Predictors of the change in burden, strain, mood, and quality of life among caregivers of Parkinson's disease patients.

BACKGROUND AND OBJECTIVE: Caregiver burden in Parkinson's disease (PD) has been studied in many cross-sectional studies but poorly in longitudinal ones. The aim of the present study was to analyze the change in burden, strain, mood, and quality of life (QoL) after a 2-year follow-up in a cohort of caregivers of patients with PD and also to identify predictors of these changes. PATIENTS AND METHODS: PD patients and their caregivers who were recruited from January/2016 to November/2017 from 35 centers of Spain from the COPPADIS cohort were included in the study. They were evaluated again at 2-year follow-up. Caregivers completed the Zarit Caregiver Burden Inventory (ZCBI), Caregiver Strain Index (CSI), Beck Depression Inventory-II (BDI-II), and EUROHIS-QOL 8-item index (EUROHIS-QOL8) at baseline (V0) and at 2-year follow-up (V2). General linear model repeated measure and lineal regression models were applied. RESULTS: Significant changes, indicating an impairment, were detected on the total score of the ZCBI (p < 0.0001), CSI (p < 0.0001), BDI-II (p = 0.024), and EUROHIS-QOL8 (p = 0.002) in 192 PD caregivers (58.82 ± 11.71 years old; 69.3% were females). Mood impairment (BDI-II; ß = 0.652; p < 0.0001) in patients from V0 to V2 was the strongest factor associated with caregiver's mood impairment after the 2-year follow-up. Caregiver's mood impairment was the strongest factor associated with an increase from V0 to V2 on the total score of the ZCBI (ß = 0.416; p < 0.0001), CSI (ß = 0.277; p = 0.001), and EUROHIS-QOL (ß = 0.397; p = 0.002). CONCLUSION: Burden, strain, mood, and QoL were impaired in caregivers of PD patients after a 2-year follow-up. Mood changes in both the patient and the caregiver are key aspects related to caregiver burden increase.

Safinamide improves sleep and daytime sleepiness in Parkinson's disease: results from the SAFINONMOTOR study.

BACKGROUND AND OBJECTIVE: Some studies observed a benefit of PD patients after treatment with safinamide in some non-motor symptoms. Our aim was to analyze the effectiveness of safinamide on sleep and daytime sleepiness in Parkinson's disease (PD) patients. MATERIAL AND METHODS: SAFINONMOTOR is a prospective open-label single-arm study conducted in 5 centers from Spain. In this analysis, a secondary objective of the study, the score in the Pittsburgh Sleep Quality Index (PSQI) and the Epworth Sleepiness Scale (ESS) at V1 (baseline) and V4 (6 months ± 1 month) were compared. RESULTS: Fifty patients were included between May/2019 and February/2020 (age 68.5 ± 9.12 years; 58% women; 6.4 ± 5.1 years from diagnosis). At 6 months, 44 patients completed the follow-up (88%). The PSQI total score was reduced by 19.8% (from 10.43 ± 4.02 at V1 to 8.36 ± 4.41 at V4; p = 0.001). By domains, improvement was observed in subjective sleep quality (PSQI-C1; - 23.9%; p = 0.009), sleep latency (PSQI-C2; - 25%; p = 0.025), sleep duration (PSQI-C3; - 40%; p = 0.001), and habitual sleep efficiency (PSQI-C4; - 25.9%; p = 0.023). A significant reduction (- 24.7%) in the ESS total score from V1 to V4 was observed as well (from 9.20 ± 5.64 to 6.93 ± 5.11; p = 0.012). Specifically, the improvement in daytime sleepiness was observed in sitting and reading (p = 0.024) and sitting inactive in a public space (p = 0.027). A total of 21 adverse events in 11 patients (22%) were reported, 5 of which were severe (not related to safinamide). CONCLUSION: Safinamide was well-tolerated and improved sleep and daytime sleepiness in PD patients at 6 months.

Molecular effects of lapatinib in patients with HER2 positive ductal carcinoma in situ.

