Osimertinib beyond disease progression in T790M EGFR-positive NSCLC patients: a multicenter study of clinicians' attitudes.

BACKGROUND: In most cases, T790M EGFR-positive NSCLC patients receiving osimertinib developed "non-drugable" progression, as the patients with common EGFR-sensitizing mutations were treated with first-line osimertinib. In both settings, chemotherapy represents the standard treatment and local ablative treatments (LATs) are potential useful options in the case of oligo-progression. METHODS: We conducted a study on "post-progression" (pp) outcomes of T790M EGFR-positive NSCLC patients treated with osimertinib, according to the therapeutic strategy applied: osimertinib beyond progression (± LATs), "switched therapies" or best supportive care only (BSC). RESULTS: 144 consecutive patients were evaluated: 53 (36.8%) did not received post-progression treatments (BSC), while 91 (63.2%) patients received at least 1 subsequent treatment; 50 patients (54.9%) received osimertinib beyond disease progression [19 (20.9%) of them with adjunctive LATs] and 41 (45.1%) a switched therapy. Median ppPFS (progression-free survival) and median ppOS (overall survival) of patients who received osimertinib beyond progression vs. switched therapies were 6.4 months vs. 4.7 months, respectively [HR 0.57 (95% CI 0.35-0.92), p = 0.0239] and 11.3 months vs 7.8 months, respectively [HR 0.57 (95% CI 0.33-0.98), p = 0.0446]. Among patients who received osimertinib beyond progression with and without LATs median ppPFS was 6.4 months and 5.7 months, respectively [HR 0.90 (95% CI 0.68-1.18), p = 0.4560], while median ppOS was 20.2 months and 9.9 months, respectively [HR 0.73 (95% CI 0.52-1.03), p = 0.0748]. At the univariate analysis, the only factor significantly related to the ppPFS was the therapeutic strategy in favor of osimertinib beyond progression (± LATs). Moreover, the only variable which was significantly related to ppOS at the multivariate analysis was osimertinib beyond progression (± LATs). CONCLUSION: Our study confirmed that in clinical practice, in case of "non-druggable" disease progression, maintaining osimertinib beyond progression (with adjunctive LATs) is an effective option.

Risk factors and survival outcomes in patients with brain metastases from breast cancer.

Development of central nervous system (CNS) metastases in breast cancer (BC) is associated with poor prognosis. The incidence of CNS metastases in metastatic BC is reported to be about 10-16 %, but different subtypes of BC are associated with different risk of developing CNS metastases. We retrospectively analysed the risk of CNS metastases and the outcome in a cohort of 473 patients with metastatic BC. CNS metastases were diagnosed in 15.6 % of patients and median survival from diagnosis of CNS metastases was 7.53 (25th-75th 2.8-18.9) months. The risk of developing CNS metastases was higher in patients with grade 3, hormone receptor negative, HER2-positive, high Ki-67 BC. When compared to luminal A subtype, only HER2-positive BC was associated with increased risk of CNS metastases. Survival from diagnosis of CNS metastases was longer in patients with HER2-positive BC, while it was shorter in patients that did not receive any locoregional treatment, or with extra-CNS disease, or with more than 3 CNS lesions.

The Nun study: clinically silent AD, neuronal hypertrophy, and linguistic skills in early life.

BACKGROUND: It is common to find substantial Alzheimer disease (AD) lesions, i.e., neuritic beta-amyloid plaques and neurofibrillary tangles, in the autopsied brains of elderly subjects with normal cognition assessed shortly before death. We have termed this status asymptomatic AD (ASYMAD). We assessed the morphologic substrate of ASYMAD compared to mild cognitive impairment (MCI) in subjects from the Nun Study. In addition, possible correlations between linguistic abilities in early life and the presence of AD pathology with and without clinical manifestations in late life were considered. METHODS: Design-based stereology was used to measure the volumes of neuronal cell bodies, nuclei, and nucleoli in the CA1 region of hippocampus (CA1). Four groups of subjects were compared: ASYMAD (n = 10), MCI (n = 5), AD (n = 10), and age-matched controls (n = 13). Linguistic ability assessed in early life was compared among all groups. RESULTS: A significant hypertrophy of the cell bodies (+44.9%), nuclei (+59.7%), and nucleoli (+80.2%) in the CA1 neurons was found in ASYMAD compared with MCI. Similar differences were observed with controls. Furthermore, significant higher idea density scores in early life were observed in controls and ASYMAD group compared to MCI and AD groups. CONCLUSIONS: 1) Neuronal hypertrophy may constitute an early cellular response to Alzheimer disease (AD) pathology or reflect compensatory mechanisms that prevent cognitive impairment despite substantial AD lesions; 2) higher idea density scores in early life are associated with intact cognition in late life despite the presence of AD lesions.

