MITO END-3: efficacy of avelumab immunotherapy according to molecular profiling in first-line endometrial cancer therapy.

BACKGROUND: Immunotherapy combined with chemotherapy significantly improves progression-free survival (PFS) compared to first-line chemotherapy alone in advanced endometrial cancer (EC), with a much larger effect size in microsatellite instability-high (MSI-H) cases. New biomarkers might help to select patients who may have benefit among those with a microsatellite-stable (MSS) tumor. PATIENTS AND METHODS: In a pre-planned translational analysis of the MITO END-3 trial, we assessed the significance of genomic abnormalities in patients randomized to standard carboplatin/paclitaxel without or with avelumab. RESULTS: Out of 125 randomized patients, 109 had samples eligible for next-generation sequencing analysis, and 102 had MSI tested. According to The Cancer Genome Atlas (TCGA), there were 29 cases with MSI-H, 26 with MSS TP53 wild type (wt), 47 with MSS TP53 mutated (mut), and 1 case with POLE mutation. Four mutated genes were present in >30% of cases: TP53, PIK3CA, ARID1A, and PTEN. Eleven patients (10%) had a BRCA1/2 mutation (five in MSI-H and six in MSS). High tumor mutational burden (≥10 muts/Mb) was observed in all MSI-H patients, in 4 out of 47 MSS/TP53 mut, and no case in the MSS/TP53 wt category. The effect of avelumab on PFS significantly varied according to TCGA categories, being favorable in MSI-H and worst in MSS/TP53 mut (P interaction = 0.003); a similar non-significant trend was seen in survival analysis. ARID1A and PTEN also showed a statistically significant interaction with treatment effect, which was better in the presence of the mutation (ARID1A P interaction = 0.01; PTEN P interaction = 0.002). CONCLUSION: The MITO END-3 trial results suggest that TP53 mutation is associated with a poor effect of avelumab, while mutations of PTEN and ARID1A are related to a positive effect of the drug in patients with advanced EC.

Observation of Massless and Massive Collective Excitations with Faraday Patterns in a Two-Component Superfluid.

We report on the experimental measurement of the dispersion relation of the density and spin collective excitation modes in an elongated two-component superfluid of ultracold bosonic atoms. Our parametric spectroscopic technique is based on the external modulation of the transverse confinement frequency, leading to the formation of density and spin Faraday waves. We show that the application of a coherent coupling between the two components reduces the phase symmetry and gives a finite mass to the spin modes.

Hypersensitivity to platinum salts according to BRCA status in ovarian cancer: A retrospective analysis of clinical outcomes and systematic review of literature.

BACKGROUND: Hypersensitivity reactions (HSRs) to platinum are an important issue in the treatment of patients (pts) with ovarian cancer (OC). Germline BRCA mutations have been proposed as a risk factor. We aimed at evaluating the incidence and severity of HSRs to platinum in OC pts. with known BRCA status. PATIENTS AND METHODS: We retrospectively analyzed 432 pts. from 5 Italian Centers. In addition, we performed a systematic review and meta-analysis of published series. RESULTS: Four hundred nine pts. received at least one prior platinum-based treatment line: 314 were BRCA wild type (77%) and 95 were BRCA mutated (23%). There was no statistical difference in exposure to platinum. Incidence of any grade HSRs was higher among BRCA mutated pts. [9% vs 18%, p = 0.019] and the time-to-HSRs curves show that the risk increases with the duration of platinum exposure, in BRCA mutated pts. more than in BRCA wild type. A multivariable analysis showed that harboring a germline BRCA mutation was related to a higher incidence of HSRs (HR: 1.84, 95% CI 1.00-3.99, p = 0.05) while having received pegylated liposomal doxorubicin (PLD) was related to a lower incidence of HSRs (HR: 0.03 95% CI 0.004-0.22, p = 0.001). The systematic review confirmed the higher incidence of HSRs in BRCA mutated pts., though heterogeneity among series was significant. CONCLUSIONS: In OC pts. with BRCA mutations, there is a significantly higher incidence of HSRs to carboplatin, not justified by longer drug exposure. On the other hand, PLD exerted a protective role in our series.