INTRODUCTION: Human epidermal growth factor receptor 2 (HER2) amplification is frequent in ductal carcinoma in situ (DCIS) of the breast and is associated with poorly differentiated tumors and adverse prognosis features. This study aimed to determine the molecular effects of the HER2 inhibitor lapatinib in patients with HER2 positive DCIS. METHODS: Patients with HER2 positive DCIS received 1,500 mg daily of lapatinib for four consecutive weeks prior to surgical resection. Magnetic resonance imaging (MRI) was used to determine changes in tumor volume. The molecular effects of lapatinib on HER2 signaling (PI3K/AKT and RAS/MAPK pathways), cell proliferation (Ki67 and p27) and apoptosis (TUNEL) were determined in pre and post-lapatinib treatment samples. RESULTS: A total of 20 patients were included. Lapatinib was well tolerated with only minor and transient side effects. The agent effectively modulated HER2 signaling decreasing significantly pHER2 and pERK1 expression, together with a decrease in tumor size evaluated by MRI. There was no evidence of changes in Ki67. CONCLUSIONS: Four weeks of neoadjuvant lapatinib in patients with HER2-positive DCIS resulted in inhibition of HER2 and RAS/MAPK signaling pathway. TRIAL REGISTRATION: 2008-004492-21 (Registered June 25th 2008).

High CAR intensity of expression confers enhanced antitumor effect against lymphoma without functional exhaustion.

Identifying factors that ameliorates clinical outcomes following CART therapy represents an unmet need. We hypothesized that CAR expression level would have a significant impact on CART efficacy and tested this with CAR30+ TSCM-LIKE enriched cells. By sorting T-cells according to CAR mean fluorescence intensity in two markedly different populations (CARHI and CARLO), we showed that a high CAR expression enhances antitumor efficacy in vitro, that is sustained after sequential re-exposures to tumor cells and is not associated with T-cell exhaustion or differentiation. Furthermore, we found a correlation between high surface CAR expression and antitumor effect with CAR19+ T-cells, thus validating our findings with CAR30. Definitive proof of CARHI T-cells improved antitumor efficacy was demonstrated in a human Hodgkin's lymphoma xenograft mouse model, where CAR30-TSCM-LIKE enriched products with high intensity of CAR expression achieved superior tumor control in vivo and longer survival than those with a low intensity of CAR expression. Our data suggest that modulation of CAR intensity of expression represents an additional strategy to increase CART therapy clinical efficacy.

Risk of Cognitive Impairment in Patients With Parkinson's Disease With Visual Hallucinations and Subjective Cognitive Complaints.

BACKGROUND AND PURPOSE: Visual hallucinations (VH) and subjective cognitive complaints (SCC) are associated with cognitive impairment (CI) in Parkinson's disease. Our aims were to determine the association between VH and SCC and the risk of CI development in a cohort of patients with Parkinson's disease and normal cognition (PD-NC). METHODS: Patients with PD-NC (total score of >80 on the Parkinson's Disease Cognitive Rating Scale [PD-CRS]) recruited from the Spanish COPPADIS cohort from January 2016 to November 2017 were followed up after 2 years. Subjects with a score of ≥1 on domain 5 and item 13 of the Non-Motor Symptoms Scale at baseline (V0) were considered as "with SCC" and "with VH," respectively. CI at the 2-year follow-up (plus or minus 1 month) (V2) was defined as a PD-CRS total score of <81. RESULTS: At V0 (n=376, 58.2% males, age 61.14±8.73 years [mean±SD]), the frequencies of VH and SCC were 13.6% and 62.2%, respectively. VH were more frequent in patients with SCC than in those without: 18.8% (44/234) vs 4.9% (7/142), p<0.0001. At V2, 15.2% (57/376) of the patients had developed CI. VH presenting at V0 was associated with a higher risk of CI at V2 (odds ratio [OR]=2.68, 95% confidence interval=1.05-6.83, p=0.0.039) after controlling for the effects of age, disease duration, education, medication, motor and nonmotor status, mood, and PD-CRS total score at V0. Although SCC were not associated with CI at V2, presenting both VH and SCC at V0 increased the probability of having CI at V2 (OR=3.71, 95% confidence interval=1.36-10.17, p=0.011). CONCLUSIONS: VH were associated with the development of SCC and CI at the 2-year follow-up in patients with PD-NC.

Identification of Two Eosinophil Subsets in Induced Sputum from Patients with Allergic Asthma According to CD15 and CD66b Expression.

