A single centre prospective study of three device-assisted therapies for Parkinson's disease.

Comparative studies assessing outcomes with the three device-assisted therapies could help to individualise treatment for patients living with Parkinson's disease. We designed a single-centre non-randomised prospective observational study assessing the quality of life (QoL), motor and non-motor outcomes at 6 and 12-months in patients treated with subcutaneous apomorphine continuous 16-hours infusion (APO), levodopa-carbidopa intestinal gel (LCIG) or subthalamic nucleus deep brain stimulation (STN-DBS). In this study, 66 patients were included (13 APO; 19 LCIG; 34 STN-DBS). At baseline, cognitive, non-motor and motor scores were significantly less severe in the STN-DBS group, whereas the LCIG group had a longer disease duration and higher non-motor scores. In the APO group, there were no statistically significant changes in non-motor, motor and QoL scales. The LCIG group had significant changes in QoL and motor scales that were significant after multiple comparison analysis at 6 and 12-months. The STN-DBS group showed improvement in QoL scores and non-motor and motor scores at 6 and 12-months after multiple comparison analysis. In this real-life prospective study, device-assisted therapies showed differences in their effects on QoL and motor and non-motor function at 12-months. However, there were also differences in baseline characteristics of the patient groups that were not based on pre-determined selection criteria. Differences in characteristics of patients offered and/or treatment with different device-assisted therapies may reflect within-centre biases that may, in turn, influence perceptions of treatment efficacy or outcomes. Treatment centres should be aware of this potential confounder when assessing and offering device-assisted treatment options to their patients and potential baseline differences need to be taken into consideration when comparing the results of non-randomised studies.

Challenges in managing late-stage Parkinson's disease: Practical approaches and pitfalls.

BACKGROUND: Parkinson's disease is a universally progressive neurodegenerative disease. People living with Parkinson's disease for many years face progression from early- to mid- to late-stage Parkinson's disease (LSPD). While levodopa-responsive, predominantly motor features constitute the majority of symptom burden in early-stage Parkinson's disease, the disability in LSPD is characterised mainly by non-motor symptoms, which may be poorly levodopa responsive. OBJECTIVE: The aim of this article is to discuss recognition of LSPD and suggest strategies that may assist patients with LSPD in the community. DISCUSSION: The milestones of frequent falls, cognitive dysfunction, hallucinations and the need for residential care signal LSPD and predict time to death. Treatment aims shift to focus on patient comfort and conscientious prevention of exacerbations. In this article, challenges such as autonomic dysregulation, pain, cognitive decline and psychosis are addressed. These authors advocate a holistic approach, including supporting not only the patient with LSPD but also their carers.

Oncogene Overlap Analysis of Circulating Cell-free Tumor DNA to Explore the Appropriate Criteria for Defining MET Copy Number-Driven Lung Cancer.

INTRODUCTION: Defining clinically relevant MET amplification levels in non-small cell lung cancer (NSCLC) remains challenging. We hypothesize that oncogene overlap and MET amplicon size decline with increase in MET plasma copy number (pCN), thus enriching for MET-dependent states. PATIENTS AND METHODS: We interrogated cell-free DNA NGS results of 16,782 patients with newly diagnosed advanced NSCLC to identify those with MET amplification as reported using Guardant360. Co-occurring genomic mutations and copy number alterations within each sample were evaluated. An exploratory method of adjusting for tumor fraction was also performed and amplicon size for MET was analyzed when available. RESULTS: MET amplification was detected in 207 (1.2%) of samples. pCN ranged from 2.1 to 52.9. Of these, 43 (20.8%) had an overlapping oncogenic driver, including 23 (11.1%) METex14 skipping or other MET mutations. The degree of (non-MET) oncogene overlap decreased with increases in pCN. Patients with MET pCN ≥ 2.7 had lower rates of overlapping drivers compared to those with MET pCN < 2.7 (6.1% vs. 16.3%, P = .033). None of the 7 patients with pCN > 6.7 had an overlapping driver. After adjusting for tumor fraction, adjusted pCN (ApCN) was also lower for those with overlapping drivers than those without (median ApCN 4.9 vs. 7.3, P =.024). There was an inverse relationship between amplicon size and pCN. CONCLUSIONS: We propose that a high MET pCN and/or ApCN, together with the absence of overlapping oncogenic drivers and small MET amplicon size, will enrich for patients most likely to derive benefit from MET targeted therapy.

