDA model showed 91.3% accuracy (98.0% specificity, 79.3% sensitivity) in predicting AF, significantly higher than any of the ABPM variables considered individually (hypotensive episodes = 82%; reverse dipping = 79%; awakening hypotension = 74%). CONCLUSION: LDA model based on 24-h ABPM parameters can effectively predict AF, allowing greater accessibility to an accurate and easy to administer test for AF. Potential applications range from systematic AF screening to monitoring and treating blood pressure dysregulation caused by PD and other neurodegenerative disorders

How resistant are levodopa-resistant axial symptoms? Response of freezing, posture, and voice to increasing levodopa intestinal infusion rates in Parkinson disease

Background and purpose: Treatment of freezing of gait (FoG) and other Parkinson disease (PD) axial symptoms is challenging. Systematic assessments of axial symptoms at progressively increasing levodopa doses are lacking. We sought to analyze the resistance to high levodopa doses of FoG, posture, speech, and altered gait features presenting in daily-ON therapeutic condition. Methods: We performed a pre-/postinterventional study including patients treated with levodopa/carbidopa intestinal gel infusion (LCIG) with disabling FoG in daily-ON condition. Patients were evaluated at their usual LCIG infusion rate (T1), and 1 h after 1.5× (T2) and 2× (T3) increase of the LCIG infusion rate by quantitative outcome measures. The number of FoG episodes (primary outcome), posture, speech, and gait features were objectively quantified during a standardized test by a blinded rater. Changes in motor symptoms, dyskinesia, and plasma levodopa concentrations were also analyzed. Results: We evaluated 16 patients with a mean age of 69 ± 9.4 years and treated with LCIG for a mean of 2.2 ± 2.1 years. FoG improved in 83.3% of patients by increasing the levodopa doses. The number of FoG episodes significantly decreased (mean = 2.3 at T1, 1.7 at T2, 1.2 at T3; p = 0.013). Posture and speech features did not show significant changes, whereas stride length (p = 0.049), turn duration (p = 0.001), and turn velocity (p = 0.024) significantly improved on doubling the levodopa infusion rate. Conclusions: In a short-term evaluation, the increase of LCIG dose can improve "dopa-resistant" FoG and gait issues in most advanced PD patients with overall good control of motor symptoms in the absence of clinically significant dyskinesia

A step towards stereotactic navigation during pelvic surgery: 3D nerve topography

Background: Long-term morbidity after multimodal treatment for rectal cancer is suggested to be mainly made up by nerve-injury-related dysfunctions. Stereotactic navigation for rectal surgery was shown to be feasible and will be facilitated by highlighting structures at risk of iatrogenic damage. The aim of this study was to investigate the ability to make a 3D map of the pelvic nerves with magnetic resonance imaging (MRI). Methods: A systematic review was performed to identify a main positional reference for each pelvic nerve and plexus. The nerves were manually delineated in 20 volunteers who were scanned with a 3-T MRI. The nerve identifiability rate and the likelihood of nerve identification correctness were determined. Results: The analysis included 61 studies on pelvic nerve anatomy. A main positional reference was defined for each nerve. On MRI, the sacral nerves, the lumbosacral plexus, and the obturator nerve could be identified bilaterally in all volunteers. The sympathetic trunk could be identified in 19 of 20 volunteers bilaterally (95%). The superior hypogastric plexus, the hypogastric nerve, and the inferior hypogastric plexus could be identified bilaterally in 14 (70%), 16 (80%), and 14 (70%) of the 20 volunteers, respectively. The pudendal nerve could be identified in 17 (85%) volunteers on the right side and in 13 (65%) volunteers on the left side. The levator ani nerve could be identified in only a few volunteers. Except for the levator ani nerve, the radiologist and the anatomist agreed that the delineated nerve depicted the correct nerve in 100% of the cases. Conclusion: Pelvic nerves at risk of injury are usually visible on high-resolution MRI w

