Unresolved Gamma-Ray Sky through its Angular Power Spectrum.

The gamma-ray sky has been observed with unprecedented accuracy in the last decade by the Fermi -large area telescope (LAT), allowing us to resolve and understand the high-energy Universe. The nature of the remaining unresolved emission [unresolved gamma-ray background (UGRB)] below the LAT source detection threshold can be uncovered by characterizing the amplitude and angular scale of the UGRB fluctuation field. This Letter presents a measurement of the UGRB autocorrelation angular power spectrum based on eight years of Fermi-LAT Pass 8 data products. The analysis is designed to be robust against contamination from resolved sources and noise systematics. The sensitivity to subthreshold sources is greatly enhanced with respect to previous measurements. We find evidence (with ∼3.7σ significance) that the scenario in which two classes of sources contribute to the UGRB signal is favored over a single class. A double power law with exponential cutoff can explain the anisotropy energy spectrum well, with photon indices of the two populations being 2.55±0.23 and 1.86±0.15.

Androgen excess and metabolic disorders in women with PCOS: beyond the body mass index.

BACKGROUND: Insulin resistance is a common feature among women with polycystic ovary syndrome (PCOS), especially in those patients with hyperandrogenism and chronic anovulation. PCOS women are at risk for developing metabolic syndrome, impaired glucose tolerance and type II diabetes mellitus (DM II). OBJECTIVE: The aim of this review is to explore the existing knowledge of the interplay between androgen excess, pancreatic ß-cell function, non-alcoholic fatty liver disease (NAFLD), intra-abdominal and subcutaneous (SC) abdominal adipocytes in PCOS, providing a better comprehension of the molecular mechanisms of diabetologic interest. METHODS: A comprehensive MEDLINE® search was performed using relevant key terms for PCOS and DM II. RESULTS: Insulin-induced hyperandrogenism could impair pancreatic ß-cell function, the SC abdominal adipocytes' lipid storage capacity, leading to intra-abdominal adipocyte hypertrophy and lipotoxicity, which in turn promotes insulin resistance, and could enhance NAFLD. Fetal hyperandrogenism exposure prompts to metabolic disorders. Treatment with flutamide showed to partially reverse insulin resistance. CONCLUSIONS: Metabolic impairment seems not to be dependent only on the total fat mass content and body weight in women with PCOS and might be ascribed to the androgen excess.

Search for Cosmic-Ray Electron and Positron Anisotropies with Seven Years of Fermi Large Area Telescope Data.

The Large Area Telescope on board the Fermi Gamma-ray Space Telescope has collected the largest ever sample of high-energy cosmic-ray electron and positron events since the beginning of its operation. Potential anisotropies in the arrival directions of cosmic-ray electrons or positrons could be a signature of the presence of nearby sources. We use almost seven years of data with energies above 42 GeV processed with the Pass 8 reconstruction. The present data sample can probe dipole anisotropies down to a level of 10^{-3}. We take into account systematic effects that could mimic true anisotropies at this level. We present a detailed study of the event selection optimization of the cosmic-ray electrons and positrons to be used for anisotropy searches. Since no significant anisotropies have been detected on any angular scale, we present upper limits on the dipole anisotropy. The present constraints are among the strongest to date probing the presence of nearby young and middle-aged sources.

Search for Spectral Irregularities due to Photon-Axionlike-Particle Oscillations with the Fermi Large Area Telescope.

We report on the search for spectral irregularities induced by oscillations between photons and axionlike-particles (ALPs) in the γ-ray spectrum of NGC 1275, the central galaxy of the Perseus cluster. Using 6 years of Fermi Large Area Telescope data, we find no evidence for ALPs and exclude couplings above 5×10^{-12} GeV^{-1} for ALP masses 0.5≲m_{a}≲5 neV at 95% confidence. The limits are competitive with the sensitivity of planned laboratory experiments, and, together with other bounds, strongly constrain the possibility that ALPs can reduce the γ-ray opacity of the Universe.

Resolving the Extragalactic γ-Ray Background above 50 GeV with the Fermi Large Area Telescope.

