Immunomodulatory effects of metronomic vinorelbine (mVRL), with or without metronomic capecitabine (mCAPE), in hormone receptor positive (HR+)/HER2-negative metastatic breast cancer (MBC) patients: final results of the exploratory phase 2 Victor-5 study.

Tregs are able of suppressing tumor-specific effector cells, such as lymphocytes CD8+, CD4+ and Natural Killer cells. Different drugs, especially different schedules of administration, like metronomic chemotherapy (mCHT), seem to be able to increase anticancer immunity, by acting on downregulation of Tregs. Most of the data available regarding the immunomodulating effect of mCHT have been obtained with Cyclophosphamide (CTX). Aim of the present study was to explore the effects of mVRL and mCAPE administration, alone or in combination, on T cells. Observation of 13 metastatic breast cancer patients lasted controlling for 56 days, where Treg frequencies and function, spontaneous anti-tumor T-cell responses were monitored, as well as the clinical outcome. No depletion in Treg absolute numbers, or percentage of T lymphocytes, was observed. Only in 5 patients, a modest and transient depletion of Tregs was observed during the first 14 days of treatment. To better describe the effect on Tregs, we subsequently looked at the variations in Memory, Naïve and Activated Treg subpopulations: we observed a trend in reduction for memory Treg (Treg MEM) and an increase for Treg Naïve (Treg NAIVE) and Treg Activated (Treg ACT) components. We finally analyzed the average trend of Treg in the Treg depleted patients and non-depleted ones, without fiding any significant differences. The trend of the Treg MEM appeared different, showing a reduction during the first 14 days, followed by an increase at the levels before treatment at Day 56 in the group of depleted patients and a progressive substantial reduction in the group of non-depleted patients along the entire course of treatment. Opposed to the data known, treatment with mVRL w/o mCAPE did not show any effect on Tregs.

A new factor involved during childbirth labor: the importance of having a good dental occlusion.

It is widely recognized that the physiology of childbirth labor largely depends on the interaction between three factors: a) the force generated by uterine contractions; b) the structure and characteristics of the birth canal and c) the fetus. Harmony between these three variables determines the initiation of maternal dynamic phenomena and the establishment of an optimal maternal-fetal balance in which both warrant for a correct delivery timing. The present study considered the above known factors and assessed if any other factor, still not recognized, could also play a role, and eventually modify the timing of delivery during the expulsive period. In particular, we focused our attention on the role played by the temporomandibular joint and dental occlusion on maternal body balance and on the stability of muscular reflected forces. The importance of assessing the temporomandibular function and the dental occlusion lies in the fact that any alteration in chewing or in temporomandibular joint (TMJ) mobility and occlusion brings to relevant modifications on the vertebral column and pelvic girdle. Our hypothesis is based on the evidence that those women who have any kind of alteration in their dental occlusion, can have an altered capability of pushing during the expulsive period, as the force applied on the pelvic floor is not expressed. Moreover, recent studies have highlighted a relationship between temporomandibular dysfunctions and sleep apnea syndrome and between sleep apnea syndromes and pregnancy. These relationships are explored in this study.

The role of CEA, CYFRA21-1 and NSE in monitoring tumor response to Nivolumab in advanced non-small cell lung cancer (NSCLC) patients.

BACKGROUND: CEA, CYFRA21-1 and NSE are tumor markers used for monitoring the response to chemotherapy in advanced adenocarcinoma, squamous cell carcinoma and small-cell lung cancer, respectively. Their role in cancer immunotherapy needs to be elucidated. METHODS: Patients with advanced non-small cell lung cancer (NSCLC) were treated with nivolumab 3 mg/kg every 2 weeks within the Italian Nivolumab Expanded Access Program. Blood samples were collected at baseline, at each cycle up to cycle 5 and then every two cycles until patient's withdrawn from the study. All patients underwent a CT-scan after every 4 cycles of treatment and responses were classified according to RECIST 1.1. The biomarkers serum levels were measured with a chemiluminescent microparticle immunoassay for CEA and with an immuno radiometric assay for CYFRA21-1 and NSE. The markers values at baseline and after 4 cycles were used to analyze the relationship between their variation over baseline and the tumor response, evaluated as disease control rate (DCR: CR + PR + SD), and survival (PFS and OS). RESULTS: A total of 70 patients were evaluable for the analysis. Overall, a disease control was obtained in 24 patients (35.8%, 4 PR + 20 SD). After 4 cycles of nivolumab a CEA or CYFRA21-1 reduction ≥ 20% over the baseline was significantly associated with DCR (CEA, p = 0.021; CYFRA21-1, p < 0.001), PFS (CEA, p = 0.028; CYFRA21-1, p < 0.001) and OS (CEA, p = 0.026; CYFRA21-1, p = 0.019). Multivariate analysis confirmed the ability of CYFRA21-1 reduction ≥ 20% to predict DCR (p = 0.002) and PFS (p < 0.001). CONCLUSION: The reduction in serum level of CYFRA21-1 or CEA might be a reliable biomarker to predict immunotherapy efficacy in NSCLC patients. NSE was not significant for monitoring the efficacy of nivolumab.

