Upfront pembrolizumab as an effective treatment start in patients with PD-L1 ≥ 50% non-oncogene addicted non-small cell lung cancer and asymptomatic brain metastases: an exploratory analysis.

INTRODUCTION: The efficacy of immune checkpoint inhibitors in patients with brain metastases (BMs) from non-oncogene addicted non-small cell lung cancer (NSCLC) is under investigation. Here, we sought to determine the optimal management of NSCLCs with PD-L1 ≥ 50% and asymptomatic BMs who were treated with first-line pembrolizumab. METHODS: Thirty patients from 15 institutions with PD-L1 ≥ 50% NSCLC had asymptomatic BMs, and met inclusion criteria. Patients were classified based on whether they had undergone upfront local radiotherapy for BMs as well as on the type of brain radiotherapy received. RESULTS: Nine patients were treated with upfront pembrolizumab alone, 8 patients with whole-brain radiotherapy (WBRT) followed by pembrolizumab and 13 patients with stereotactic radiosurgery (SRS) followed by pembrolizumab. Patients' characteristics were similar among the three groups of patients except for a higher number of BMs ≥ 3 in the WBRT group. One complete and 4 partial intracranial responses were observed with upfront pembrolizumab alone. The median survival was not reached for the pembrolizumab and WBRT (n = 8) groups, and it was 7.6 months for the SRS (n = 13) group (P = 0.09), with 12-month survival rates being 55.5%, 62.5%, and 23.0%, respectively. Salvage WBRT was delivered in 1 patient in the upfront pembrolizumab group and in 4 patients in the SRS group. CONCLUSIONS: Upfront pembrolizumab showed efficacy in selected patients with PD-L1 ≥ 50% non-oncogene addicted NSCLC and asymptomatic BMs. Prospective studies should address whether pembrolizumab alone, and deferral of radiotherapy, could be pursued in this patient population.

A magnetization transfer study of mild and advanced Parkinson's disease.

BACKGROUND AND PURPOSE: Magnetization transfer ratio (MTR) technique has identified brain changes in grey and white matter in Parkinson's disease (PD), even in the early phase. However, how these tissue changes differ along the course of the illness is still unclear. This study was aimed at investigating how MTR values change from mild PD (PD1) to patients with advanced PD (PD2). METHODS: We measured MTR values by region of interest, in 11 PD1, 11 PD2 and 10 healthy age-matched subjects. RESULTS: Compared with controls, patients with PD1 exhibited a significant MTR reduction in substantia nigra pars compacta, substantia nigra pars reticulata, putamen, periventricular white matter and parietal white matter. In addition to the changes observed in PD1, the PD2 group exhibited a significant MTR reduction in caudate, pons, frontal white matter and lateral thalamus. CONCLUSION: These results suggest that MTR might reflect morphological changes induced by the disease in distinct brain areas at different stages.

Association of 99mTc-MIBI brain SPECT and proton magnetic resonance spectroscopy (1H-MRS) to assess glioma recurrence after radiotherapy.

AIM: The aim of this study was to compare 99mTc-MIBI brain SPECT and proton magnetic resonance spectroscopy (1H-MRS) findings and to evaluate their association. METHODS: Both exams were performed on 30 glioma patients, previously operated and treated with radiotherapy, having MRI doubtful between recurrence and radiotherapy effects. SPECT images were acquired 15 minutes after radiopharmaceutical administration with a dual-head gamma camera. T1/B1 uptake ratio was calculated between a tumor ROI (T1) and a normal mirror symmetric ROI (B1) and T2/B2 ratio was obtained between a ROI in the hottest neoplastic part (T2) and a normal mirror symmetric ROI (B2). 1H-MRS was performed using a 1.5 T system equipped with a spectroscopy package. SPECT and 1H-MRS data were compared with histology after new surgery or with follow-up. RESULTS: SPECT and 1H-MRS showed recurrence in 18 patients (confirmed by biopsy, coinciding only in 17 cases) and were negative in 10 (1 false negative). SPECT and 1H-MRS disagreed in 2 cases of recurrence (1 diagnosed by brain SPECT, 1 by 1H-MRS). T1/B1 ratio mean value (4.26+/-2.5) was significantly lower than T2/B2 (4.93+/-2.81; P<0.001). SPECT and 1H-MRS sensitivity in detecting recurrence was 90%, specificity 100%, accuracy 93%, negative predictive value (NPV) 83% and positive predictive value (PPV) 100%; the associated exams sensitivity was 95%, specificity 100%, accuracy 96.6%, NPV 90.9%, PPV 100%. CONCLUSIONS: Brain SPECT and 1H-MRS have equivalent values of diagnostic parameters in differentiating tumor recurrence and radiation effects, and their association might provide additional information.

Magnetization transfer changes of grey and white matter in Parkinson's disease.