Two subsets of eosinophils have been described: resident eosinophils with homeostatic functions (rEOS) in healthy subjects and in patients with nonallergic eosinophilic asthma, and inflammatory eosinophils (iEOS) in blood and lung samples from patients with allergic asthma. We explored if it would be possible to identify different subsets of eosinophils using flow cytometry and the gating strategy applied to induced sputum. We conducted an observational cross-sectional single-center study of 62 patients with persistent allergic asthma. Inflammatory cells from induced sputum samples were counted by light microscopy and flow cytometry, and cytokine levels in the supernatant were determined. Two subsets of eosinophils were defined that we call E1 (CD66b-high and CD15-high) and E2 (CD66b-low and CD15-low). Of the 62 patients, 24 were eosinophilic, 18 mixed, 10 paucigranulocytic, and 10 neutrophilic. E1 predominated over E2 in the eosinophilic and mixed patients (20.86% vs. 6.27% and 14.42% vs. 4.31%, respectively), while E1 and E2 were similar for neutrophilic and paucigranulocytic patients. E1 correlated with IL-5, fractional exhaled nitric oxide, and blood eosinophils. While eosinophil subsets have been identified for asthma in blood, we have shown that they can also be identified in induced sputum.

Motor Fluctuations Development Is Associated with Non-Motor Symptoms Burden Progression in Parkinson's Disease Patients: A 2-Year Follow-Up Study.

Objective: The aim of the present study was to analyze the progression of non-motor symptoms (NMS) burden in Parkinson's disease (PD) patients regarding the development of motor fluctuations (MF). Methods: PD patients without MF at baseline, who were recruited from January 2016 to November 2017 (V0) and evaluated again at a 2-year follow-up (V2) from 35 centers of Spain from the COPPADIS cohort, were included in this analysis. MF development at V2 was defined as a score ≥ 1 in the item-39 of the UPDRS-Part IV, whereas NMS burden was defined according to the Non-motor Symptoms Scale (NMSS) total score. Results: Three hundred and thirty PD patients (62.67 ± 8.7 years old; 58.8% males) were included. From V0 to V2, 27.6% of the patients developed MF. The mean NMSS total score at baseline was higher in those patients who developed MF after the 2-year follow-up (46.34 ± 36.48 vs. 34.3 ± 29.07; p = 0.001). A greater increase in the NMSS total score from V0 to V2 was observed in patients who developed MF (+16.07 ± 37.37) compared to those who did not develop MF (+6.2 ± 25.8) (p = 0.021). Development of MF after a 2-year follow-up was associated with an increase in the NMSS total score (ß = 0.128; p = 0.046) after adjustment to age, gender, years from symptoms onset, levodopa equivalent daily dose (LEDD) and the NMSS total score at baseline, and the change in LEDD from V0 to V2. Conclusions: In PD patients, the development of MF is associated with a greater increase in the NMS burden after a 2-year follow-up.

Parkinson's Disease Motor Subtypes Change with the Progression of the Disease: Results from the COPPADIS Cohort at 2-Year Follow-Up.

BACKGROUND: Motor phenotype (MP) can be associated with a different prognosis in Parkinson's disease (PD), but it is not fixed and can change over time. OBJECTIVE: Our aim was to analyze how the MP changed over time and to identify factors associated with the changes in PD patients from a multicenter Spanish PD cohort. METHODS: PD patients who were recruited from January-2016 to November-2017 (baseline visit; V0) and evaluated again at a 2-year±30 days follow-up (V2) from 35 centers of Spain from the COPPADIS cohort, were included in this study.MP was calculated at both visits based on Jankovic classification in TD (tremor dominant), IND (indeterminate), or PIGD (postural instability and gait difficulty). Sociodemographic and clinical data were collected, including serum biomarkers. RESULTS: Five hundred eleven patients (62.57±8.59 years old; 59.2%males) were included in the study. At V0, MP was: 47.4%(242/511) TD; 36.6%(187/511) PIGD; 16%(82/511) IND. Up to 38%(194/511) of the patients changed their phenotype from V0 to V2, being the most frequent from TD to IND (8.4%) and from TD to PIGD (6.7%). A worse cognitive status (OR = 0.966) and less autonomy for activities of daily living (OR  =  0.937) at V0 and a greater increase in the globalNMS burden (OR  =  1.011) from V0 to V2 were associated with changing from TD to another phenotype after 2-year follow-up. CONCLUSION: The MP in PD can change over time. With disease progression, the percentage of cases with non-tremoric MP increases. PD patients who changed from TD to postural instability and gait difficulty increased NMS burden significantly.