Measurement of the Canonical Equation of State of a Weakly Interacting 3D Bose Gas.

Using a multiple-image reconstruction method applied to a harmonically trapped Bose gas, we determine the equation of state of uniform matter across the critical transition point, within the local density approximation. Our experimental results provide the canonical description of pressure as a function of the specific volume, emphasizing the dramatic deviations from the ideal Bose gas behavior caused by interactions. They also provide clear evidence for the nonmonotonic behavior with temperature of the chemical potential, which is a consequence of superfluidity and Bose-Einstein condensation. The measured thermodynamic quantities are compared to mean-field predictions available for the interacting Bose gas. The limits of applicability of the local density approximation near the critical point are also discussed, focusing on the behavior of the isothermal compressibility.

Observation of Magnetic Solitons in Two-Component Bose-Einstein Condensates.

We experimentally investigate the dynamics of spin solitary waves (magnetic solitons) in a harmonically trapped, binary superfluid mixture. We measure the in situ density of each pseudospin component and their relative local phase via an interferometric technique we developed and as such, fully characterize the magnetic solitons while they undergo oscillatory motion in the trap. Magnetic solitons exhibit nondispersive, dissipationless longtime dynamics. By imprinting multiple magnetic solitons in our ultracold gas sample, we engineer binary collisions between solitons of either the same or opposite magnetization and map out their trajectories.

Exacerbations and Pseudomonas aeruginosa colonization are associated with altered lung structure and function in primary ciliary dyskinesia.

BACKGROUND: Recurrent bacterial infections of the respiratory tract are one of the major clinical features of the primary ciliary dyskinesia (PCD), a rare genetic disease due to malfunctioning of motile cilia. Chronic infections and persistent inflammation of the respiratory system result in progressive lung disease. Aim of the study was to highlight the main factors associated with clinical, functional and anatomical deterioration in PCD patients. METHODS: We retrospectively analyzed data from 58 patients with PCD, 37 adults and 21 children. The demographic and clinical data, forced expiratory volume at 1 s (FEV1) and forced vital capacity (FVC), sputum microbiology and imaging results (chest CT scores-modified Bhalla) were recorded. Patients were stratified according to the number of exacerbations (< 2/year vs ≥ 2/year) and chronic Pseudomonas aeruginosa (PA) colonization. The possible correlations between lung function and chest CT scores were assessed; we also evaluated the correlation between these parameters and the severity scores for bronchiectasis (BSI, FACED and e-FACED). RESULTS: Chest CT scores showed a significant correlation with FEV1 (p = 0.0002), age (p <  0.0001), BMI (p = 0.0002) and number of lung lobes involved (p <  0.0001). PA colonization had an overall prevalence of 32.6%: no significant difference in FEV1 between PA colonized and non-colonized patients was found (p = 0.70), while chest CT score was significantly worse in chronic PA colonized patients (p = 0.009). Patients with a high number of exacerbation (≥ 2/year) were older (p = 0.01), had lower FEV1 (p = 0.03), greater number of lobes involved (p < 0.001) and worse CT score than patients with low number of exacerbations (p = 0.001); they also had higher prevalence of PA chronic bronchial infection (33.3% versus 13.6%, p = 0.10). Multivariable linear regression analyses adjusted for gender, age and BMI showed positive associations between PA colonization and number of exacerbations with severity of disease (number of lobes involved, CT score, BSI, FACED, and e-FACED). CONCLUSIONS: In our PCD population the number of exacerbations (≥ 2/year) and PA colonization were the two most relevant factors associated with severity of disease.

Design and characterization of a compact magnetic shield for ultracold atomic gas experiments.

We report on the design, construction, and performance of a compact magnetic shield that facilitates a controlled, low-noise environment for experiments with ultracold atomic gases. The shield was designed to passively attenuate external slowly varying magnetic fields while allowing for ample optical access. The geometry, number of layers, and choice of materials were optimized using extensive finite-element numerical simulations. The measured performance of the shield is in good agreement with the simulations. From measurements of the spin coherence of an ultracold atomic ensemble, we demonstrate a residual field noise of 2.6 µG and a suppression of external dc magnetic fields by more than five orders of magnitude.