An approach to acute clinical deterioration in patients with late-stage Parkinson's disease.

BACKGROUND: Idiopathic Parkinson's disease is a slowly progressive neurodegenerative disease. In the absence of disease-modifying therapies, patients inevitably progress to late-stage disease, characterised by a shift towards increasing disability from predominantly non-motor symptoms, which may be poorly levodopa responsive. OBJECTIVE: The aim of this article is to provide general practitioners (GPs) with a practical approach to the diagnosis and management of acute clinical deterioration in patients with late-stage Parkinson's disease. The authors outline common causes for such change and an approach to their workup and management. DISCUSSION: With an ageing population, we are seeing an increased prevalence of Parkinson's disease at all stages. Neurologists, geriatricians and GPs alike should therefore be familiar with the syndrome of late-stage Parkinson's disease and be equipped with treatment strategies to address acute non-motor and motor deteriorations.

Association of anticoagulant use with clinical outcomes from crizotinib in ALK- and ROS1-rearranged advanced non-small cell lung cancers: A retrospective analysis of PROFILE 1001.

BACKGROUND: ROS1- and ALK-rearranged advanced NSCLCs are associated with increased thromboembolic risk. We hypothesized that a prothrombotic phenotype offers an evolutionary advantage to subsets of these cancers. The impact of this phenotype could alter outcomes from targeted therapy. METHODS: In a retrospective analysis of ROS1- and ALK-rearranged NSCLCs treated with crizotinib in a phase 1 trial, we compared progression-free survival (PFS) and objective response rate (ORR) based on the history of anticoagulation use (a possible surrogate of thromboembolism) at baseline (within 90 days before study enrollment) or within 90 days of study treatment. RESULTS: Twelve out of 53 (22.6%) ROS1- and 39 out of 153 (25.5%) ALK-rearranged NSCLCs received anticoagulation before or during the trial. Most ROS1 and ALK patients on anticoagulation received low-molecular-weight heparin (75% and 64.1%, respectively). In the ROS1-rearranged group, the median PFS (95% CI) values were 5.1 (4.4-14.4) and 29.0 (16.5-48.8) months, and the ORR values were 41.7% (95% CI: 15.2 to 72.3) and 80.5% (95% CI: 65.1 to 91.2) among those with and without anticoagulation treatment, respectively. In the ALK-rearranged group, the median PFS (95% CI) was 7.1 (5.4-7.7) and 12.0 (9.4-18.3) months, and the ORR was 41% (95% CI: 25.6 to 57.9) and 74.3% (95% CI: 65.3 to 82.1) among those with and without anticoagulation, respectively. CONCLUSIONS: Anticoagulation (as a potential surrogate of a prothrombotic subset) in ROS1- and ALK-rearranged NSCLCs may be associated with a lower PFS and ORR to crizotinib. CLINICALTRIAL: gov: NCT00585195.

Managing Central Nervous System Spread of Lung Cancer: The State of the Art.

Brain metastases (BrM) are common in both non-small-cell lung cancer and small-cell lung cancer. Substantial progress in BrM management has occurred in the past decade related to advances in both radiation and medical oncology. Recent and ongoing radiation trials have focused on increasing the candidacy for focal therapy of BrM with stereotactic radiosurgery; reducing the toxicity and improving patient selection for whole brain radiotherapy; and, in small-cell lung cancer, evaluating brain magnetic resonance imaging surveillance without prophylactic cranial irradiation, hippocampal avoidance in prophylactic cranial irradiation and whole brain radiotherapy, and the role of upfront stereotactic radiosurgery for BrM. In medical oncology, the development of multiple tyrosine kinase inhibitors with encouraging CNS activity and emerging data on the CNS activity of immune checkpoint inhibitors in some patients have opened the door to novel systemic and multidisciplinary treatment strategies for the management of BrM. Future research will focus on more robust characterizations of the CNS activity of targeted therapy and immunotherapies, as well as optimal integration and patient selection for multidisciplinary strategies involving CNS-active drugs, radiation therapy, and CNS surveillance.

Nursing and Parkinson's Disease: A Scoping Review of Worldwide Studies.

