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PubMed2025

Comprehensive clinical and genetic characterization of hyperprogressive biliary tract cancer during PD-1 blockade monotherapy: case report and literature review.

BACKGROUND: Some genetically characterized patients show the rapid disease progression during immune checkpoint inhibitors (ICIs) monotherapy, a phenomenon known as hyperprogressive disease (HPD). CASE PRESENTATION: Herein we report a relevant case of biliary tract cancer (BTC) that initially responded to gemcitabine plus oxaliplatin (GEMOX) and PD-1 blockade but subsequently developed HPD in the process of PD-1 blockade maintenance therapy, leading to death within two weeks. Genomic analysis revealed mutations in CDKN2A, PIK3CA, KRAS and EPHA2 in both baseline and hyperprogressive plasma and tumor samples. Notably, higher KRAS mutation abundance was observed in plasma and ascites after disease progression. CONCLUSIONS: These findings suggest a potential association between these negative genes especially KRAS mutation and HPD. Therefore, administration of PD-1 blockade monotherapy in this subgroup of patients harboring KRAS mutation should be performed with caution. Further studies are warranted to confirm these results and explore the correlation between genomic mutations and HPD.

Humans↗
PubMed2003

An exploratory study of the consistency of balance control and the mobility of people with Parkinson's disease (PD) between medication doses.

OBJECTIVE: To evaluate the consistency of balance control, mobility and perceived difficulties with functional tasks by people on carefully controlled anti-parkinsonian medication programmes, between doses on a single day and across days using standard clinical measures. DESIGN: Small group prospective study. SETTING: A hospital outpatient physiotherapy department. SUBJECTS: Subjects, recruited from a specialist Parkinson's disease (PD) clinic, had to be independently mobile, diagnosed with PD at least five years previously and on a stable drug regime. METHOD: Assessments (timed up and go, functional reach and a tap test) were completed 30 minutes prior to medication and hourly for 4 hours. They were repeated on a second day within a seven-day period. The self-assessment of functional disability was completed during the worst and best periods of the drug cycle. A general linear model (repeated measures analysis of variance) was used to analyse the data. RESULTS: Nine subjects (8 males) with PD (grade III Hoehn and Yahr, average duration of symptoms eight years), average age 72 years, were recruited to the study. Four subjects had worse Hoehn and Yahr scores (grade 4) during the worst phase of the L-dopa cycle. Balance and mobility data did not change significantly over the medication cycle. Tests on day 2 were similar to day 1 with only the tap test showing a significant mean difference (p = 0.02) (2.6, 95% confidence interval (CI) 0.5-4.8). Individuals perceived significantly greater difficulty (mean difference = 7.9, 95% CI 3.6-12.2) (p < 0.001) in achieving functional tasks at the end of dose than peak dose of the medication cycle. CONCLUSION: Measures of balance and mobility remained stable over the cycle. Fluctuations in the perception of difficulties with daily functional tasks were not accompanied by observed fluctuations in performance. The improvement in the mean of the tap test over the days could reflect a learning effect.

Aged↗
PubMed1999

Expression of platelet-derived endothelial cell growth factor (PD-ECGF) related to angiogenesis in ovarian endometriosis.

Platelet-derived endothelial cell growth factor (PD-ECGF) is expressed in the lining epithelial cells of ovarian endometriomas, and in interstitial cells of the subepithelial area with angiogenesis. The expression of PD-ECGF persists in endometriotic endometrium during the menstrual cycle. This might suggest that PD-ECGF contributes to the growth of ovarian endometriomas via subepithelial angiogenesis independently of the sex steroidal milieu.

Adult↗
PubMed2002

Cognitive impairments in advanced PD without dementia.

OBJECTIVE: To determine the nature and frequency of cognitive impairments in nondemented patients with advanced PD and their relationship to other variables potentially predictive of neuropsychological performance. METHODS: The neuropsychological performance of nondemented, nondepressed patients with idiopathic PD (n = 61) was quantified with respect to clinically available normative data. The relationship of neuropsychological measures to motor symptoms, age, years of education, disease duration, age at disease onset, disease deterioration rate, and dopaminergic therapy was assessed. RESULTS: Impairment was most frequent on measures sensitive to frontal lobe function (67% on Wisconsin Card Sorting Test number of categories, 30% on letter fluency, 30% on verbal learning). Poorer performance on multiple neuropsychological measures was related to greater overall motor abnormality (total Unified Parkinson's Disease Rating Scale score), increased bradykinesia on medication, older age, longer disease duration, and reduced education. CONCLUSIONS: Even in the absence of dementia or depression, patients with advanced PD are likely to show clinically significant impairments on neuropsychological measures sensitive to changes in dorsolateral prefrontal regions participating in cognitive basal ganglia-thalamocortical circuits.