Fertility concerns, preservation strategies and quality of life in young women with breast cancer: Baseline results from an ongoing prospective cohort study in selected European Centers.

OBJECTIVES: Most research addressing needs and concerns of young patients with breast cancer (≤40 years) is retrospective. The HOHO European protocol is a prospective multicenter cohort study of young women with newly diagnosed breast cancer, about fertility, psychosocial and quality of life concerns. Here we report the baseline data and focus on predictors of fertility concerns. MATERIALS AND METHODS: Patient surveys and medical record review were used. The baseline survey included sociodemographic, medical and treatment data as well as questions on fertility concerns and preservation strategies. Subscales from the CAncer Rehabilitation Evaluation System-Short Form (CARES-SF) were administered to measure specific quality of life aspects. Uni- and multivariable modeling were used to investigate predictors of greater fertility concern. RESULTS: Among 297 eligible respondents, 67% discussed fertility issues before starting therapy, 64% were concerned about becoming infertile after treatment, and 15% decided not to follow prescribed therapies. Fifty-four percent of women wished future children before diagnosis; of these, 71% still desired biologic children afterwards. In multivariable analysis, not having children was the only patient characteristic significantly associated with fertility concerns at diagnosis. Twenty-seven percent used fertility preservation strategies. Women who received chemotherapy reported greater physical (p = 0.021) and sexual difficulties (p = 0.039) than women who did not. Women who were married or had a partner reported less psychosocial problems than single women (p = 0.039). CONCLUSIONS: Young women with newly diagnosed breast cancer have several concerns, including, but not limited to, fertility. The HOHO European study provides valuable information to develop targeted interventions.

Differences in biological features of breast cancer between Caucasian (Italian) and African (Tanzanian) populations.

Information on hormone receptor and human epidermal growth factor receptor-2 (HER2) expression in breast cancer is acknowledged as mandatory for prognostic stratification and treatment planning. Data on the biological features of African breast cancers are poor. We decided to compare histopathological and biomolecular characteristics (estrogen and progesterone receptor­ER, PgR, and HER2) of Tanzanian and Italian breast cancers. Differences in proliferating index and androgen receptor (AR) expression in triple-negative patients from the two case series were also assessed. Of the 103 consecutive patients seen at the Bugando Medical Center (Mwanza, Tanzania) from 2003 to 2010, who underwent biopsy or surgical resection of primary breast cancer, 69 patients had tissue samples that were evaluable for estrogen receptor (ER), progesterone receptor (PgR), and HER2. Histopathological assessment and biomolecular determinations were performed at the Cancer Institute of Romagna (IRST IRCCS, Meldola, Italy). Caucasian breast cancers were randomly extracted from an electronic database and matched (1:2 ratio) for year of diagnosis and age at diagnosis. Median age of both populations was 51 years (range 27­84). With respect to Caucasian tumors, Tanzanian breast cancers at diagnosis more frequently showed high histological grade (mainly grade 3) (P = 0.03), advanced clinical stage (III or IV) (P\0.001), ER negativity (52.2 %, P\0.001) and high proliferation (P = 0.0002). Triple-negative tumors were over-represented in Tanzanian women. AR was positive in 38.5 and 38 %of triple-negative Tanzanian and Italian breast cancers, respectively. Our results show that histopathological and biomolecular characteristics in Tanzanian and Italian breast cancers differ substantially. The high frequency of poorly differentiated, ER-negative, highly proliferating tumors, together with advanced stage at presentation, could be considered as the main prognostic factors linked to the high mortality rates for breast cancer in the African population.

Liver metastases from melanoma: hepatic intra-arterial chemotherapy. A retrospective study.