The Fermi Large Area Telescope (LAT) Collaboration has recently released a catalog of 360 sources detected above 50 GeV (2FHL). This catalog was obtained using 80 months of data re-processed with Pass 8, the newest event-level analysis, which significantly improves the acceptance and angular resolution of the instrument. Most of the 2FHL sources at high Galactic latitude are blazars. Using detailed Monte Carlo simulations, we measure, for the first time, the source count distribution, dN/dS, of extragalactic γ-ray sources at E>50 GeV and find that it is compatible with a Euclidean distribution down to the lowest measured source flux in the 2FHL (∼8×10^{-12} ph cm^{-2} s^{-1}). We employ a one-point photon fluctuation analysis to constrain the behavior of dN/dS below the source detection threshold. Overall, the source count distribution is constrained over three decades in flux and found compatible with a broken power law with a break flux, S_{b}, in the range [8×10^{-12},1.5×10^{-11}] ph cm^{-2} s^{-1} and power-law indices below and above the break of α_{2}∈[1.60,1.75] and α_{1}=2.49±0.12, respectively. Integration of dN/dS shows that point sources account for at least 86_{-14}^{+16}% of the total extragalactic γ-ray background. The simple form of the derived source count distribution is consistent with a single population (i.e., blazars) dominating the source counts to the minimum flux explored by this analysis. We estimate the density of sources detectable in blind surveys that will be performed in the coming years by the Cherenkov Telescope Array.

Alexithymia, more than depression, influences glycaemic control of type 2 diabetic patients.

PURPOSE: Psychiatric disorders could affect the patients' abilities to cope with diabetes. The objectives of this study were to assess the prevalence of depression and alexithymia among type 2 diabetic patients and investigate the possible correlations between these psychopathological phenomena and glycaemic control assessed through glycated hemoglobin (HbA1c). METHODS: All the patients were evaluated through 20-item Toronto Alexithymia Scale (TAS-20), Hamilton rating scale for depression and Quality of Life Index. HbA1c values, diabetes duration, therapy and socio-demographic characteristics were recorded. RESULTS: One hundred and twenty-eight patients (75 males and 53 female, mean age 64.7 ± 11.2 years) were enrolled. Alexithymic patients, compared to non-alexithymic ones, presented a significantly higher HbA1c (7.7 ± 1.5 vs. 7 ± 1.5, p = 0.016). No statistically significant difference was found when comparing the HbA1c of depressed versus non-depressed patients. Considering the raw values of HbA1c, the higher percentage was recorded among patients suffering from depression plus alexithymia (comorbidity group) followed by patients presenting alexithymia only, patients with neither depression nor alexithymia (control group) and, finally, those presenting depression only. The comorbidity group presented a significantly higher value of HbA1c (7.7 ± 1.2) than the control group (7 ± 1.6, p < 0.04) and the depressed patients (6.9 ± 1.3, p = 0.04). At the logistic regression, the HbA1c was found to be significantly associated only with alexithymia (TAS-20 total score) and insulin therapy. CONCLUSIONS: Alexithymia more than depression influences glycaemic control. When evaluating a diabetic patient, a rapid screening for psychopathological alterations would guarantee a more accurate management. The treatment of any associated psychiatric disorders would improve the patients' quality of life.

Balance control impairment induced after OKS in patients with vestibular migraine: an intercritical marker.

The aim of the study was to assess the effects of optokinetic stimulation (OKS) on vestibular postural control in migraine patients with recurrent vertigo. 15 patients with vestibular migraine (VM) were enrolled in a posturographic study in eyes open (OE) and eyes closed (CE) condition. The tests were performed between attacks of headache and vertigo at three different time: before, during, and 60 min after OKS. Data of patients with VM were compared with those obtained from two control groups matched for sex and age (15 for each group): (a) normal subjects not suffering from migraine without history of recurrent vertigo (N group); (b) subjects suffering from migraine with no history of recurrent vertigo (M group). Mean sway path velocity and sway area were analyzed. OKS increased the instability in all groups during the stimulus, and both the velocity and area values were higher in M and VM group. However, there was not significant difference between these two groups when stability was examined in OE condition before, during and after OKS stimulation. Conversely, in CE condition a significant greater instability was induced after OKS stimulation only in VM. In particular, post-stimulus values were significantly higher than the pre-stimulus one only in this group, while no significant difference was observed in other groups. A spatial analysis of the sway area evidenced that the instability induced by the OKS in VM group occurred along the direction of OKS. We suggest that this enhanced instability observed after OKS during the intercritical period may be considered an useful marker to support the diagnostic definition of VM in the absence of other vestibular signs.