Since the attempt to evidence structural brain damage in Parkinson's disease (PD) by conventional magnetic resonance imaging (MRI) is usually disappointing, we have investigated whether the magnetization transfer ratio (MTR) can reflect changes in grey and white matter of PD patients. MTR was quantified in 44 regions of interest (ROIs) in both grey and white matter of 11 non-demented PD patients, ranging from 2 to 4 on the Hoehn and Yahr Scale, and eight age-matched healthy subjects. MTR differences between patients and controls were found in the supratentorial white matter and in the brainstem. In particular, lower MTR values were found in the paraventricular white matter of PD patients (p<0.05) while no differences were observed in corpus callosum, frontal, parietal, occipital lobes or centrum semiovalis. Lower MTR values were found in substantia nigra (p<0.001), red nucleus (p<0.05) and pons (p<0.05) of the patient group. No differences were discovered in basal ganglia and thalamus. These findings suggest that MTR measurements in the paraventricular white matter and brainstem may help to recognize a marker for probable PD.

Localized (1)H magnetic resonance spectroscopy in mainly cortical gray matter of patients with multiple sclerosis.

The brain water fraction (R), the brain water transverse relaxation time (T2), the atrophy index (alpha) and the absolute concentration of the principal brain metabolites (NAA, Cho and Cr) were measured by localized proton magnetic resonance spectroscopy in the occipito-parietal cortex (mainly gray matter) of 15 relapsing-remitting (R-R) multiple sclerosis (MS) patients, 15 secondary progressive (SP) MS patients and 8 healthy subjects. Significantly lower values of N-acetylaspartate (NAA), creatine (Cr) and the NAA/Cr ratio in the occipito-parietal cortex were detected in SP MS patients than in R-R MS and control subjects (p < 0.01). Moreover, MS patients showed shorter T2 water relaxation times and reduced brain water fraction compared with controls. Higher atrophy indices were also detected in the mainly occipito-parietal gray matter of MS patients, particularly in those with the progressive form. These findings suggest that the pathological process in MS is not limited to either white matter lesions or normal-appearing white matter but extends into the cortical gray matter (occipito-parietal), particularly in the progressive form of the disease. This can involve changes in neural metabolism or neural shrinkage and neuron loss. The significant increase in atrophy indices could be the expression of the relatively higher cerebrospinal fluid signal from the occipito-parietal cortex, even in the absence of obvious cortical atrophy.

Magnetic resonance imaging and 1H-magnetic resonance spectroscopy in amyotrophic lateral sclerosis.

We aimed to increase confidence in the combined use of MRI and proton MR spectroscopy (1H-MRS) in diagnosis of amyotrophic lateral sclerosis (ALS). We investigated 12 patients with ALS, seven definite and five probable, taking into account clinical measures of motor neuron function. On T2-weighted images we found high signal in the corticospinal tract in six and low signal in the primary motor cortex in seven of the 12 patients. Atrophy of the precentral gyrus was apparent in all the patients apart from one with probable ALS. Absolute quantification of cerebral metabolites using 1H-MRS demonstrated a significantly lower mean concentration of N-acetylaspartate (NAA) in the precentral gyrus of patients with probable and definite ALS (8.5 +/- 0.62) than in control subjects (10.4 +/- 0.71; P < 0.001). NAA concentration in primary motor cortex correlated with Norris scale scores (r = 0.30; P < 0.0001) but not with the ALS Functional Rating Scale score or disease duration. Significantly lower levels of NAA were detected in patients with low signal in the motor cortex than in those without (P < 0.01). Mean choline (Cho) and creatine (Cr) values did not differ between patients with ALS and controls.

Absolute quantification of brain metabolites by proton magnetic resonance spectroscopy in normal-appearing white matter of multiple sclerosis patients.

The aim of this research was to obtain an absolute quantification of the N-acetyl-aspartate, choline, creatine and phosphocreatine levels in normal-appearing white matter by means of 1H magnetic resonance spectroscopy in a group of multiple sclerosis patients (27 with the relapsing-remitting form and 13 with the secondary progressive form). These values were compared with those of a group of 12 age-matched healthy control subjects. A significant decrease in the N-acetyl-aspartate concentration was found in normal-appearing white matter of frontal and parietal brain areas in multiple sclerosis patients compared with the same areas in control subjects. This reduction was more evident in progressive patients. The decrease in the N-acetyl-aspartate concentration in normal-appearing white matter significantly correlated with the Expanded Disability Status and the lesional load. No significant change was found in the concentration of creatine or choline. This finding concurs with previous evidence of heterogeneity in the multiple sclerosis pathological process which is not confined to the lesions and involves not only myelin, but also axons, even in white matter which appears normal on MRI.

1H-MRS, MRI-based hippocampal volumetry, and 99mTc-HMPAO-SPECT in normal aging, age-associated memory impairment, and probable Alzheimer's disease.