The liver is the primary site of metastases in most uveal melanoma patients. We retrospectively investigated intraarterial chemotherapy (IAC) as treatment for patients with hepatic melanoma metastases.Twenty-three patients (18 with uveal melanoma) received fotemustine (14 patients, 61.9%) or carboplatin (9 patients, 31.1%) via hepatic IAC delivery. The catheter was introduced through percutaneous access to the femoral artery with drugs delivered directly to the hepatic artery, and was removed at the end of each treatment cycle. A total of 3 cycles was planned, repeated every 21 days. However, patients with a clinical response could receive more than 3 cycles, provided that the toxic effects were acceptable.IAC was well tolerated and no catheter-related complications or grade 4 toxicities were reported. Considering only uveal melanoma patients, the overall response rate and disease control rate was 16.7% and 38.9%, respectively. Median time to progression was 6.2 months (95% CI 3.7-10.5) and median overall survival was 21 months (95% CI 8-39).IAC is well tolerated and is a valid choice for patients with a poor prognosis since median survival rates are among the longest reported.

Double blind, controlled study of the efficacy and safety of alpidem in the treatment of anxiety in schizophrenic in-patients.

In this double-blind study, alpidem, a new imidazo-pyridine anxiolytic drug, was compared with placebo in order to test its efficacy and safety in chronic schizophrenic in-patients suffering from anxiety not directly related to the schizophrenic process. Sixty-six patients aged from 18 to 65 entered the trial. They also scored at least 18 on the Hamilton Rating Scale for Anxiety (HRSA) after a seven-day placebo run-in. Improvement in symptoms was evaluated by means of the HRSA, the Brief Psychiatric Rating Scale (BPRS), a Visual Analogue Scale (VAS), and the Clinical Global Impression score (CGI). Thirty-three patients were randomly allocated to alpidem and 33 to placebo. Alpidem was significantly more effective (P less than 0.0001) than placebo in improving HRSA scores (total score and factorial scores for somatic and psychic anxiety), BPRS, and VAS. Considering the results of CGI at 21 day, more patients were moderately to markedly improved on alpidem (30/33) than on placebo (2/33) (P less than 0.0001). The efficacy index, according to CGI, was significantly better (P less than 0.001 at least) for alpidem than for placebo. Side-effects were negligible in both groups.

A double-blind, placebo-controlled study of alpidem, a novel anxiolytic of imidazopyridine structure, in chronically anxious patients.

In this double-blind study alpidem, a new imidazopyridine anxiolytic drug, was compared with placebo to assess its efficacy and safety in severely anxious patients at the fixed dose of 150 mg/day (50 mg t.i.d.) for 3 weeks. Fifty-nine patients with a score of at least 18 on the Hamilton Rating Scale for Anxiety (HRSA) entered the trial after a 3- to 7-day placebo run-in period. Symptom improvement was evaluated with the HRSA, the State and Trait Anxiety Inventory (STAI-1 and STAI-2), a Visual Analogue Scale (VAS) and the Clinical Global Impression (CGI). Alpidem was more effective than placebo in improving mean HRSA (total score and factorial scores for somatic and psychic anxiety), STAI-1 and STAI-2 and VAS scores. The efficacy index of the CGI was better for alpidem than for placebo. Side effects were negligible in both groups. Alpidem appears to be a new interesting anxiolytic drug devoid of significant sedative effects on mental functions.

Alpidem, a novel anxiolytic drug. A double-blind, placebo-controlled study in anxious outpatients.

The anxiolytic activity of alpidem (150 mg/day) and its effects on psychomotor performances were compared with placebo in 60 outpatients. The trial was a double-blind, parallel group, and the two treatments were administered orally in three divided doses for 3 weeks. Eighteen male and 42 female patients (mean age, 39.6 years) suffering from generalized anxiety or adjustment disorder with anxious mood of at least 1-month duration entered the trial at the end of a 1-week placebo run-in period designed to exclude early placebo responders. Efficacy was assessed with the Hamilton rating scale for anxiety (HRSA), the state-trait anxiety inventory (STAI x 1: anxiety as state), a visual analogue scale (VAS), and clinical global impression (CGI). Psychomotor performance was assessed by the digit symbol substitution test (DSST). Alpidem was significantly more effective than placebo in decreasing the severity of anxiety, both in the physician's judgment [total HRSA (p = 0.007), psychic symptoms (p = 0.0040), somatic symptoms (p = 0.0002)] and in the patients' evaluation [STAI x 1 (p = 0.0001) and VAS (p = 0.0003)]. Psychomotor performance was improved by both treatments; there was no difference between results with alpidem and placebo at the DSST (p = 0.2801), but the improvement was almost twofold on alpidem. Side effects were negligible with both treatments and the efficacy index, obtained from the CGI, was significantly better with alpidem than with placebo after day 7 (at least p less than 0.03).