Prevalence of male accessory gland inflammations/infections in patients with Type 2 diabetes mellitus.

BACKGROUND: MAGI is an acronym that identifies the "male accessory gland inflammations/infections", a potential cause of male infertility. Type 2 diabetes mellitus (DM2) prevalence is going to increase among men of reproductive age. Due to the high prevalence of these two conditions, we could suppose that they might appear together in the same patient. AIM: To evaluate MAGI prevalence in patients with DM2 in fertile age. SUBJECTS AND METHODS: A cross-sectional study carried out on patients with DM2 of fertile age. All patients underwent andrological evaluation for the identification of conventional MAGI diagnostic criteria. RESULTS: DM2 patients showed a frequency of MAGI about 43%, significantly lower (p<0.05) than in infertile patients of the same age without diabetes, which showed a MAGI overall frequency of 61%. Among examined diabetic patients the prevalence of MAGI did not significantly differ between patients attending for diabetes care problems (glycemic control) and patients with andrological disorders. Finally, no significant difference in seminal inflammatory signs frequency was detected between patients with DM2 and infertile patients without diabetes. Finally, the correlation analysis showed a significant direct correlation between duration of diabetes and glycemic control with the prevalence of MAGI. CONCLUSION: MAGI prevalence in DM2 is lower than the one detected in age-matched infertile non-diabetic patients, however, as in infertile patients, there is a high frequency of seminal inflammatory signs. Moreover, the observed prevalence among diabetic patients with diabetes care problems and diabetic patients with andrological problems is not statistically different.

The immunobiology of apotransferrin in type 1 diabetes.

The transferrin (Tf) family of iron binding proteins includes important endogenous modulators of the immune function that may modulate autoimmune diseases. To define more clearly the role of apotransferrin (apoTf) in type 1 diabetes we determined the impact of this protein on type 1 diabetes as investigated in islet cells, animal models and patient sera. First, we demonstrated that recombinant apoTf counteracts the cytokine-induced death of murine pancreatic islet cells. Secondly, human apoTf administration favourably influences the course of type 1 diabetes in animal models, resulting in protection against disease development that was associated with reduction of insulitis and reduced levels of proinflammatory cytokines. Finally, we confirmed that patients with newly diagnosed type 1 diabetes manifest significantly lower apoTf serum levels compared to healthy controls and patients with long-lasting disease. In conclusion, our data suggest the apoTf pivotal role in the perpetuation of type 1 diabetes pathology.

Serial measurements of NT-proBNP are predictive of not-high-dose anthracycline cardiotoxicity in breast cancer patients.

BACKGROUND: The aim of this study was to assess the value of N-terminal pro-brain natriuretic peptide (NT-proBNP) in predicting late cardiotoxicity in patients treated with not-high-dose chemotherapy (NHDC), and to compare the predictive value of NT-proBNP and cardiac troponin I (cTnI). METHODS: In 71 patients undergoing NHDC with anthracyclines, NT-proBNP and cTnI levels were measured before and 24 h after each NHDC cycle. Left ventricular (LV) function was assessed by echocardiography at baseline, every two NHDC cycles, at the end of chemotherapy, and at 3-, 6- and 12-month follow-up. RESULTS: During NHDC, only NT-proBNP showed abnormal values. According to NT-proBNP behaviour, patients were divided into two groups: group A (n=50) with normal (n=23) or transiently elevated NT-proBNP levels (n=27), and group B (n=21) with persistently elevated NT-proBNP levels. At follow-up, LV impairment was significantly worse in group B than in group A. %Δ (baseline-peak) NT-proBNP was predictive of LV impairment at 3-, 6- and 12-month follow-up, with a cutoff of 36%. CONCLUSION: Serial measurements of NT-proBNP may be a useful tool for the early detection of patients treated with NHDC at high risk of developing cardiotoxicity.

Left ventricular surgical remodeling after the STICH trial.