Constipation Predicts Cognitive Decline in Parkinson's Disease: Results from the COPPADIS Cohort at 2-Year Follow-up and Comparison with a Control Group.

BACKGROUND: Constipation has been linked to cognitive impairment development in Parkinson's disease (PD). OBJECTIVE: Our aim was to analyze cognitive changes observed in PD patients and controls from a Spanish cohort with regards to the presence or not of constipation. METHODS: PD patients and controls recruited from 35 centers of Spain from the COPPADIS cohort from January 2016 to November 2017 were followed-up during 2 years. The change in cognitive status from baseline (V0) to 2-year follow-up was assessed with the PD-CRS (Parkinson's Disease Cognitive Rating Scale). Subjects with a score ≥1 on item 21 of the NMSS (Non-Motor Symptoms Scale) at baseline (V0) were considered as "with constipation". Regression analyses were applied for determining the contribution of constipation in cognitive changes. RESULTS: At V0, 39.7% (198/499) of PD patients presented constipation compared to 11.4% of controls (14/123) (p < 0.0001). No change was observed in cognitive status (PD-CRS total score) neither in controls without constipation (from 100.24±13.72 to 100.27±13.68; p = 0.971) and with constipation (from 94.71±10.96 to 93.93±13.03; p = 0.615). The PD-CRS total score decreased significantly in PD patients with constipation (from 89.14±15.36 to 85.97±18.09; p < 0.0001; Coehn's effect = -0.35) compared to patients without constipation (from 93.92±15.58 to 93.14±17.52; p = 0.250) (p = 0.018). In PD patients, to suffer from constipation at V0 was associated with a decrease in the PD-CRS total score from V0 to V2 (ß= -0.1; 95% CI, -4.36 - -0.27; p = 0.026) and having cognitive impairment at V2 (OR = 1.79; 95% CI, 1.01 - 3.17; p = 0.045). CONCLUSION: Constipation is associated with cognitive decline in PD patients but not in controls.

Safinamide Improves Non-Motor Symptoms Burden in Parkinson's Disease: An Open-Label Prospective Study.

Some studies observed a benefit of Parkinson's disease (PD) patients after treatment with safinamide in some non-motor symptoms (NMSs). The aim of this study was to analyze the effectiveness of safinamide on NMS burden in PD. SAFINONMOTOR (an open-label study of the effectiveness of safinamide on non-motor symptoms in Parkinson's disease patients) is a prospective open-label single-arm study conducted in five centers from Spain. The primary efficacy outcome was the change from baseline (V1) to the end of the observational period (6 months) (V4) in the non-motor symptoms scale (NMSS) total score. Between May/2019 and February/2020 50 patients were included (age 68.5 ± 9.12 years; 58% females; 6.4 ± 5.1 years from diagnosis). At 6 months, 44 patients completed the follow-up (88%). The NMSS total score was reduced by 38.5% (from 97.5 ± 43.7 in V1 to 59.9 ± 35.5 in V4; p < 0.0001). By domains, improvement was observed in sleep/fatigue (-35.8%; p = 0.002), mood/apathy (-57.9%; p < 0.0001), attention/memory (-23.9%; p = 0.026), gastrointestinal symptoms (-33%; p = 0.010), urinary symptoms (-28.3%; p = 0.003), and pain/miscellaneous (-43%; p < 0.0001). Quality of life (QoL) also improved with a 29.4% reduction in the PDQ-39SI (from 30.1 ± 17.6 in V1 to 21.2 ± 13.5 in V4; p < 0.0001). A total of 21 adverse events in 16 patients (32%) were reported, 5 of which were severe (not related to safinamide). Dyskinesias and nausea were the most frequent (6%). Safinamide is well tolerated and improves NMS burden and QoL in PD patients with severe or very severe NMS burden at 6 months.

Pain Improvement in Parkinson's Disease Patients Treated with Safinamide: Results from the SAFINONMOTOR Study.