OBJECTIVE: To better understand how to differentiate the "in vivo" normal aging brain from pathological conditions, namely dementia of the Alzheimer type (DAT), by means of magnetic resonance imaging (MRI), single photon emission computerized tomography (SPECT), and proton magnetic resonance spectroscopy (1H-MRS), to show neuroanatomical, perfusional and neurochemical details, respectively. DESIGN: 1H-MRS, MRI-based hippocampal volumetry and 99mTc-HMPAO SPECT were performed in healthy older subjects as well as patients suffering from age-associated memory impairment (AAMI) and dementia of Alzheimer type (DAT). SUBJECTS AND SETTING: Eighteen subjects were selected from those referred to an outpatient clinic for diagnostic evaluation of cognitive impairment entered the study. Six patients fulfilled NINCDS-ADRDA diagnostic criteria for DAT, six subjects were affected by AAMI, and six cognitively healthy subjects, selected from among relatives of the patients, were defined as controls. METHODS: The 1H-MRS and MRI studies were performed on a 1.5 Tesla NMR-imaging system equipped with a spectroscopy research package. SPECT scans were performed on a Gamma 11 computer system. FINDINGS: 1H-MRS showed significantly lower N-acetylasparatate concentration in DAT and AAMI compared with controls. Conversely, mean inositol concentration was significantly higher in DAT than in controls, whereas AAMI subjects registered intermediate values. MRI measurements showed significantly reduced volumes of hippocampal formations in DAT and AAMI groups compared with controls. Finally, 99mTc-HMPAO SPECT showed a significant frontal, temporo-parietal, and occipital hypoperfusion in DAT patients only. CONCLUSIONS: These findings support the hypothesis of a continuum among the three conditions studied, or at least between AAMI and DAT, where AAMI seems to be an early, monosymptomatic stage of Alzheimer disease. Accepting this view, it would be questionable to maintain the term "age-associated memory impairment" as a discrete entity.

[Reactivation of the allogenous component of experimental skin inflammation after exposure to ultraviolet rays]. / Riattivazione della componente algogena della flogosi cutanea sperimentale dopo esposizione a raggi ultravioletti.

The effects of U.V. radiation induced cutaneous erythema on an experimental inflammation focus in another part of the body have been studied. The skin inflammation caused by carbon dioxide snow was used as a model. The onset of erythema is followed by reactivation of the diminishing inflammation process. It is therefore deduced that such effects are transmitted humorally and that reactivation is caused by histamine circulation. Histamine is released locally from the U.V. induced erythema and, entering into the circulation, increased the permeability of the microvessels in the inflamed area. This sends inactive chemical mediators to the interstitial sector where the appropriate conditions for their activation exist.

[Reactivation of the algogenic component in experimental inflammation induced by histamine administration]. / Riattivazione della componente algogena nella flogosi sperimentalmente indotta dopo somministrazione di istamina.

The action of i.v. histamine on human skin inflammation experimentally induced with carbon dioxide snow in man is described. Histamine was injected when the skin reaction was on the wane to determine its possible reactivation of inflammation. Complete recrudescence of erythralgia was noted (reappearance of pain and of erythralgic halo, with a fresh spread of secondary hyperalgesia). It is felt that histamine was responsible. Its arrival to the reaction site through microvessels in a state of increased permeability during the remission of inflammation may be assumed to promote the passage of chemical mediators in the preactive stage from the vascular to the interstitial sector, and thus to pave the way for their activation.

Effects of calcitonin on limb blood vessels in human obstructive arterial disease.

To check the possibility of a vasoactive effect of calcitonin in man, the authors treated ten hospitalized patients (seven males and three females, mean age 66.3 +/- 3.24), suffering from obstructive arterial disease in the lower extremities, with 100 units M.R.C. i.m. daily, for a period of 15 days. Five patients presented Raynaud's phenomenon. Treatment (B) led to an improvement of subjective symptomatology and to the disappearance of Raynaud's phenomenon in comparison with symptoms before treatment (A) and after a placebo period of 15 days (C). With respect to instrumental parameters, calcitonin induced: a) a slight increase of segmental plethysmography values (height/width ratio of curves) if compared with A (p less than 0.05) and more significantly if compared with C (p less than 0.01 and less than 0.0125, from right and left sides, respectively); b) a small change in venous-occlusion plethysmography values, if compared with A and C, both in basal conditions and after the "ischaemic test"; c) a significantly lesser reduction of digital photoelectric plethysmography values (height/width ratio of curves) after the "cold test" in comparison with A (p less than 0.01, both on the second and on the third fingers of the right hand), as well as with C (p less than 0.01 and p less than 0.025, on the second and on the third fingers, respectively). The present investigation points out the vasoactive influence of calcitonin in human obstructive disease. Results show the improvement in collateral limb circulation and, above all, in the amount of cutaneous flow. Little information is available on the mechanism of this effect, for which only hypotheses can at present be advanced.