Cortical rhythms reactivity in AD, LBD and normal subjects: a quantitative MEG study.

The present study evaluated the reactivity of cortical rhythms in 15 Alzheimer's disease (AD) patients, 7 Lewy body dementia (LBD) patients and 9 control subjects using a 165 SQUID whole-head MEG system. The absolute power values of the rhythms recorded over different areas over the brain (frontal, parietal, temporal, occipital) were analysed in the 3-47Hz frequency range. The cortical reactivity of the alpha (9-14Hz) and pre-alpha rhythms (7-9Hz) during open and closed eyes conditions differentiated the control group from the patient groups and moderate AD from severe AD and LBD groups, respectively. The cortical reactivity of the slow-band (3-7Hz) obtained by comparing a simple mental task and the rest discriminated the severe AD group from the other groups. In addition, spectral coherence analysis in the alpha band showed that the loss of coherence in AD and LBD patients mainly involved long connections. These results suggest that investigations on rhythms reactivity and spectral coherence might help on the study of the dementias with different etiology.

Clinically evidenced unilateral dissociation of saccades and pursuit eye movements.

A patient affected by an ischaemic lesion of the right medial thalamic nucleus presented with a uniocular dissociation of upward vertical saccades and pursuit movement, with absent upward vertical saccades in the left eye. Clinical observations were confirmed by magnetic field scleral search coils analysis. During the vertical eye movement the patient denied any diplopia, thus suggesting a transient visual suppression in the left eye.

Duration of amantadine benefit on dyskinesia of severe Parkinson's disease.

BACKGROUND: Recent short-term studies suggested that amantadine (Ama) might ameliorate dyskinesia in patients with Parkinson's disease. A double-blind study programmed over 12 months was designed to assess the duration of the antidyskinetic effect of amantadine on levodopa induced dyskinesia. METHODS: 40 patients treated for 7.5 (2.2) years with levodopa (729.3 (199.4) mg/day) and dopaminoagonists, having peak dose or dyphasic dyskinesia with or without pain, were assessed with the Unified Parkinson's Disease Rating Scale subscale IV, Items 32-34, the Dyskinesia Rating Scale and Investigator Global Assessment. Twenty patients received amantadine chloridrate (100 mg) and 20 received a placebo. The Ama or placebo could be withdrawn when scores indicated worsening of dyskinesia, after agreement with the patient. RESULTS: After 15 days of amantadine treatment there was a reduction by 45% in the total dyskinesia scores. All patients in the placebo group were withdrawn in 1-3 months and all patients in the Ama group were withdrawn in 3-8 months (p = 0.01, p<0.001). Ama withdrawal induced a rebound with increase of dyskinesia by 10-20% in 11 patients. CONCLUSION: 300 mg amantadine reduces dyskinesia in Parkinson's disease by approximately 45% but the benefit lasted less than eight months.

Acute akinesia or akinetic crisis in Parkinson's disease.

In 22 patients with idiopathic Parkinson's disease we observed a sudden worsening of motor symptoms and severe akinesia during hospitalization because of infectious diseases, bone fractures, surgery for gastrointestinal tract diseases, and iatrogenic causes. Of these patients, 12 recovered completely, 6 had a partial recovery, and 4 died. Treatments included subcutaneous apomorphine/lisuride infusion and dantreolene (with a creatine phosphokinase level higher than 200 IU). In all patients a definite refractoriness to therapy was shown with a transient lack of response to apomorphine.

Mirtazapine induces REM sleep behavior disorder (RBD) in parkinsonism.

Shortly after initiation of mirtazapine (a noradrenergic and serotonergic antidepressant) treatment in four patients with parkinsonism, the authors observed the appearance of REM sleep behavior disorder (RBD). In the two patients with severe motor symptoms, RBD was accompanied by hallucinations and confusion. These disturbances resolved with drug discontinuation, and remained resolved by 12- to 24-month follow-up, suggesting that RBD can be triggered by a drug lacking anticholinergic activity.

Incidence of RBD and hallucination in patients affected by Parkinson's disease: 8-year follow-up.

We describe the 8-years follow-up of 80 patients affected by idiopathic, L-dopa-responsive Parkinson's disease. All patients were evaluated at baseline and during the follow-up with visual evoked potential, P300 event related potentials and polysomnography. The patients and their relatives compiled sleep and hallucination questionnaires. Statistical analysis was performed to evaluate if visual abnormalities, abnormal P300 recordings or sleep disturbances were linked to the development and hallucinations. Our results show that abnormal vision and abnormal P300 did not correlate with the incidence of hallucinations. However, the presence of REM sleep behavioral disorder (RBD) was significantly related to the development of hallucinations,independently of age, gender or duration of disease but dependent on the amount of dopaminoagonist treatment.