Functional neurological disorders in Parkinson disease

OBJECTIVE: To ascertain demographic and clinical features of Parkinson disease (PD) associated with functional neurological features. METHODS: A standardised form was used to extract data from electronic records of 53 PD patients with associated functional neurological disorders (PD-FND) across eight movement disorders centres in the USA, Canada and Europe. These subjects were matched for age, gender and disease duration to PD patients without functional features (PD-only). Logistic regression analysis was used to compare both groups after adjusting for clustering effect. RESULTS: Functional symptoms preceded or co-occurred with PD onset in 34% of cases, nearly always in the most affected body side. Compared with PD-only subjects, PD-FND were predominantly female (68%), had longer delay to PD diagnosis, greater prevalence of dyskinesia (42% vs 18%; P=0.023), worse depression and anxiety (P=0.033 and 0.025, respectively), higher levodopa-equivalent daily dose (972±701 vs 741±559 mg; P=0.029) and lower motor severity (P=0.019). These patients also exhibited greater healthcare resource utilisation, higher use of [(123)I]FP-CIT SPECT and were more likely to have had a pre-existing psychiatric disorder (P=0.008) and family history of PD (P=0.036). CONCLUSIONS: A subtype of PD with functional neurological features is familial in one-fourth of cases and associated with more psychiatric than motor disability and greater use of diagnostic and healthcare resources than those without functional features. Functional manifestations may be prodromal to PD in one-third of patients

Involvement of a specificity proteins-binding element in regulation of basal and estrogen-induced transcription activity of the BRCA1 gene

INTRODUCTION:Increased estrogen level has been regarded to be a risk factor for breast cancer. However, estrogen has also been shown to induce the expression of the tumor suppressor gene, BRCA1. Upregulation of BRCA1 is thought to be a feedback mechanism for controlling DNA repair in proliferating cells. Estrogens enhance transcription of target genes by stimulating the association of the estrogen receptor (ER) and related coactivators to estrogen response elements or to transcription complexes formed at activator protein (AP)-1 or specificity protein (Sp)-binding sites. Interestingly, the BRCA1 gene lacks a consensus estrogen response element. We previously reported that estrogen stimulated BRCA1 transcription through the recruitment of a p300/ER-alpha complex to an AP-1 site harbored in the proximal BRCA1 promoter. The purpose of the study was to analyze the contribution of cis-acting sites flanking the AP-1 element to basal and estrogen-dependent regulation of BRCA1 transcription.METHODS:Using transfection studies with wild-type and mutated BRCA1 promoter constructs, electromobility binding and shift assays, and DNA-protein interaction and chromatin immunoprecipitation assays, we investigated the role of Sp-binding sites and cAMP response element (CRE)-binding sites harbored in the proximal BRCA1 promoter.RESULTS:We report that in the BRCA1 promoter the AP-1 site is flanked upstream by an element (5'-GGGGCGGAA-3') that recruits Sp1, Sp3, and Sp4 factors, and downstream by a half CRE-binding motif (5'-CGTAA-3') that binds CRE-binding protein. In ER-alpha-positive MCF-7 cells and ER-alpha-negative Hela cells expressing exogenous ER-alpha, mutation of the Sp-binding site interfered with basal and estrogen-induced BRCA1 transcription. Conversely, mutation of the CRE-binding element reduced basal BRCA1 promoter activity but did not prevent estrogen activation. In combination with the AP-1/CRE sites, the Sp-binding domain enhanced the recruitment of nuclear proteins to the BRCA1 promoter. Finally, we report that the MEK1 (mitogen-activated protein kinase kinase-1) inhibitor PD98059 attenuated the recruitment of Sp1 and phosphorylated ER-alpha, respectively, to the Sp and AP-1 binding element.CONCLUSION:These cumulative findings suggest that the proximal BRCA1 promoter segment comprises cis-acting elements that are targeted by Sp-binding and CRE-binding proteins that contribute to regulation of BRCA1 transcription.This item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at [email protected]