BACKGROUND AND OBJECTIVE: Pain is a frequent and disabling symptom in Parkinson's disease (PD) patients. Our aim was to analyze the effectiveness of safinamide on pain in PD patients from the SAFINONMOTOR (an open-label study of the effectiveness of SAFInamide on NON-MOTOR symptoms in Parkinson´s disease patients) study. MATERIAL AND METHODS: SAFINONMOTOR is a prospective open-label single-arm study conducted in five centers from Spain. In this analysis, a secondary objective of the study, the score in the KPPS (King´s Parkinson´s Disease Pain Scale) at V1 (baseline) and V4 (6 months ± 1 month) were compared. Wilcoxon´s rank sum test was performed to test the changes from V1 to V4. RESULTS: Forty-four (88%) out of 50 PD patients (age 68.5 ± 9.12 years; 58% women; 6.4 ± 5.1 years from diagnosis) completed the study. The KPPS total score was reduced by 43.6% (from 40.04 ± 36.18 in V1 to 22.60 ± 21.42 in V4; p < 0.0001). By domains, improvement was observed in musculoskeletal (-35.9%; p = 0.009), fluctuation-related (-51.7%; p = 0.020), nocturnal (-46.1%; p = 0.001), discoloration and/or edema/swelling (-50.4%; p = 0.009) and radicular pain (-40.1%; p = 0.048). A total of 21 adverse events in 11 patients (22%) were reported, five being severe, but not related to safinamide. CONCLUSION: Safinamide is well tolerated and improves pain in PD patients at 6 months. Future studies are necessary to analyze the possible beneficial effect of safinamide on pain in PD patients.

Effectiveness of Safinamide over Mood in Parkinson's Disease Patients: Secondary Analysis of the Open-label Study SAFINONMOTOR.

INTRODUCTION: Mood disorders are frequent in Parkinson's disease (PD) and a favorable effect of safinamide on mood has been observed. We aimed to analyze the effectiveness of safinamide on mood as a secondary objective from the SAFINONMOTOR (an open-label study of the effectiveness of SAFInamide on NON-MOTOR symptoms in patients with Parkinson's disease) study. METHODS: SAFINONMOTOR is a prospective open-label single-arm study conducted in five centers from Spain. Patients with PD were required to have at baseline a Non-Motor Symptoms Scale (NMSS) total score of at least 40. In this analysis, the changes from V1 (baseline) to V4 (6 months ± 1 month) in the BDI-II (Beck Depression Inventory-II), NMSS mood/apathy domain, and PDQ-39 (Parkinson's Disease Questionnaire-39) emotional well-being domain were analyzed. Depression was identified and classified (DSM-IV and Judd criteria) at baseline and at the end of follow-up as major depression (MD), minor depression (mD), subthreshold depression (subD), and non-depression (nonD). RESULTS: Fifty patients with PD were included (age 68.5 ± 9.12 years; 58% women; 6.4 ± 5.1 years from diagnosis) and 44 patients (88%) completed the follow-up at 6 months. The BDI-II total score was reduced by 35.9% (from 15.88 ± 10.46 at V1 to 10.18 ± 6.76 at V4; p < 0.0001). A significant decrease in the NMSS mood/apathy domain and PDQ-39 emotional well-being domain was observed as well (p < 0.0001). At baseline, 52% of the patients presented MD, 34% mD, 12% subD, and 2% nonD whereas at V4 the percentages were 31.8%, 34.1%, 22.7%, and 11.4%, respectively (p = 0.029). CONCLUSIONS: Safinamide improves mood in patients with PD at 6 months.

Memory stem T cells modified with a redesigned CD30-chimeric antigen receptor show an enhanced antitumor effect in Hodgkin lymphoma.