Adult↗
PubMed2002

Bilateral subthalamic nucleus stimulation improves health-related quality of life in PD.

In order to assess the impact of bilateral subthalamic nucleus (STN) stimulation in PD on quality of life, the PD Quality of Life questionnaire was assessed in 60 consecutive patients with PD before surgery and 12 months after surgery. All aspects of quality of life, including motor (+48%), systemic (+34%), emotional (+29%), and social (+63%) dimensions, significantly improved with long-term STN stimulation.

Antiparkinson Agents↗
PubMed2003

Cognition following bilateral implants of embryonic dopamine neurons in PD: a double blind study.

OBJECTIVES: To determine if bilateral transplantation of embryonic mesencephalic dopamine cells into the putamen of patients with PD significantly affected their cognitive functioning when compared with patients receiving sham surgery and to examine the effect of age on cognitive performance after implantation. METHODS: Forty patients (19 women, 21 men; age 34 to 75 years) with idiopathic PD of at least 7 years' duration (mean 14 years) who had disabling motor signs despite optimal drug management were randomly assigned to tissue implants or sham craniotomies in a double-blind design. Neuropsychological tests assessing orientation, attention, language, verbal and visual memory, abstract reasoning, executive function, and visuospatial and construction abilities were administered before and 1 year after surgery. Treatment groups did not differ at baseline in demographic, neuropsychological, motor, depression, or levodopa equivalent measures. RESULTS: Postsurgical change in cognitive performance was not significantly different for real or sham surgery groups. Performance in both groups remained unchanged at follow-up for most measures. CONCLUSIONS: Embryonic dopamine producing neurons can be implanted safely into the putamen bilaterally without impairing cognition in patients with PD, but within the first year, improved cognition should not be expected.

Adult↗
PubMed2003

Assessment of a DJ-1 (PARK7) polymorphism in Finnish PD.

Mutations in DJ-1 are a cause of autosomal recessive parkinsonism. Polymorphism of genes implicated in hereditary forms of parkinsonism may be a predisposing factor in sporadic Parkinson's disease (PD). The authors analyzed whether a polymorphism (g.168_185del) within exon 1 of DJ-1 contributes to the risk of sporadic PD in a Finnish case-control series. This gene does not play a major role in the genetic predisposition to PD in this population.

Adult↗
PubMed2004

Stimulation of STN impairs aspects of cognitive control in PD.

OBJECTIVE: To test the hypothesis that subthalamic nucleus (STN) stimulation in Parkinson disease (PD) patients affects working memory and response inhibition performance, particularly under conditions of high demand on cognitive control. METHODS: To test this hypothesis, spatial working memory (spatial delayed response [SDR]) and response inhibition (Go-No-Go [GNG]) tasks requiring varying levels of cognitive control were administered to patients with PD with previously implanted bilateral STN stimulators (n = 24). Patients did not take PD medications overnight. Data were collected while bilateral stimulators were on and off, counterbalancing the order across subjects. RESULTS: On the SDR task, STN stimulation decreased patients' working memory performance under a high but not low memory load condition (effect of stimulator condition on high load only and condition x load interaction, p < 0.05). On the GNG task, STN stimulation reduced discriminability on a high but not medium inhibition condition (effect of stimulator condition on high inhibition level only, p = 0.05; condition x inhibition level interaction, p = 0.07). CONCLUSION: STN stimulation reduces working memory and response inhibition performance under conditions of greater challenge to cognitive control despite significant improvement of motor function.

Cognition Disorders↗
PubMed2005

"Applause sign" helps to discriminate PSP from FTD and PD.

The "applause sign" is a simple test of motor control that helps to differentiate PSP from frontal or striatofrontal degenerative diseases. It was found in 0/39 controls, 0 of 24 patients with frontotemporal dementia (FTD), 0 of 17 patients with Parkinson disease (PD), and 30/42 patients with progressive supranuclear palsy (PSP). It discriminated PSP from FTD (p < 0.001) and PD (p < 0.00). The "three clap test" correctly identified 81.8% of the patients in the comparison PSP and FTD and 75% of the patients in the comparison of PSP and PD.

Aged↗
PubMed2005

Medical decision-making in neurodegenerative disease: mild AD and PD with cognitive impairment.

The authors compared medical decision-making capacity in patients with mild Alzheimer disease (AD), Parkinson disease (PD) with cognitive impairment, and older controls. Relative to controls and patients with PD, patients with AD were impaired on the consent ability of understanding the medical treatment situation and choices. Patients with PD were impaired on the consent ability of electing a treatment choice.

Aged↗
PubMed1999

Loss of long-duration response to levodopa over time in PD: implications for wearing-off.

