The lung immuno-oncology prognostic score (LIPS-3): a prognostic classification of patients receiving first-line pembrolizumab for PD-L1 ≥ 50% advanced non-small-cell lung cancer.

BACKGROUND: To stratify the prognosis of patients with programmed cell death-ligand 1 (PD-L1) ≥ 50% advanced non-small-cell lung cancer (aNSCLC) treated with first-line immunotherapy. METHODS: Baseline clinical prognostic factors, the neutrophil-to-lymphocyte ratio (NLR), PD-L1 tumour cell expression level, lactate dehydrogenase (LDH) and their combination were investigated by a retrospective analysis of 784 patients divided between statistically powered training (n = 201) and validation (n = 583) cohorts. Cut-offs were explored by receiver operating characteristic (ROC) curves and a risk model built with validated independent factors by multivariate analysis. RESULTS: NLR < 4 was a significant prognostic factor in both cohorts (P < 0.001). It represented 53% of patients in the validation cohort, with 1-year overall survival (OS) of 76.6% versus 44.8% with NLR > 4, in the validation series. The addition of PD-L1 ≥ 80% (21% of patients) or LDH < 252 U/l (25%) to NLR < 4 did not result in better 1-year OS (of 72.6% and 74.1%, respectively, in the validation cohort). Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 [P < 0.001, hazard ratio (HR) 2.04], pretreatment steroids (P < 0.001, HR 1.67) and NLR < 4 (P < 0.001, HR 2.29) resulted in independent prognostic factors. A risk model with these three factors, namely, the lung immuno-oncology prognostic score (LIPS)-3, accurately stratified three OS risk-validated categories of patients: favourable (0 risk factors, 40%, 1-year OS of 78.2% in the whole series), intermediate (1 or 2 risk factors, 54%, 1-year OS 53.8%) and poor (>2 risk factors, 5%, 1-year OS 10.7%) prognosis. CONCLUSIONS: We advocate the use of LIPS-3 as an easy-to-assess and inexpensive adjuvant prognostic tool for patients with PD-L1 ≥ 50% aNSCLC.

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.

Dialysis-related amyloidosis: challenges and solutions.

Amyloidosis refers to the extracellular tissue deposition of fibrils composed of low-molecular-weight subunits of a variety of proteins. These deposits may result in a wide range of clinical manifestations depending upon their type, location, and the amount of deposition. Dialysis-related amyloidosis is a serious complication of long-term dialysis therapy and is characterized by the deposition of amyloid fibrils, principally composed of ß2 microglobulins (ß2M), in the osteoarticular structures and viscera. Most of the ß2M is eliminated through glomerular filtration and subsequent reabsorption and catabolism by the proximal tubules. As a consequence, the serum levels of ß2M are inversely related to the glomerular filtration rate; therefore, in end-stage renal disease patients, ß2M levels increase up to 60-fold. Serum levels of ß2M are also elevated in several pathological conditions such as chronic inflammation, liver disease, and above all, in renal dysfunction. Retention of amyloidogenic protein has been attributed to several factors including type of dialysis membrane, prolonged uremic state and/or decreased diuresis, advanced glycation end products, elevated levels of cytokines and dialysate. Dialysis treatment per se has been considered to be an inflammatory stimulus, inducing cytokine production (such as interleukin-1, tumor necrosis factor-α, interleukin-6) and complement activation. The released cytokines are thought to stimulate the synthesis and release of ß2M by the macrophages and/or augment the expression of human leukocyte antigens (class I), increasing ß2M expression. Residual renal function is probably the best determinant of ß2M levels. Therefore, it has to be maintained as long as possible. In this article, we will focus our attention on the etiology of dialysis-related amyloidosis, its prevention, therapy, and future solutions.

Effects of muscle composition and architecture on specific strength in obese older women.

NEW FINDINGS: What is the central question of this study? Do obesity-specific factors affect skeletal muscle performance in older individuals? What is the main finding and its importance? Older obese women have a larger quadriceps femoris size but develop lower tension per unit of skeletal muscle than their normal-weight counterparts. Muscle impairment and excess body mass are very common among older people. Given that the effect of obesity on strength production has scarcely been studied in older individuals, we analysed functional and structural characteristics of quadriceps femoris (QF) in obese (OB) and normal-weight (NW) older women with comparable habitual physical activity. In five OB (body mass index 36.8 ± 1.9 kg m(-2), age 72.4 ± 2.3 years) and six NW well-functioning older women (body mass index 24.3 ± 1.8 kg m(-2), age 72.7 ± 1.9 years), peak knee-extension torque (KET) was measured in isometric (90 deg knee flexion) and isokinetic conditions (240, 180, 120 and 60 deg s(-1)). Mid-thigh QF cross-sectional area (CSA) and muscle tissue fat content (MF%) were determined with magnetic resonance imaging (Dixon sequence). Muscle fascicle length and pennation angle (PA) were assessed with ultrasonography for each muscle belly of the QF (vastus lateralis, vastus intermedius, rectus femoris and vastus intermedius). Despite similar values of KET, CSA was 17.0% larger in OB than in NW women (P < 0.05), so that KET/CSA was significantly lower (P < 0.05) in OB women. Compared with NW women, OB women had 28.7% higher MF% (P < 0.05) and 24.9% higher average PA (P < 0.05), while fascicle length was similar. Overall, isometric KET/CSA was negatively affected by both MF% (P < 0.05) and PA (P < 0.05), while isokinetic KET/CSA was negatively affected only by MF% (P < 0.01). Muscle composition and architecture seem to be important determinants of KET/CSA in elderly women. In fact, owing to the effect of obesity overload, OB women have a larger QF size than NW women, but unfavourable muscle composition and architecture. The higher MF% and steeper PA observed in OB women are associated with reduced levels of muscle specific strength.