OBJECTIVES: Adoptive cell therapy (ACT) with mature T cells modified with a chimeric antigen receptor has demonstrated improved outcome for B-cell malignancies. However, its application for others such as Hodgkin lymphoma remains a clinical challenge. CD30 antigen, expressed in Hodgkin lymphoma cells, is absent in most healthy tissues, representing an ideal target of ACT for this disease. Despite that, efficacy of CD30-chimeric antigen receptor (CAR) T cells for Hodgkin lymphoma remains modest. Here, we have developed and tested a novel CD30-CAR T to improve efficacy of CD30-CAR therapy, using a targeting epitope within the non-cleavable part of CD30 receptor, and memory stem T cells (TSCM) to improve engraftment, persistence and antitumor activity. METHODS: TSCM-like cultures were generated and expanded ex vivo and transduced at day 1 or 2 with a lentiviral vector encoding the CD30-CAR. Therapeutic in vivo experiments were performed using NSG mice injected with L540 (sc) or L428 (iv) and treated with CD30-CAR T cells when the tumor was established. RESULTS: CD30-CAR TSCM-like cells generated and expanded ex vivo, despite CD30 expression and fratricide killing of CD30+ CAR T cells, were not impaired by soluble CD30 and completely eradicated Hodgkin lymphoma in vivo, showing high persistence and long-lasting immunity. In addition, highly enriched CD30-CAR TSCM-like products confer a survival advantage in vivo, in contrast to more differentiated CAR T cells, with higher tumor infiltration and enhanced antitumor effect. CONCLUSION: This study supports the use of a refined CD30-CAR T cells with highly enriched TSCM-like products to improve clinical efficacy of CAR T for Hodgkin lymphoma.

Predictors of Loss of Functional Independence in Parkinson's Disease: Results from the COPPADIS Cohort at 2-Year Follow-Up and Comparison with a Control Group.

BACKGROUND AND OBJECTIVE: The aim of this study was to compare the progression of independence in activities of daily living (ADL) in Parkinson's disease (PD) patients versus a control group, as well as to identify predictors of disability progression and functional dependency (FD). PATIENTS AND METHODS: PD patients and control subjects, who were recruited from 35 centers of Spain from the COPPADIS cohort between January 2016 and November 2017 (V0), were included. Patients and subjects were then evaluated again at the 2-year follow-up (V2). Disability was assessed with the Schwab & England Activities of Daily Living Scale (S&E-ADLS) at V0 and V2. FD was defined as an S&E-ADLS score less than 80%. RESULTS: In the PD group, a significant decrease in the S&E-ADLS score from V0 to V2 (N = 507; from 88.58 ± 10.19 to 84.26 ± 13.38; p < 0.0001; Cohen's effect size = -0.519) was observed but not in controls (N = 124; from 98.87 ± 6.52 to 99.52 ± 2.15; p = 0.238). When only patients considered functional independent at baseline were included, 55 out of 463 (11.9%) converted to functional dependent at V2. To be a female (OR = 2.908; p = 0.009), have longer disease duration (OR = 1.152; p = 0.002), have a non-tremoric motor phenotype at baseline (OR = 3.574; p = 0.004), have a higher score at baseline in FOGQ (OR = 1.244; p < 0.0001) and BDI-II (OR = 1.080; p = 0.008), have a lower score at baseline in PD-CRS (OR = 0.963; p = 0.008), and have a greater increase in the score from V0 to V2 in UPDRS-IV (OR = 1.168; p = 0.0.29), FOGQ (OR = 1.348; p < 0.0001) and VAFS-Mental (OR = 1.177; p = 0.013) (adjusted R-squared 0.52; Hosmer and Lemeshow test = 0.94) were all found to be independent predictors of FD at V2. CONCLUSIONS: In conclusion, autonomy for ADL worsens in PD patients compared to controls. Cognitive impairment, gait problems, fatigue, depressive symptoms, more advanced disease, and a non-tremor phenotype are independent predictors of FD in the short-term.

Predictors of Global Non-Motor Symptoms Burden Progression in Parkinson's Disease. Results from the COPPADIS Cohort at 2-Year Follow-Up.