This scoping review aims to evaluate the characteristics of worldwide studies evolving the scope of nursing practice in Parkinson's disease (PD). We conducted a three-step search strategy using 11 databases and reference lists. Of the 4,174 screened studies we included 324 (8%). Most were published during 1978 to 2020, with significant increasing in publications from 2002 onwards and a forecast to double in the next 10 years (total expected = 614, ±62.2, R2 = .998). We identified studies involving nine contexts of nursing practice in PD, in four continents and 31 countries, most of them of observational design (47.2%), funded (52.2%), authored by nurses (70.1%), and related to Nursing care/Guidelines (32.1%), Educational/Research content (16.4%), Symptom management/Medication adherence (14.5%), and Family caregiving (11.1%). The worldwide studies evolving the scope of nursing practice in PD is growing in several health context. These results can guide future research and evidence-based practice involving the role of nurses in PD.

24-hour levodopa-carbidopa intestinal gel may reduce troublesome dyskinesia in advanced Parkinson's disease.

Levodopa-carbidopa intestinal gel (LCIG) is effective for the control of motor fluctuations in Parkinson's disease (PD). The objective of this study is to report the reduction of dyskinesias after transitioning from 16 to 24-h/day LCIG infusion. From a cohort of 74 PD patients treated with LCIG for motor fluctuations, we identified 12 patients that were treated with 24-h per day infusion with the aim to control troublesome daytime dyskinesia. Clinical, demographic, dyskinesia rating scales were evaluated. Daytime dyskinesia was reduced in 75% (9/12) patients following treatment with 24-h therapy, including 7 who were compared with 16-h therapy and 2 that were transitioned from oral dopaminergic therapy to 24-h LCIG. Combining the data from all 12 subjects, troublesome dyskinesias were reduced during 24-h LCIG; UPDRS 4.1 (time spent with dyskinesias) mean change was -1.5 ± 0.75, p = 0.010 (Wilcoxon signed-rank test) and UPDRS 4.2 (functional impact of dyskinesias) mean change was -1.7 ± 0.90, p = 0.016, without changing their UPDRS part 3 "ON" scores (p = 0.138) or H&Y (p = 0.157). In 5 patients, improvement in dyskinesia occurred despite an overall increase in the total daily levodopa dose. None of the patients had worsening of dyskinesia after a median follow-up of 28 months. 24-h per day infusion of LCIG may be a useful strategy in the management of troublesome dyskinesias in PD patients with disabling dyskinesias resistant to attempts to optimise 16-hours per day therapy. We postulate that this may be due to a pharmacodynamic as opposed to pharmacokinetic mechanism.

Intraduodenal levodopa-carbidopa intestinal gel infusion improves both motor performance and quality of life in advanced Parkinson's disease.

We report the efficacy and adverse effect profile of intraduodenal levodopa-carbidopa intestinal gel (LCIG) infusion from patients treated in a single Australian movement disorder centre. We conducted an open-label, 12 month prospective study of treatment with LCIG in patients with advanced Parkinson's disease in a single tertiary referral hospital unit specialising in movement disorders. Patients with levodopa-responsive, advanced Parkinson's disease with motor fluctuations despite optimal pharmacological treatment were enrolled and underwent a 16 hour daily infusion of LCIG for 12 months. Fifteen participants completed the trial. The mean (± standard deviation) improvement in Unified Parkinson's Disease Rating Scale part III was 37 ± 11%, mean daily "off" period reduced from 6.3 ± 2 to 1.9 ± 2 hours, total daily "on" time increased from 10.2 ± 3 to 13.7 ± 2 hours, "on" period without dyskinesia increased from 4.5 ± 3 to 7.5 ± 5 hours, and 39-item Parkinson's Disease Questionnaire Summary Index score improved by 32.5 ± 35%. The most common adverse event was reversible peripheral neuropathy secondary to vitamin B12 ± B6 deficiency (40%), local tube problems (40%), and impulse control disorder (ICD) (27%). No patient had stoma bleeding or peritonitis. All patients with ICD had a past psychiatric diagnosis of depression with or without anxiety and a higher daily levodopa intake at 6 and 12 months of LCIG infusion. Intraduodenal LCIG improves motor performance, quality of life and daily "on" period. Prior to and during duodenal LCIG infusion, clinicians should monitor for peripheral neuropathy and vitamin B12 and B6 deficiency, as supplementation can reverse peripheral neuropathy. This trial is registered at Clinicaltrials.gov as CT00335153.

24 h Levodopa-carbidopa intestinal gel may reduce falls and "unresponsive" freezing of gait in Parkinson's disease.