Age-related changes of evoked potentials.

The aim of this review is to analyse the current state of our knowledge on evoked potentials (EPs) in ageing and to report some conclusions on the relation between EPs and elder age. Evoked potentials provide a measure of the function of sensory systems that change during the different stages of life. Each sensory system has its own time of maturation. The individuation of the exact period of life when brain ageing starts is difficult to define. Normally, the amplitude of EPs decreases, and their latency increases from adult to elder life. Many authors speculate that these modifications might depend on neuronal loss, changes in cell membrane, composition or senile plaques present in older patients, but there is no evidence that these changes might modify the cerebral function in healthy aged individuals. This review emphasises some incongruities present in different studies confirmed by daily neurophysiologic practice. Different techniques as event-related desynchronization (ERD), contingent negative variation (CNV) and Bereitschaftspotential, are available to study central neuronal changes in normal and pathologic ageing.

Switch-over from tolcapone to entacapone in severe Parkinson's disease patients.

Forty patients affected by severe Parkinson's disease (PD) were treated with tolcapone as an adjunctive therapy to L-DOPA, for 3-7 months, until this drug was discontinued because of side-effects (2 diarrhoea, one of them with orthostatic hypotension, 2 increments of liver enzymes) or because of mandatory indications of the European drugs authority. All patients, after 3-6 months of L-DOPA therapy adjustments, received entacapone for 3 months again followed by withdrawal. L-DOPA daily dosage was significantly reduced by tolcapone and entacapone (p = 0.01 and 0.05). "On" time was increased by 15% during tolcapone treatment (p < 0.05), and by 8% during entacapone treatment. "Off" time was decreased by 16% during tolcapone and by 7% during entacapone treatment. Entacapone was withdrawn in the same patient who experienced diarrhoea and orthostatic hypotension during tolcapone because of recurrence of side-effects, in 6 patients because of increment of dyskinesias (with hallucinations) and in 1 patients because of rhythmic, jerking myoclonus.

Donepezil, rivastigmine, and vitamin E in Alzheimer disease: a combined P300 event-related potentials/neuropsychologic evaluation over 6 months.

The latency of P300 "cognitive" event-related potentials changes if cholinergic activities of the central nervous system are pharmacologically manipulated. We tested the hypothesis that the new cholinesterase inhibitors donepezil (DPZ) and rivastigmine (Riv) may have an effect on the frequently abnormal P300 component in patients with Alzheimer disease (AD), thereby allowing a significant evaluation of cholinesterase inhibitors. We evaluated 60 patients with mild to moderately severe probable AD, in comparison with 60 age-matched control subjects, with P300 recordings and neuropsychologic examinations. Forty patients were randomly assigned in a double-blinded trial to 5-10 mg/d DPZ versus 2,000 IU/d vitamin E, and 20 patients were instead treated in an open trial with 1.5 to 12 mg/d Riv. In patients treated with vitamin E, we observed latency increments (7.4 +/- 3.5 msec) correlated with worsening neuropsychologic test scores. In patients treated with DPZ and Riv, we found significant P300 latency reductions (15.3 +/- 3.2 msec and 22.0 +/- 3.3 msec). Shorter P300 latencies were associated with higher Wechsler Adult Intelligence Scale scores and with lower AD Assessment Scale-cognitive subscale (ADAS-cog) scores (R = 0.72). Correlations between ADAS-cog changes and P300 changes significantly separated patients treated with DPZ and Riv from those treated with vitamin E. Administration of DPZ and Riv reduced the latencies of P300 components proportionately to neuropsychologic test improvements. Combined P300 and neuropsychologic test evaluation significantly separated DPZ-treated patients and Riv-treated patients from vitamin E-treated patients.

Leucopenia induced by low dose clozapine in Parkinson's disease recedes shortly after drug withdrawal. Clinical case descriptions with commentary on switch-over to olanzapine.

Four patients affected by severe Parkinson's disease developed leucopenia (900-1200 WBC) during treatment of psychosis (3) or untreatable insomnia (1) with clozapine (37.5-75 mg/day). Clozapine withdrawal was followed by recovery of leucopenia (4000-6000 WBC) in two weeks with no need for the administration of leucokines. After 1-6 months olanzapine was administered (increasing the dose from 2.5 to 10 mg/day) to treat persisting disturbances, but the drug induced severe worsening of parkinsonism and also this drug had to be withdrawn.