Background and Objective: Non-motor symptoms (NMS) progress in different ways between Parkinson's disease (PD) patients. The aim of the present study was to (1) analyze the change in global NMS burden in a PD cohort after a 2-year follow-up, (2) to compare the changes with a control group, and (3) to identify predictors of global NMS burden progression in the PD group. Material and Methods: PD patients and controls, recruited from 35 centers of Spain from the COPPADIS cohort from January 2016 to November 2017, were followed-up with after 2 years. The Non-Motor Symptoms Scale (NMSS) was administered at baseline (V0) and at 24 months ± 1 month (V2). Linear regression models were used for determining predictive factors of global NMS burden progression (NMSS total score change from V0 to V2 as dependent variable). Results: After the 2-year follow-up, the mean NMS burden (NMSS total score) significantly increased in PD patients by 18.8% (from 45.08 ± 37.62 to 53.55 ± 42.28; p < 0.0001; N = 501; 60.2% males, mean age 62.59 ± 8.91) compared to no change observed in controls (from 14.74 ± 18.72 to 14.65 ± 21.82; p = 0.428; N = 122; 49.5% males, mean age 60.99 ± 8.32) (p < 0.0001). NMSS total score at baseline (ß = -0.52), change from V0 to V2 in PDSS (Parkinson's Disease Sleep Scale) (ß = -0.34), and change from V0 to V2 in NPI (Neuropsychiatric Inventory) (ß = 0.25) provided the highest contributions to the model (adjusted R-squared 0.41; Durbin-Watson test = 1.865). Conclusions: Global NMS burden demonstrates short-term progression in PD patients but not in controls and identifies worsening sleep problems and neuropsychiatric symptoms as significant independent predictors of this NMS progression.

Predictors of clinically significant quality of life impairment in Parkinson's disease.

Quality of life (QOL) plays an important role in independent living in Parkinson's disease (PD) patients, being crucial to know what factors impact QoL throughout the course of the disease. Here we identified predictors of QoL impairment in PD patients from a Spanish cohort. PD patients recruited from 35 centers of Spain from the COPPADIS cohort from January 2016, to November 2017, were followed up during 2 years. Health-related QoL (HRQoL) and global QoL (GQoL) were assessed with the 39-item Parkinson's disease Questionnaire (PDQ-39) and the EUROHIS-QOL 8-item index (EUROHIS-QOL8), respectively, at baseline (V0) and at 24 months ± 1 month (V2). Clinically significant QoL impairment was defined as presenting an increase (PDQ-39SI) or decrement (EUROHIS-QOL8) at V2 ≥ 10% of the score at baseline (V0). A comparison with a control group was conducted for GQoL. GQoL did not change significantly in PD patients (N = 507; p = 0.686) or in the control group (N = 119; p = 0.192). The mean PDQ-39SI was significantly increased in PD patients (62.7 ± 8.5 years old; 58.8% males; N = 500) by 21.6% (from 16.7 ± 13 to 20.3 ± 16.4; p < 0.0001) at V2. Ninety-three patients (18.6%) presented a clinically significant HRQoL impairment at V2. To be younger (OR = 0.896; 95% CI 0.829-0.968; p = 0.006), to be a female (OR = 4.181; 95% CI 1.422-12.290; p = 0.009), and to have a greater increase in BDI-II (Beck Depression Inventory-II) (OR = 1.139; 95% CI 1.053-1.231; p = 0.001) and NMSS (Non-Motor Symptoms Scale) (OR = 1.052; 95% CI 1.027-1.113; p < 0.0001) total scores from V0 to V2 were associated with clinically significant HRQoL impairment at the 2-year follow-up (Hosmer-Lemeshow test, p = 0.665; R2 = 0.655). An increase in ≥5 and ≥10 points of BDI-II and NMSS total score at V2 multiplied the probability of presenting clinically significant HRQoL impairment by 5 (OR = 5.453; 95% CI 1.663-17.876; p = 0.005) and 8 (OR = 8.217; 95% CI, 2.975-22.696; p = 0.002), respectively. In conclusion, age, gender, mood, and non-motor impairment were associated with clinically significant HRQoL impairment after the 2-year follow-up in PD patients.

Diplopia Is Frequent and Associated with Motor and Non-Motor Severity in Parkinson's Disease: Results from the COPPADIS Cohort at 2-Year Follow-Up.