Surgical treatment of anteroseptal scars has been, and still is, a challenging task for cardiac surgeons. Most patients are in heart failure and the infarcted areas can include different parts of the septum and the anterior wall. The core problem of ischemic congestive heart failure is the undue demand placed on the residual viable left ventricle myocardium. The surgical techniques used to correct the mismatch between contractile and asynergic areas differ, but the evolution of surgical techniques for left ventricular surgical remodeling (LVSR) is still a work in progress. The most popular one was proposed by Dor et al. in the 1980s and is still in general use. This technique addressed the problem of recovering a predictable volume but not necessarily the problem of rebuilding a physiologically conical shape. This anatomical aspect is becoming increasingly important, and the purpose of septal reshaping, as proposed by us in 2004, is more to recover a conical shape than to achieve volume reduction. Thus, we use the Dor operation only when septoapical scars are present. The need for a different surgical strategy is emphasized by the result of the STICH trial, which reports the data of 1000 patients randomized for coronary artery bypass grafting (CABG, n = 499) or CABG and LVSR (n = 501) and which failed to show any benefit of LVSR. However, the only surgical technique used was the classic Dor operation, where the purpose was to reestablish volume and not to recreate a physiological shape. This study, however, does not provide a definitive answer, as echocardiography results included only 212 patients in the CABG arm and 161 in the CABG and LVSR arm. Furthermore, previous myocardial infarction (MI) was not a prerequisite for study inclusion (13 % of patients in each group had no previous MI) and whether a previous MI was Q-wave or not was not specified. In conclusion, the long-term results after LVSR are satisfactory but appear to be better if a conical shape has been recreated. The role of preemptive surgery in selected cases and how to establish the limits of LVSR (grade of preoperative diastolic dysfunction, diastolic diameter, ventricular volumes, function of the remote zone, etc.) is still unclear. The impact of each individual treatment in the individual patient (medical treatment, CABG alone, CABG and LVSR) has still to be identified.

A double blind randomized controlled trial investigating efficacy and safety of varenicline for smoking cessation in patients with type 2 diabetes: study protocol.

Reducing exposure to cigarette smoke is an imperative for public health and for diabetic patients. Patients with diabetes who continue to smoke face challenges at quitting and the delivery of effective smoking cessation interventions is a major unmet need. The high-affinity α4ß2 nicotinic acetylcholine receptor partial agonist varenicline in combination with counseling is effective for smoking cessation, but evidence in patients with diabetes is limited. A clinical trial of varenicline targeted specifically at smokers with T2DM is warranted. This randomized, double blind, placebo-controlled trial will be the first study to test efficacy and safety of varenicline in smokers with type 2 diabetes mellitus (T2DM) over the course of 52 weeks. We hypothesize that varenicline treatment (1 mg BID, administered for 12 weeks) would increase quit rates, maintain smoking abstinence up to 1 year after treatment, and be well-tolerated in T2DM smokers intending to quit. Efficacy end points will include carbon monoxide-confirmed continuous abstinence rate (CAR) and 7-day point prevalence of abstinence. The results of this RCT will help inform medical/health authorities and physicians worldwide whether an optimally varenicline-treated cohort of T2DM patients who smoke will experience significant success rates, without significant side effects.Trial registration NCT01387425 ( https://clinicaltrials.gov/ct2/show/NCT01387425 ).

NAD(P)H oxidase and pro-inflammatory response during maximal exercise: role of C242T polymorphism of the P22PHOX subunit.

Intense exercise induces a pro-inflammatory status through a mechanism involving the NAD(P)H oxidase system. We focused our attention on p22phox, a subunit of the NAD(P)H oxidase, and on its allelic polymorphism C242T, which is known to affect the functional activity of the enzyme. We investigated whether the p22phox C242T variants exhibit systemic effects in healthy subjects by analyzing the proinflammatory and cardiocirculatory responses to physical exercise in endurance athletes. The group of study consisted of 97 long distance runners, 37 +/- 4.4 yrs of age, with similar training history. The subjects underwent a maximal stress test during which both inflammatory and cardiopulmonary parameters were monitored. Our results demonstrate that T allele deeply influences the neutrophil activation in response to intense exercise, since T carriers were characterized by significantly lower release of myeloperoxidase (MPO), a classical leukocyte derived pro-inflammatory cytokine. In addition, the presence of T allele was associated with a higher cardiopulmonary efficiency as evidenced by a significantly lower Heart Rate (HR) at the peak of exercise and, when a dominant model was assumed, by a higher maximal oxygen uptake (VO2 max). On the other hand, no effects of 242T mutation on the plasmatic total antioxidant capacity (TAC) and on the cortisol responses to the physical exercise were detected. In conclusion, our data support a systemic role for p22phox C242T polymorphism that, modifying the intensity of the inflammatory response, can influence the cardiovascular adaptations elicited by aerobic training. These results contribute to support the hypothesis of a systemic effect for the C242T polymorphism and of its possible functional rebound in healthy subjects.

