Delayed immune-related adverse events with anti-PD-1-based immunotherapy in melanoma.

BACKGROUND: Immune-related adverse events (irAEs) typically occur within 4 months of starting anti-programmed cell death protein 1 (PD-1)-based therapy [anti-PD-1 ± anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4)], but delayed irAEs (onset >12 months after commencement) can also occur. This study describes the incidence, nature and management of delayed irAEs in patients receiving anti-PD-1-based immunotherapy. PATIENTS AND METHODS: Patients with delayed irAEs from 20 centres were studied. The incidence of delayed irAEs was estimated as a proportion of melanoma patients treated with anti-PD-1-based therapy and surviving >1 year. Onset, clinical features, management and outcomes of irAEs were examined. RESULTS: One hundred and eighteen patients developed a total of 140 delayed irAEs (20 after initial combination with anti-CTLA4), with an estimated incidence of 5.3% (95% confidence interval 4.0-6.9, 53/999 patients at sites with available data). The median onset of delayed irAE was 16 months (range 12-53 months). Eighty-seven patients (74%) were on anti-PD-1 at irAE onset, 15 patients (12%) were <3 months from the last dose and 16 patients (14%) were >3 months from the last dose of anti-PD-1. The most common delayed irAEs were colitis, rash and pneumonitis; 55 of all irAEs (39%) were ≥grade 3. Steroids were required in 80 patients (68%), as well as an additional immunosuppressive agent in 27 patients (23%). There were two irAE-related deaths: encephalitis with onset during anti-PD-1 and a multiple-organ irAE with onset 11 months after ceasing anti-PD-1. Early irAEs (<12 months) had also occurred in 69 patients (58%), affecting a different organ from the delayed irAE in 59 patients (86%). CONCLUSIONS: Delayed irAEs occur in a small but relevant subset of patients. Delayed irAEs are often different from previous irAEs, may be high grade and can lead to death. They mostly occur in patients still receiving anti-PD-1. The risk of delayed irAE should be considered when deciding the duration of treatment in responding patients. However, patients who stop treatment may also rarely develop delayed irAE.

The prognostic impact of the extent of ulceration in patients with clinical stage I-II melanoma: a multicentre study of the Italian Melanoma Intergroup (IMI).

BACKGROUND: The presence of ulceration has been recognized as an adverse prognostic factor in primary cutaneous melanoma (PCM). OBJECTIVES: To investigate whether the extent of ulceration (EoU) predicts relapse-free survival (RFS) and overall survival (OS) in PCM. MATERIALS AND METHODS: We retrieved data for 477 patients with ulcerated PCM from databases of the Italian Melanoma Intergroup. Univariate and multivariable Cox proportional hazard models were used to assess the independent prognostic impact of EoU. RESULTS: A significant interaction emerged between Breslow thickness (BT) and EoU, considering both RFS (P < 0·0001) and OS (P = 0·0006). At multivariable analysis, a significant negative impact of EoU on RFS [hazard ratio (HR) (1-mm increase) 1·26, 95% confidence interval (CI) 1·08-1·48, P = 0·0047] and OS [HR (1-mm increase) 1·25, 95% CI 1·05-1·48, P = 0·0120] was found in patients with BT ≤ 2 mm, after adjusting for BT, age, tumour-infiltrating lymphocytes, sentinel lymph node status and mitotic rate. No impact of EoU was found in patients with 2·01-4 mm and > 4 mm BT. CONCLUSIONS: This study demonstrates that EoU has an independent prognostic impact in PCM and should be recorded as a required element in pathology reports.

Obesity in pregnancy as a model to identify women at risk for later metabolic syndrome.

The aim of our study is to identify - in a cohort of obese women - cardiovascular and clinical risk factors in women with previous complicated pregnancies and protective factors in women with previous physiological pregnancies. A total of 135 nonpregnant obese women referring to Policlinico Gemelli in Rome were prospectively collected in 2009-2010. Thirty-two women matched inclusion criteria: 16 reported a previous physiological pregnancy and 16 reported previous obstetric complications. A clinical, instrumental and laboratory evaluation has been performed for each patient. Statistical analysis was performed using StatView Software. Values are expressed as mean ± standard error (SEM). All tests were two-tailed with a confidence level of 95% (p < .05). Statistically significant reduced flow-mediated dilatation (p = .0338), increased serum values of vascular cell adhesion molecule (p = .0154) and higher systolic blood pressure values (p = .0427) have been detected in obese women with previous complicated pregnancies due to gestational diabetes and/or hypertension. In conclusion, obese patients with previous complicated pregnancies develop signs of endothelial dysfunction in the postpartum period. Future research should focus on the early identification of possible molecular mechanisms implicated in the development of glyco-metabolic and cardiovascular diseases in obese patients, since they are at higher risk of metabolic syndrome.

Effect of pravastatin on endothelial function and endothelial progenitor cells in healthy postmenopausal women.