BACKGROUND AND OBJECTIVE: Diplopia is relatively common in Parkinson's disease (PD) but is still understudied. Our aim was to analyze the frequency of diplopia in PD patients from a multicenter Spanish cohort, to compare the frequency with a control group, and to identify factors associated with it. PATIENTS AND METHODS: PD patients who were recruited from January 2016 to November 2017 (baseline visit; V0) and evaluated again at a 2-year ± 30 days follow-up (V2) from 35 centers of Spain from the COPPADIS cohort were included in this longitudinal prospective study. The patients and controls were classified as "with diplopia" or "without diplopia" according to item 15 of the Non-Motor Symptoms Scale (NMSS) at V0, V1 (1-year ± 15 days), and V2 for the patients and at V0 and V2 for the controls. RESULTS: The frequency of diplopia in the PD patients was 13.6% (94/691) at V0 (1.9% in controls [4/206]; p < 0.0001), 14.2% (86/604) at V1, and 17.1% (86/502) at V2 (0.8% in controls [1/124]; p < 0.0001), with a period prevalence of 24.9% (120/481). Visual hallucinations at any visit from V0 to V2 (OR = 2.264; 95%CI, 1.269-4.039; p = 0.006), a higher score on the NMSS at V0 (OR = 1.009; 95%CI, 1.012-1.024; p = 0.015), and a greater increase from V0 to V2 on the Unified Parkinson's Disease Rating Scale-III (OR = 1.039; 95%CI, 1.023-1.083; p < 0.0001) and Neuropsychiatric Inventory (OR = 1.028; 95%CI, 1.001-1.057; p = 0.049) scores were independent factors associated with diplopia (R2 = 0.25; Hosmer and Lemeshow test, p = 0.716). CONCLUSIONS: Diplopia represents a frequent symptom in PD patients and is associated with motor and non-motor severity.

Biweekly docetaxel and gemcitabine as neoadjuvant chemotherapy in stage II and III breast cancer patients: preliminary results of a phase II and pharmacogenomic study.

The purpose of this study is to evaluate the efficacy and safety of a biweekly neoadjuvant docetaxel/gemcitabine regimen in patients with histologically confirmed stage II and III breast cancer. In addition, a cDNA microarray study attempted to correlate pretreatment gene-expression profile with clinical and pathologic responses. Docetaxel 65 mg/m(2) was given in a 60-minute intravenous infusion followed by gemcitabine 2,500 mg/m(2) in a 30-minute intravenous infusion every 2 weeks for six cycles; prophylaxis with growth factors was allowed. Four cycles of standard AC (doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2)every 21 days) was routinely delivered to all patients postsurgery. Thirty patients are accrued on-study so far. The overall response rate for 24 evaluable patients was 79% (95% confidence interval, 9.7 to 53.5) with six complete responses and 13 partial responses. One patient (4%) out of 23 achieved a pathologic complete response in the breast at the time of definitive surgery. Breast conservation procedure was possible in 14 patients (61%). A total of 161 cycles has been delivered. Grade 1/2 alopecia and a mild grade 1/2 LDH increase were the most frequently reported adverse events (78% and 55% of cycles, respectively). Grade 3/4 neutropenia was reported in 18 cycles (11%). These preliminary results show that biweekly docetaxel and gemcitabine is an optimal regimen as neoadjuvant treatment of stage II and III breast cancer. In spite of the large tumor size, breast conservation was possible in 61% of the patients. In general, toxicity was very manageable.

Current perspectives of treatment of ductal carcinoma in situ.

DCIS is a genetically diverse group of diseases with different prognosis. The similarities between DCIS and ductal infiltrating carcinoma (DIC) suggest that the key step in tumorigenesis is the transformation from high grade ductal hyperplasia to DCIS. The prognostic factors of DCIS include anatomo-pathologic factors, age and molecular factors. The key questions for DCIS management include: which patients are more likely to present an invasive failure; in which an excision is sufficient and who can be spared from radiation therapy. The role of post operative radiation therapy to reduce by 50-60% ipsilateral invasive and non-invasive local failure has been established in four randomized clinical trials. The question whether radiation therapy can be avoided in some patients remains controversial. Treatment with tamoxifen should be recommended to patients with estrogen receptor positive tumors who have been treated with conservative surgery. However, data from randomized trials suggest that addition of tamoxifen to locoregional treatment decreases the recurrence rate of invasive cancer as well as contralateral tumors. Sentinel lymph node biopsy is recommended for patients with clinically palpable, large DCIS in which the risk of microinvasion is high as well as in extensive DCIS requiring mastectomy. Mammography continues to be the best method to detect DCIS. Newer digital mammography improves the detection of microcalcifications. Current ultrasound can detect associated invasive cancer. MRI is also useful in DCIS. Combined with mammography, MRI increases the diagnoses of DCIS. Current trend includes the use of radiology guided-vacuum assisted-large bore needles that allow obtaining larger amounts of tissue, improving diagnostic yield.