Noradrenaline modulates neuronal responses to GABA in vestibular nuclei.

The effects of noradrenaline (NA) on the inhibitory responses to GABA were studied in vivo in neurons of the vestibular nuclei of the rat using extracellular recordings of single unit electrical activity and a microiontophoretic technique of drug application in loco. NA application influenced GABA-evoked inhibitions in 82% of tested neurons, depressing them in 42% and enhancing them in 40% of cases. The more frequent action of NA on GABA responses was depressive in lateral and superior vestibular nuclei (50% of neurons) and enhancing in the remaining nuclei (56% of neurons). The most intense effect of NA application was the enhancement of GABA responses induced in a population of lateral vestibular nucleus neurons, characterized by a background firing rate significantly higher than that of other units. The alpha(2) noradrenergic receptor agonist clonidine mimicked the enhancing action of NA on GABA responses; this action was blocked by application of the specific alpha(2) antagonist yohimbine. The beta adrenergic agonist isoproterenol induced either depressive or enhancing effects on GABA responses; the former more than the latter were totally or partially blocked by application of the beta antagonist timolol. It is concluded that NA enhances GABA responses by acting on noradrenergic alpha(2) and to a lesser extent beta receptors, whereas depressive action involves beta receptors only. These results confirm the hypothesis that the noradrenergic system participates in the regulation of the vestibulospinal and the vestibulo-ocular reflexes and suggest that conspicuous changes of NA content in brain due to aging or stress could lead to a deterioration in the mechanisms of normal vestibular function.

Testosterone therapy improves the clinical response to conventional treatment for male patients with metabolic syndrome associated to late onset hypogonadism.

AIM: Recently, the clinic characterization of the gonadic male function has been put in tight correlation on the pathogenetic level with the main variables forming the condition of metabolic syndrome (MS); probably the serum testosterone (T) concentration in males is to be considered as an additional parameter completely related to the traditional clinical-metabolic findings. Currently the matter of the substitutive hormonal therapy with androgens is apparently influenced by some important unresolved aspects: 1) who really benefits from the T therapy? 2) are the actual dosage methods of T reliable? 3) which vascular and metabolic targets are to be monitored during the T therapy? METHODS: In an analytical longitudinal study, carried out 12 months long on 60 men (average age 58 years, range 54-63 years) affected by metabolic syndrome (MS) and combined hypogonadism late onset (LOH), authors have evaluated the clinical response (androgenic asset, non-invasive hospital monitoring of the arterial pressure, lipidic asset study, body composition and the biologic resistance to the insulinic action) after conventional medical therapy (insulin-sensibilizing and anti-hypertensive) and after substitutive hormonal therapy with testosterone (T) by transdermic way. A group of five patients with MS and LOH, not treated, was used as group of control. RESULTS: The group of patients treated with T showed a profile of clinical response better than the group of controls. CONCLUSIONS: In conclusion, the seric determination of T is useful to better characterize the dismetabolic patient at the moment of the first level active medical therapy planning on the controls of the main risk factors constituting MS, expressing a potential role of conditioning.

Investigating the Nature of Late-Time High-Energy GRB Emission Through Joint Fermi /Swift Observations.