OBJECTIVE: To determine the modifications of the long-duration response to levodopa in PD over a 1-year period. BACKGROUND: The development of predictable motor fluctuations in PD has been attributed mainly to modifications over time of the short-duration response to levodopa, whereas the role of the long-duration response has not been widely investigated. METHODS: In 17 patients with PD the authors examined prospectively both the short-duration response and the long-duration response to levodopa under standardized conditions on two different occasions separated by a period of approximately 1 year (11.7 +/- 3.6 months). RESULTS: At the end of the follow-up period, the short-duration response increased in magnitude but did not change significantly in duration. A total of 24% of patients lost the long-duration response 1 year after their first examination, but a sustained long-duration response could be reestablished by shortening the interdose interval for levodopa intake. Moreover, the duration of the long-duration response after discontinuation of treatment became significantly shorter during 1 year. CONCLUSION: Modifications of the long-duration response may have a pivotal role in generating a fluctuating response, and suggest that therapeutic strategies based on maintenance of the long-duration response should be sought to avoid the appearance of motor fluctuations.

Aged↗
PubMed1999

Short-term effects of high-dose 17beta-estradiol in postmenopausal PD patients: a crossover study.

OBJECTIVE: To examine the effect of 17beta-estradiol on the severity of the cardinal signs of PD in postmenopausal women. BACKGROUND: Although the impact of estrogens on the manifestations of PD has not been subjected to rigorous study, their use is generally thought to be associated with a detrimental antidopaminergic effect. METHODS: A double-blind, placebo-controlled, two-arm crossover study of high-dose transdermal 17beta-estradiol was conducted in eight postmenopausal women with mild to moderate PD, all but one of whom exhibited levodopa-induced dyskinesias. Patients were randomized initially to either hormonal treatment or placebo for 2 weeks, followed by a 2-week washout period, and then another 2-week crossover treatment period. Active treatment employed four skin patches each releasing 0.1 mg of estradiol daily, replaced every 2 to 3 days. RESULTS: After 10 days of treatment a significant reduction was observed in the antiparkinsonian threshold dose of IV levodopa. Mean duration and magnitude of the antiparkinsonian response to threshold or high doses of levodopa were unchanged, and dyskinesia scores were unaltered during 17beta-estradiol treatment compared with placebo. No worsening in "on" time or motor ratings with estrogen treatment was documented. CONCLUSIONS: 17beta-estradiol appears to display a slight prodopaminergic (or antiparkinsonian) effect without consistently altering dyskinesias. Standard postmenopausal replacement therapy with transdermal 17beta-estradiol is likely to be well tolerated by many female parkinsonian patients.

Administration, Cutaneous↗
PubMed1999

Pharmacodynamics of the long-duration response to levodopa in PD.

OBJECTIVE: To determine the latency, magnitude, and duration of the long-duration response (LDR) to levodopa in PD in relationship to the administration of levodopa at different interdose intervals. METHODS: In six patients with PD, two different 15-day treatment regimens were used in which the drug was administered with interdose intervals of 24 or 8 hours. RESULTS: The LDR built up within a few days with either regimen, but a faster rate of administering levodopa shortened the latency to the appearance of a sustained LDR. Once a sustained response had been reached, the magnitude of the LDR showed a stable ceiling effect that was independent of the levodopa schedule. After discontinuation of treatment, the decay of the LDR was similar for both regimens. CONCLUSIONS: The system underlying the LDR to levodopa may be completely saturated when a sustained response has been fully developed. The intervals between doses of levodopa shorter than the interval effective to reach a sustained LDR should not be used in the clinical management of patients with PD because the antiparkinsonian benefit deriving from the LDR is already maximal and briefer intervals do not provide a greater benefit.

Aged↗
PubMed1999

Immediate-release and controlled-release carbidopa/levodopa in PD: a 5-year randomized multicenter study. Carbidopa/Levodopa Study Group.

OBJECTIVE: To compare effects of immediate-release (IR) and sustained-release (CR) carbidopa/levodopa in levodopa-naive PD patients. BACKGROUND: It was hypothesized that the long-acting preparation would be associated with fewer long-term complications. METHODS: A total of 618 patients were studied in 36 centers worldwide in a blinded, randomized parallel study. Measures of efficacy and adverse reactions were recorded at 3-month intervals for 5 years. Motor fluctuations and dyskinesias were evaluated by a patient diary and a physician-recorded questionnaire. The Nottingham Health Profile (NHP) was used to evaluate quality of life. RESULTS: Approximately 60% of patients completed the trial. After 5 years, the mean dose of IR was 426 mg/day, and the bioavailable dose of CR was 510 mg/day (mean dose, 736 mg/day). After 5 years, 20.6% of the IR group and 21.8% of the CR group had motor fluctuations or dyskinesia. Sixteen percent of both groups had changes in motor response by the questionnaire's definition. There was no significant difference between the two treatment groups. Disability scores and the motor score of the Unified Parkinson Disease Rating Scale (UPDRS) were highest at baseline, improved with therapy, and thereafter worsened over time to reach baseline scoring at the end of 5 years. The CR group was superior to IR for the Activities of Daily Living subsection of the UPDRS for all 5 years and for emotional reactivity and social isolation on the NHP; however, this may have resulted from higher doses of CR that were used. CONCLUSION: Despite the progressive nature of PD, both the immediate-release and sustained-release carbidopa/levodopa formulations maintained a similar level of control in PD after 5 years compared with baseline. Additionally, the low incidence of motor fluctuations or dyskinesia was not significantly different between the treatment groups and may be partly attributed to the relatively low doses of levodopa used throughout the 5-year study.