OBJECTIVE: We report a prospective, open label study of 24 h levodopa-carbidopa intestinal gel (LCIG) as treatment for levodopa "unresponsive" freezing of gait (FOG) associated with Parkinson's disease. METHOD: 5 patients with disabling FOG, documented as being levodopa "unresponsive", were commenced on continuous 24 h infusion LCIG therapy with the night-time rate at 50-80% of the daytime infusion rate. Patients underwent baseline, 3 and 6 month gait assessments, documentation of their falls frequency and completed FOG questionnaires. RESULT: Median 360° turn time improved by 54%, fall frequency score reduced from 3 to 0 at 6 months, FOG questionnaire score improved by 14% and Timed Up- and -Go 8 m walk was unchanged. CONCLUSION: 24 h LCIG therapy may reduce levodopa "unresponsive" FOG and associated falls. A larger prospective study is needed for confirmation.

CBP regulates the differentiation of interneurons from ventral forebrain neural precursors during murine development.

The mechanisms that regulate appropriate genesis and differentiation of interneurons in the developing mammalian brain are of significant interest not only because interneurons play key roles in the establishment of neural circuitry, but also because when they are deficient, this can cause epilepsy. In this regard, one genetic syndrome that is associated with deficits in neural development and epilepsy is Rubinstein-Taybi Syndrome (RTS), where the transcriptional activator and histone acetyltransferase CBP is mutated and haploinsufficient. Here, we have asked whether CBP is necessary for the appropriate genesis and differentiation of interneurons in the murine forebrain, since this could provide an explanation for the epilepsy that is associated with RTS. We show that CBP is expressed in neural precursors within the embryonic medial ganglionic eminence (MGE), an area that generates the vast majority of interneurons for the cortex. Using primary cultures of MGE precursors, we show that knockdown of CBP causes deficits in differentiation of these precursors into interneurons and oligodendrocytes, and that overexpression of CBP is by itself sufficient to enhance interneuron genesis. Moreover, we show that levels of the neurotransmitter synthesis enzyme GAD67, which is expressed in inhibitory interneurons, are decreased in the dorsal and ventral forebrain of neonatal CBP(+/-) mice, indicating that CBP plays a role in regulating interneuron development in vivo. Thus, CBP normally acts to ensure the differentiation of appropriate numbers of forebrain interneurons, and when its levels are decreased, this causes deficits in interneuron development, providing a potential explanation for the epilepsy seen in individuals with RTS.

FoxP2 regulates neurogenesis during embryonic cortical development.

The transcription factor FoxP2 has been associated with the development of human speech but the underlying cellular function of FoxP2 is still unclear. Here we provide evidence that FoxP2 regulates genesis of some intermediate progenitors and neurons in the mammalian cortex, one of the key centers for human speech. Specifically, knockdown of FoxP2 in embryonic cortical precursors inhibits neurogenesis, at least in part by inhibiting the transition from radial glial precursors to neurogenic intermediate progenitors. Moreover, overexpression of human, but not mouse, FoxP2 enhances the genesis of intermediate progenitors and neurons. In contrast, expression of a human FoxP2 mutant that causes vocalization deficits decreases neurogenesis, suggesting that in the murine system human FoxP2 acts as a gain-of-function protein, while a human FoxP2 mutant acts as a dominant-inhibitory protein. These results support the idea that FoxP2 regulates the transition from neural precursors to transit-amplifying progenitors and ultimately neurons, and shed light upon the molecular changes that might contribute to evolution of the mammalian cortex.

Metformin activates an atypical PKC-CBP pathway to promote neurogenesis and enhance spatial memory formation.

VIDEO ABSTRACT: Although endogenous recruitment of adult neural stem cells has been proposed as a therapeutic strategy, clinical approaches for achieving this are lacking. Here, we show that metformin, a widely used drug, promotes neurogenesis and enhances spatial memory formation. Specifically, we show that an atypical PKC-CBP pathway is essential for the normal genesis of neurons from neural precursors and that metformin activates this pathway to promote rodent and human neurogenesis in culture. Metformin also enhances neurogenesis in the adult mouse brain in a CBP-dependent fashion, and in so doing enhances spatial reversal learning in the water maze. Thus, metformin, by activating an aPKC-CBP pathway, recruits neural stem cells and enhances neural function, thereby providing a candidate pharmacological approach for nervous system therapy.