High density lipoprotein cholesterol levels are an independent predictor of the progression of chronic kidney disease.

OBJECTIVES: Patients with chronic kidney disease (CKD) often present with reduced plasma HDL cholesterol (HDL-C) levels. Whether this reduction in an epiphenomenon or is involved in disease progression is unclear. The aim of this study was to investigate the relation between HDL-C levels/function and CKD progression in patients with different degrees of disease. DESIGN: A total of 176 patients with CKD [glomerular filtration rate (GFR) 50.3 ± 29.1 mL min⁻¹] were recruited and followed for up to 84 months. Lipid profile, metabolic status and kidney function were evaluated at predetermined times. Age-matched control subjects were selected from the PLIC study (n = 453). Scavenger receptor class B member 1 (SR-BI) and ATP-binding cassette transporter A1 (ABCA-1)-dependent efflux of cholesterol were measured in CKD patients and in age-matched control subjects. RESULTS: Low HDL-C levels, diabetes and hypertension were associated with reduced GFR. At follow-up, low HDL-C levels were associated with earlier entry in dialysis or doubling of the plasma creatinine level (P = 0.017); HDL-C levels were the only lipid parameter that affected the progression of CKD (hazard ratio 0.951, 95% confidence interval 0.917-0.986, P = 0.007), independently of the presence of diabetes. Only SR-BI-mediated serum cholesterol efflux was significantly reduced in the group of CKD patients with low HDL-C levels compared to the control group. CONCLUSIONS: CKD patients with low levels of plasma HDL-C have a poor prognosis. HDL functionality is also impaired in renal dysfunction. These data support the relevance of HDL in influencing CKD progression.

Energy cost and cardiovascular response to upper and lower limb rhythmic exercise with different equipments in normal-weight and severely obese individuals.

AIMS: The purpose of the study was to assess energy expenditure and cardiovascular response to rhythmic activity with 6 machines exercising different arm and leg muscle groups in normal-weight (NW) and obese (OB) individuals. METHODS: In 16 extremely OB subjects and 15 NW controls, oxygen uptake (VO2), heart rate (HR), blood lactate (LA) concentration and ratings of perceived exertion (RPE) were determined during submaximal rhythmic exercise at different intensities obtained by increasing the frequency of the movement (FOM) with each machine. Peak VO2 (VO2p) for each equipment was determined with incremental tests up to exhaustion, whereas maximal VO2 was estimated at cycle ergometer. RESULTS: Net energy cost (Enet) of exercise increased (p<0.001) for effect of FOM, in both NW and OB with all equipments. Enet was higher in OB than NW during submaximal exercise with Chest/Back, Shoulder Press/Lat Pull, and Leg Press. Higher VO2p were attained with lower limbs than with upper limbs, in both NW (p<0.001) and OB (p<0.001). At the same VO2 (relative to maximal), HR, LA, and RPE were similar in NW and OB but higher during arm than leg activity (p<0.001), while at the same VO2 (relative to VO2p) no difference was detected. CONCLUSION: Enet of rhythmic exercise is higher in OB than NW with machines requiring wide displacement of large body segments. For both NW and OB, physiological responses and RPE are importantly affected by the relative activation of involved muscles. LA concentration is an important determinant of RPE, independent of the limb in activity.

Growth hormone and lactate responses induced by maximal isometric voluntary contractions and whole-body vibrations in healthy subjects.