Activities of Daily Living↗
PubMed2000

Improvement of sleep architecture in PD with subthalamic nucleus stimulation.

High-frequency stimulation of the subthalamic nucleus (STN) was used to investigate the relationship of sleep disorders with motor handicap in PD. In 10 insomniac patients with PD, stimulation reduced nighttime akinesia by 60% and completely suppressed axial and early morning dystonia, but did not alleviate periodic leg movements (n = 3) or REM sleep behavior disorders (n = 5). Total sleep time increased by 47%; wakefulness after sleep onset decreased by 51 minutes. Insomnia in patients with PD may predominantly result from nighttime motor disability.

Adult↗
PubMed2001

Influence of L-dopa and pramipexole on striatal dopamine transporter in early PD.

BACKGROUND: Animal data indicate that chronic exposure to dopaminergic drugs can alter levels of the dopamine transporter (DAT), which is critically involved in regulation of synaptic dopamine levels. DAT changes could influence the response to therapy in PD. METHODS: A randomized, assessor-blinded, placebo-controlled clinical trial was performed in subjects with early PD to determine whether L-dopa or pramipexole might regulate striatal DAT binding as measured by PET with [(11)C]RTI-32. Thirty clinically asymmetrical patients were randomly assigned to receive 6 weeks of L-dopa (300/75 mg/d), pramipexole (1.5 mg/d), or placebo; PET studies were performed before and after treatment. RESULTS: Mean interval change in DAT binding was significantly reduced by 16% to 22% in all striatal regions (caudate, anterior and posterior putamen) of the L-dopa-treated patients, whereas significant changes in the pramipexole-treated patients were limited to the contralateral caudate (-15%), ipsilateral anterior putamen (-14%), and posterior putamen (-20%). In the placebo group there were significant changes in contralateral caudate (-11%) and ipsilateral anterior putamen (-12%). L-dopa and pramipexole produced similar clinical benefit. CONCLUSIONS: Short-term therapy with L-dopa and, to a lesser extent, pramipexole can modestly down-regulate striatal DAT in patients with early PD. Decreased striatal DAT could increase dopaminergic neurotransmission with potential benefit, but might also play a role in the development of dopamine-related response fluctuations in patients with advanced disease. Our data also suggest caution in interpretation of longitudinal imaging studies employing DAT to assess disease progression and the efficacy of neuroprotective agents.

Aged↗
PubMed2001

Transdermal nicotine in PD: a randomized, double-blind, placebo-controlled study.

BACKGROUND: An inverse association between cigarette smoking and the risk of idiopathic PD has been found in many epidemiologic studies. The therapeutic and possible neuroprotective effects of nicotine formulations on parkinsonian symptoms are controversial. METHODS: In a 12-week, randomized, double-blind, placebo-controlled trial, the efficacy and tolerability of transdermal nicotine patches as an add-on treatment for cardinal symptoms were evaluated in 32 nonsmoking patients with PD. After a 1-week run-in phase, patients were randomized to receive nicotine patches (containing 17.5 mg nicotine in the first and 35.0 mg nicotine in the second and third weeks) or identically appearing placebo patches. After this treatment, 3 weeks without patch application followed. The same blinded examiner assessed the patients with the Columbia University Rating Scale, the Webster scale, the Schwab-England scale, a timed walking test, with an instrumental test for fine motor skills and hand tremor, and with the Hamilton Depression Scale. RESULTS: No significant drug effects between both groups were observed in any of the scores and quantitative tests. Side effects were mild and comparable in frequency between both groups. CONCLUSIONS: With the dosage and the period of treatment chosen, transdermal nicotine patches are not effective as an add-on treatment for symptoms of PD.

Administration, Cutaneous↗
PubMed2002

Predictors of effective bilateral subthalamic nucleus stimulation for PD.

To identify factors predictive of effective bilateral subthalamic nucleus (STN) stimulation for PD with severe motor complications, pre- and postoperative Unified PD Rating Scale (UPDRS) scores were analyzed in a series of 54 patients who received bilateral STN stimulation. Younger age and levodopa responsiveness predict a favorable response to bilateral STN stimulation. For individual PD symptoms, those that improve with a suprathreshold dose levodopa challenge are likely to improve with stimulation.

Adult↗