We use joint observations by the Neil Gehrels Swift X-ray Telescope (XRT) and the Fermi Large Area Telescope (LAT) of gamma-ray burst (GRB) afterglows to investigate the nature of the long-lived high-energy emission observed by Fermi LAT. Joint broadband spectral modeling of XRT and LAT data reveal that LAT non-detections of bright X-ray afterglows are consistent with a cooling break in the inferred electron synchrotron spectrum below the LAT and/or XRT energy ranges. Such a break is sufficient to suppress the high-energy emission so as to be below the LAT detection threshold. By contrast, LAT-detected bursts are best fit by a synchrotron spectrum with a cooling break that lies either between or above the XRT and LAT energy ranges. We speculate that the primary difference between GRBs with LAT afterglow detections and the non-detected population may be in the type of circumstellar environment in which these bursts occur, with late-time LAT detections preferentially selecting GRBs that occur in low wind-like circumburst density profiles. Furthermore, we find no evidence of high-energy emission in the LAT-detected population significantly in excess of the flux expected from the electron synchrotron spectrum fit to the observed X-ray emission. The lack of excess emission at high energies could be due to a shocked external medium in which the energy density in the magnetic field is stronger than or comparable to that of the relativistic electrons behind the shock, precluding the production of a dominant synchrotron self-Compton (SSC) component in the LAT energy range. Alternatively, the peak of the SSC emission could be beyond the 0.1-100 GeV energy range considered for this analysis.

Bioelectrical impedance analysis and diabetes mellitus: which correlation among fructosamine, glycosylated haemoglobin and exchangeable potassium.

AIM: Bioelectrical impedance analysis (BIA) can monitor diabetics suffering from the frequently occurring state of hyperglycemia, as this can cause alterations in the water distribution in the body. The aim of the present study was to evaluate the relationship between the composition of the body and the diabetic disease during decompensation through the impedanciometric analysis in diabetic patients of type 1 and type 2 and to understand the possible alterations of water distribution. METHODS: The study was carried out with 52 subjects (8 males, 44 females), average years 46.5; 15 of them were diabetic, 7 characterised by diabetes of type 1 and 8 by diabetes of type 2. All the patients recruited were in poor metabolic control (glycosylated hemoglobin [HbAlc] >6%). In order to avoid any errors during the evaluation ofa water distribution in the body, patients suffering from hypertension were excluded from the recruitment process. All patients underwent impedanciometry total body using the HUMAN IM SCAN apparatus multifrequency. RESULTS: Through the application of BIA, our work has shown how diabetic patients have a lower quantity of extracellular water (ECW) and exchangeable potassium (Ke) in the body, as compared to non-diabetic patients. The causes of this could be the alteration of the plasmic osmolarity and the possible reduction of the mass of metabolically active cells. Further-more a relationship between fructosamine in the blood and Ke has been found and, alongside another, more significant, between HbA1c and Ke. According to the opinions of the authors, such results are worthy for further studies in order to obtain a greater accuracy in the evaluation of the amount of Ke and an alternative in estimation of metabolic control.

Randomized trial of fenretinide to prevent second breast malignancy in women with early breast cancer.

BACKGROUND: Fenretinide, a vitamin A analogue, has been shown to inhibit breast carcinogenesis in preclinical studies. We determined the efficacy of fenretinide in preventing a second breast malignancy in women with breast cancer. METHODS: We randomly assigned 2972 women, aged 30-70 years, with surgically removed stage I breast cancer or ductal carcinoma in situ to receive for 5 years either fenretinide orally (200 mg/day) or no treatment. The primary end point was the incidence of contralateral breast cancer or ipsilateral breast cancer 7 years after randomization. Other end points considered post hoc were the same outcomes stratified by menopausal status, incidence of distant metastases, overall mortality, and tumors in other organs. The hazards of breast cancer occurrence were determined by Cox proportional hazards regression analysis. Statistical tests were two-sided. RESULTS: At a median observation time of 97 months, there were no statistically significant differences in the occurrence of contralateral breast cancer (P =.642) or ipsilateral breast cancer (P =.177) between the two arms. However, an interaction was detected between fenretinide treatment and menopausal status in both outcomes (P for interaction in both outcomes =.045), with a possible beneficial effect in premenopausal women (contralateral breast cancer: adjusted hazard ratio [HR] = 0.66, and 95% confidence interval [CI] = 0.41-1.07; ipsilateral breast cancer: adjusted HR = 0.65, and 95% CI = 0.46-0. 92) and an opposite effect in postmenopausal women (contralateral breast cancer: adjusted HR = 1.32, and 95% CI = 0.82-2.15; ipsilateral breast cancer: adjusted HR = 1.19, and 95% CI = 0.75-1. 89). There were no statistically significant differences between the two arms in tumors in other organs, incidence of distant metastasis, and all-cause mortality. CONCLUSIONS: Fenretinide treatment of women with breast cancer for 5 years appears to have no statistically significant effect on the incidence of second breast malignancies overall, although a possible benefit was detected in premenopausal women. These studies, particularly the post hoc analyses, are considered exploratory and need to be confirmed.