BACKGROUND: In contrast with maximal voluntary resistance exercise, which is allegedly considered a potent GH stimulus in young subjects, evaluation of GH response to whole-body vibrations (WBV) has yielded conflicting results. METHODS: The acute effects of WBV alone (test A), maximal voluntary isometric contractions (MVC) (test B), and combination of WBV and MVC (test C) on serum GH and blood lactate (LA) levels were studied in 9 healthy adult males. Muscle soreness was assessed 24 and 48 h after exercise by a visual analogue scale. RESULTS: GH responses were significantly higher after tests B and C than after test A (GH peaks: 18.8 ± 9.5 ng/ml or 20.8 ± 13.7 ng/ml, respectively, vs 4.3 ± 3.5 ng/ml; p<0.05), with no difference between tests B and C. LA concentrations significantly increased after tests A, B, and C, being significantly higher after tests B and C than after test A (LA peaks: 2.0 ± 0.5 mmol/l or 6.7 ± 2.3 mmol/l, respectively, vs 7.6 ± 0.9 mmol/l; p<0.05). Peak LA values were significantly correlated to GH peaks in the 3 tests (r=0.48; p<0.05). Muscle soreness was significantly higher 24-48 h after tests B and C than after test A, no significant differences being present between tests B and C. CONCLUSIONS: WBV stimulates GH secretion and LA production, with no additive effect when combined with repeated isometric voluntary contractions. Optimization of protocols based on WBV seems important to maximize the positive effects of this intervention on the somatotropic function.

GH responses to two consecutive bouts of whole body vibration, maximal voluntary contractions or vibration alternated with maximal voluntary contractions administered at 2-h intervals in healthy adults.

BACKGROUND: Pharmacological or exercise stimuli repeated at a short interval (but not electrical muscle stimulation) are associated with a blunting of GH responsiveness. AIM: To compare GH responses to repeated bout of three different GH-releasing stimuli. METHODS: The effects of two consecutive bouts (with a 2-h interval) of whole body vibrations (WBV), maximal voluntary contractions alone (MVC), or alternated with WBV (MVC-WBV) on blood GH and lactate (LA) were assessed in nine young males. RESULTS: Baseline levels of both GH and LA increased significantly after the first bout of all the tested stimuli, and were significantly lower after WBV than after MVC or MVC alternated with WBV, no difference being detected between these last. The administration of a second bout resulted in significantly lower GH increases than those elicited in the first bout in the three different tests; significantly lower LA responses were recorded after the second bout of MVC and MVC-WBV when compared with those obtained after the first bout, while no significant differences were observed after the two WBV bouts for LA. All responses after the second bout of MVC and MVC-WBV were significantly higher than those observed after WBV alone. GH concentrations were significantly correlated with LA after all stimuli, although LA concentrations after the second bout were associated with markedly lower GH levels. CONCLUSIONS: A significant blunting of GH responsiveness ensues after a second bout of different GH-releasing stimuli, independent from the amount of GH released after the first bout. This is a pattern also observed for other pharmacological stimuli and exercise modalities, and suggests a common mechanism underlying different GH-releasing stimuli.

[Unilateral spatial neglect: a dramatic but often neglected consequence of right hemisphere damage]. / Négligence spatiale unilatérale: une conséquence dramatique mais souvent négligée des lésions de l'hémisphère droit.

INTRODUCTION: Unilateral Spatial Neglect (USN) is a common consequence of right brain damage. In the most severe cases, behavioral signs of USN can last several years and compromise patients' autonomy and social rehabilitation. These clinical facts stress the need for reliable procedures of diagnosis and rehabilitation. STATE OF THE ART: The last 3 decades have witnessed an explosion of studies on USN, which raises issues related to complex cognitive activities such as mental representation, spatial attention and consciousness. USN is probably a heterogeneous syndrome, but some of its underlying mechanisms might be understood as an association of disorders of spatial attention. A bias of automatic orienting towards right-sided objects seems typical of left USN. Afterwards, patients find it difficult to disengage their attention in order to explore the rest of the visual scene. Neglected objects are sometimes processed in an "implicit" way. PERSPECTIVES: The development of behavioural paradigms and of neuroimaging techniques and their application to the study of USN has advanced our understanding of the functional mechanisms of attention and spatial awareness, as well as of their neural bases. A number of new procedures for rehabilitation have recently been proposed. CONCLUSION: The present review describes the clinical presentation of USN, its anatomical basis and some of possible accounts of different aspects of neglect behavior. Results of computer simulations and of rehabilitation techniques are also presented with implications for the functioning of normal neurocognitive systems.

Posterior composite restorations in primary molars: an in vivo comparison of three restorative techniques.

This in vivo study evaluated the clinical performance of class II restorations, in primary molars after 12 months. Three restorative techniques were used: filling the cavities in bulk; filling with three horizontal increments and placement in three horizontal increments using pre-polymerized composite inserts. The composite resin used was Prisma TP.H (Caulk-Dentsply) with the adhesive system ScotchbondMultipurpose (3M). Initially 90 class II restorations were placed in 27 patients from 8 to 10 years of age and followed-up for 12 months. After this period 55 restorations were evaluated for anatomic form, color alterations at the margins, presence of decay and marginal adaptation. The results showed that all groups presented similar rates of wear, the bulk insertion technique showed better results for marginal adaptation, color alterations of the margins and less presence of caries at occlusal margins, and that composite resin TP.H could be used in class II restorations in primary molars.