PURPOSE: Coronary heart disease is the leading cause of morbidity and mortality in postmenopausal women. Among statins, pravastatin has been shown to significantly reduce fatal and non-fatal cardiovascular events in primary and secondary prevention trials. The aim of the present research was to investigate whether treatment with pravastatin can modify some indices of cardiovascular risk in healthy postmenopausal women such as significant reductions in total and LDL cholesterol and triglyceride levels. METHODS: 20 patients were randomized in double-blind fashion to treatment for eight weeks with either pravastatin 40 mg/day or placebo, and subsequently, after one-week wash-out, crossed-over to the alternative treatment (placebo or pravastatin) for the following eight weeks. We performed clinical and laboratory investigations, before and at the end of each treatment period, to evaluate patient response to the treatment with pravastatin. RESULTS: After eight weeks pravastatin therapy reduced the median low density lipoprotein (LDL) and total cholesterol (p < 0.01 in both cases). In contrast, insulin level and insulin sensitivity did not show any difference with regard to values observed after placebo treatment. The absolute number of endothelial progenitor cells-colony forming unit (EPC-CFU) was significantly increased by pravastatin treatment (30.6% increase, p < 0.05) and the number of senescent cells was significantly decreased. However pravastatin did not increase tube-like formation by EPC and did not improve endothelial function. CONCLUSIONS: Despite beneficial effect on lipids and EPC, short term pravastatin does not seem to improve other cardiovascular risk factors, at least in healthy postmenopausal women.

[Role of vaginal infection in fetal and neonatal mortality]. / Ruolo delle infezioni vaginali nella mortalità fetale e neonetale.

Preterm delivery is the chief problem in obstetrics today and the main determinant of infant mortality and morbidity. Despite the dramatic decrease in infant mortality rate during the past several years, the percentage of preterm (<37 weeks gestation) and low birth weight (LBW) (<2500) rates remain elevated. Approximately 10% of all births are preterm, with a rate of 1-2% of infant born before the end of the 32 weeks of gestation and with a weight <1500 g. Despite the importance of the problem, the majority of preterm live births remain unexplained, and programmatic attempts at reversing the high level of preterm births have not been successful. Numerous studies have linked bacterial vaginosis, chorioamniotitis and endometritis with preterm birth and LBW, especially among African women. The number of preterm live births among African women is twice the one among Caucasians. Bacterial vaginosis is an independent risk factor for preterm and LBW births and the mechanism by which bacterial vaginosis causes the preterm birth of an infant with LBW is unknown. The aim of this article was to underline the importance of the treatment and early identification of vaginal infection, in particular if due to bacterial vaginosis, as it can have a substantial affect on the incidence of preterm delivery with LBW.

Attention-based visual routines: sprites.

A central role of visual attention is to generate object descriptions that are not available from early vision. Simple examples are counting elements in a display or deciding whether a dot is inside or outside a closed contour (Ullman, Cognition 18 (1984) 97). We are interested in the high-level descriptions of dynamic patterns - the motions that characterize familiar objects undergoing stereotypical action - such as a pencil bouncing on a table top, a butterfly in flight, or a closing door. We examine whether the perception of these action patterns is mediated by attention as a high-level animation or 'sprite'. We have studied the discrimination of displays made up of simple, rigidly linked sets of points in motion: either pairs of points in orbiting motion or 11 points in biological motion mimicking human walking. We find that discrimination of even the simplest dynamic patterns demands attention.

Limits of attentive tracking reveal temporal properties of attention.

The maximum speed for attentive tracking of targets was measured in three types of (radial) motion displays: ambiguous motion where only attentive tracking produced an impression of direction, apparent motion, and continuous motion. The upper limit for tracking (about 50 deg s-1) was an order of magnitude lower than the maximum speed at which motion can be perceived for some of these stimuli. In all cases but one, the ultimate limit appeared to be one of temporal frequency, 4-8 Hz, not retinal speed or rotation rate. It was argued that this rate reflects the temporal resolution of attention, the maximum rate at which events can be individuated from those that precede or follow them. In one condition, evidence was also found for a speed limit to attentive tracking, a maximum rate at which attention could follow a path around the display.

Contrast perception across changes in luminance and spatial frequency.

The interaction of the effects of luminance and spatial frequency on perception of suprathreshold contrast was studied with use of a contrast-matching paradigm. Four subjects matched the appearance of Gabor patches at different luminances and spatial frequencies. The contrast of a 1-octave Gabor test patch at one of five frequencies [1-16 cycles/degree (c/deg) in 1-octave steps] and at one of seven mean luminance levels (0.5-50 cd/m2 in 1/3-log-unit steps) was matched, by the method of adjustment to a standard patch of 3 c/deg at 50 cd/m2 at a nominal contrast of 0.3. For each block of trials the spatial frequency of the test patch was randomly changed (three repetitions at each frequency per block) while the luminance was fixed. The subject regularly shifted fixation between the two targets in response to a metronome tone every 1.5 s. Contrast constancy was demonstrated across the entire luminance range tested for all but the two highest frequencies. For 8 c/deg the perceived test contrast was reduced only when the luminance was less than 2 cd/m2. For 16 c/deg, perceived contrast decreased linearly (with a slope of -1/2 on a log scale) with decreases in luminance across the entire luminance range. As at threshold, reduction in luminance across the levels commonly available on a CRT display has only minimal effects on low-frequency suprathreshold contrast perception. However, the apparent contrast of high-frequency features, in binocular free-viewing conditions, is rapidly reduced with a local reduction in screen luminance. This effect has important implications for visual models used in image-quality analysis.