Safety of the synthetic retinoid fenretinide: long-term results from a controlled clinical trial for the prevention of contralateral breast cancer.

PURPOSE: To describe the pattern of occurrence of adverse events commonly arising during treatment with fenretinide, a synthetic retinoid under investigation for cancer prevention. PATIENTS AND METHODS: The series includes 2,867 women accrued in a trial aimed at assessing the effect of fenretinide on the prevention of second breast malignancy. Women were randomly assigned to receive no treatment (1,435 patients) or 5-year fenretinide treatment (1,432 patients). In terms of disease recurrence in the breast, the trial showed a possible beneficial effect of the compound in premenopausal women, and an opposite trend in postmenopausal women. End points considered for safety assessment were the occurrence of diminished dark adaptation, dermatologic disorders, gastrointestinal symptoms, disorders of the ocular surface, and abnormal laboratory values. RESULTS: The most common adverse events were diminished dark adaptation (cumulative incidence, 19.0%) and dermatologic disorders (18.6%). Less common events were gastrointestinal symptoms (13.0%) and disorders of the ocular surface (10.9%). In comparison, incidence figures in the control arm were 2.9% for diminished dark adaptation, 2.9% for dermatologic disorders, 5.4% for gastrointestinal symptoms, and 3.2% for disorders of the ocular surface. Symptoms occurring during fenretinide treatment tended to recover with time. No between-group difference was observed for the occurrence of laboratory data abnormalities. Overall, 63 (4.4%) treatment discontinuations were caused by adverse events. CONCLUSION: Given the number of patients involved in the study and the prolonged intake of the drug, the experience on fenretinide tolerability can be considered sufficiently reassuring to justify further testing of the retinoid.

Five-year administration of fenretinide: pharmacokinetics and effects on plasma retinol concentrations.

PURPOSE: Monitoring of fenretinide (4HPR) levels, kinetics, and effects on retinal was performed in patients who participated in a phase I trial and who continued to be treated for 5 years as phase III trial patients. Accumulation of 4HPR in the breast was also assessed. PATIENTS AND METHODS: Plasma concentrations of 4HPR, of its main metabolite N-(4-methoxyphenyl)retinamide (4MPR), and of retinol were assayed by high-performance liquid chromatography (HPLC) in breast cancer patients treated orally with 4HPR 200 mg/d for 5 years with a 3-day drug interruption at the end of each month. RESULTS: 4HPR, at 200 mg/d, resulted in average 4HPR plasma levels of approximately 1 mumol/L, which remained steady and caused steady retinol level reduction; 4MPR levels, similar to those of 4HPR, slightly but significantly increased during the first 35 months, but at 5 years they were similar to those at 5 months. During daily treatment, baseline retinol concentrations were reduced by 71%; after a 3-day drug interruption, all patients recovered and the mean reduction was 38%. After discontinuation of 5-year treatment, 4HPR and 4MPR half-lives (t1/2 beta) were 27 and 54 hours, respectively, similar to those reported after 28 daily treatments. After 6 and 12 months, the concentrations of 4HPR were at the limit of detectability (0.01 mumol/L), whereas those of 4MPR were five times higher. Baseline retinol concentrations were already recovered after 1 month. Accumulation of this retinoid in the breast was evidenced by concentrations of 4HPR and 4MPR in nipple discharge and in breast biopsies that were 10 and 20 times higher, respectively, than those found in plasma. CONCLUSION: 4HPR, at 200 mg/d for 5 years, resulted in constant drug plasma levels and constant retinol level reduction. After treatment interruption, 4HPR plasma concentrations decreased at the limit of detectability at 6 months and baseline retinol plasma concentrations were recovered after 1 month.