[Cyclic alternating pattern. A new approach to the pharmacology of sleep disorders]. / Les tracés alternants cycliques. Une nouvelle approche en pharmacologie du sommeil.

The Cyclic Alternating Pattern (CAP) is an intrinsic component of normal NREM sleep. This periodic activity is organized in biphasic 40-sec cycles clustered in sequences. CAP sequences are functionally correlated to long lasting arousal instability. CAP is induced by endogenous stimuli (change in sleep stage, body movements) but it is considerably increased by exogenous impulses (noise). CAP rate (CAPR) is a novel polysomnographic variable that measures the amount of CAP during sleep, and it may be calculated for total sleep time and total NREM sleep. We demonstrated that all-night exposure to a 45 dB(A) white noise induced a significant CAPR increase, correlated with impaired sleep quality, even without changes in sleep architecture. We hypothesized that administration of an hypnotic should attenuate this CAPR rise. This hypothesis was verified in a double-blind placebo study, in which 12 healthy young adults received zolpidem, a new imidazopyridine hypnotic. During the noise perturbed nights, zolpidem clearly demonstrated a protective effect on CAPR (mainly during slow wave sleep) and on sleep quality. CAPR appears to be a sensitive indicator of sleep quality, and the cumulative distribution of CAPR throughout the night represents a new method to evaluate the effects of an hypnotic in sleep.

Zolpidem-polysomnographic study of the effect of a new hypnotic drug in sleep apnea syndrome.

Clinical studies have shown that zolpidem, an original imidazopyridine derivative, induces and maintains sleep and does not have daytime side-effects. Polysomnography has revealed that this drug has several interesting qualities that benzodiazepines do not possess: stages 3-4 increase, stage 2 is unchanged or slightly reduced and no abnormal changes are detected on the EEG tracing. Like benzodiazepines, zolpidem slightly reduces REM sleep. The Multiple Sleep Latency Test confirmed that the drug does not cause daytime drowsiness. All the hypnotic drugs studied up to now worsen heavy snoring and obstructive sleep apnea syndrome. A controlled double blind cross-over trial assessed the effects of a single dose of zolpidem 20 mg on nocturnal breathing in patients with mild forms of sleep apnea syndrome. The results indicate that, at this dose, the drug does not overcome the existing contraindications to the use of hypnotics in this syndrome.

Variations of cyclic alternating pattern rate and homeostasis of sleep organization: a controlled study on the effects of white noise and zolpidem.

The Cyclic Alternating Pattern (CAP) is a physiologic structure of normal non-REM (NREM) sleep, functionally correlated to long-lasting arousal instability. In 12 healthy volunteers, a continuous 45 dB (A) white noise induced no remarkable changes on the standard sleep parameters. However, compared to the baseline conditions, the acoustic perturbation determined a significant increase of the Cyclic Alternating Pattern Rate (CAPR), that measures the amount of CAP during sleep. Ten mg of zolpidem, a novel imidazopyridine hypnotic compound, did not modify the structure of unperturbed sleep, but induced a highly significant reduction of the increased values of CAP Rate due to white noise. The homeostatic function of CAP is stressed. CAPR appears to be a highly sensitive indicator of environmental modification during sleep.

[Long-term development of chronic hepatitis caused by virus B in childhood]. / L'evoluzione a distanza dell'epatite cronica da virus B in età pediatrica.

Ten children with chronic hepatitis B have been followed for at least 3 years. All patients received 2 liver biopsies, the first after 1 year of continuous liver disfunction and HBsAg positivity, and the second 2 years after, that showed a mild improvement of the histologic lesions in 4 cases of chronic persistent hepatitis (CPH) and in 1 case of chronic lobular hepatitis (CLH). Three children out of 5 with chronic active hepatitis (CAN) changed to CPH and the other 2 remained unchanged without any evidence of cirrhosis. No patient received any drug for the treatment of hepatitis.