Serum proteomic test in advanced non-squamous non-small cell lung cancer treated in first line with standard chemotherapy.

BACKGROUND: VeriStrat is a blood-based proteomic test with predictive and prognostic significance in second-line treatments for non-small cell lung cancer (NSCLC). This trial was designed to investigate the role of VeriStrat in first-line treatment of advanced NSCLC with standard chemotherapy. Here we present the results for 76 non-squamous patients treated with a combination of carboplatin or cisplatin with pemetrexed. METHODS: The test-assigned classifications of VeriStrat Good or VeriStrat Poor to samples collected at baseline. The primary end point was progression-free survival (PFS); secondary end points included overall survival (OS) and objective response. Exploratory analyses of end points separately in carboplatin/pemetrexed and cisplatin/pemetrexed subgroups were also conducted. RESULTS: Patients classified as VeriStrat Good had longer PFS and OS than VeriStrat Poor: 6.5 vs 1.6 months and 10.8 vs 3.4 months, respectively; the corresponding hazard ratios (HRs) were 0.36 (P<0.0001) and 0.26 (P<0.0001); they were also more likely to achieve objective response. Prognostic significance of VeriStrat was confirmed in multivariate analysis. Significant differences in OS and PFS between Veristrat classifications were also found when treatment subgroups were analysed separately. CONCLUSIONS: The trial demonstrated clinical utility of VeriStrat as a prognostic test for standard first-line chemotherapy of non-squamous advanced NSCLC.

Severe obstructive sleep apnoea syndrome and erectile dysfunction: a prospective randomised study to compare sildenafil vs. nasal continuous positive airway pressure.

BACKGROUND: A high incidence of erectile dysfunction (ED) among patients with obstructive sleep apnoea syndrome (OSAS) has been reported, with a strong correlation between obstructive sleep apnoea, ED, and quality of life (QOL), and it has been estimated that 10-60% of patients with OSAS suffer from ED. In this prospective randomised controlled trial, we investigated 82 men with ED consecutively who were referred to the outpatient clinic for sleep disorders and had severe OSAS (AHI> 30 events/h) without any other comorbidities as a possible cause of ED. The aim of this study was to evaluate and compare the efficacy of sildenafil vs. continuous positive airway pressure (CPAP) in men with ED and severe OSAS. METHODS: Eighty-two patients were randomised to two main treatment groups: group 1 patients (n = 41) were treated with 100-mg sildenafil 1 h before sexual intercourse without CPAP, and group 2 patients (n = 41 men) were treated with only nasal CPAP during night time sleep. Both groups were evaluated with the same questionnaires (International Index of Erectile Function-EF domain; Sex Encounter Profile; Erectile Dysfunction Inventory Treatment Satisfaction) 12 weeks after treatment. RESULTS: In patients receiving sildenafil treatment, 58.2% of those who attempted sexual intercourses were successful compared to 30.4% in the CPAP group. The mean number of successful attempts per week was significantly higher in the sildenafil group compared with the CPAP group (2.9 vs. 1.7, respectively; p < 0.0001). The mean IIEF-EF domain scores were significantly higher in the sildenafil group compared with the CPAP group (p < 0.0001). The overall satisfaction rate was 68% with sildenafil treatment and 29% with CPAP treatment. CONCLUSIONS: This study confirms that severe OSAS is strongly associated with erectile dysfunction. CPAP and sildenafil (100 mg) are safe and effective therapies for OSAS-related ED patients. In the present study sildenafil was more effective than CPAP in treating ED associated with OSAS, as indicated by a significantly higher rate of successful attempts at intercourse and higher IIEF-EF domain scores. Our study, to date, is the only that has investigated sildenafil in patients with severe OSAS.

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.

CHRONOBIOLOGY OF HIGH BLOOD PRESSURE.

BIOCOS, the project aimed at studying BIOlogical systems in their COSmos, has obtained a great deal of expertise in the fields of blood pressure (BP) and heart rate (HR) monitoring and of marker rhythmometry for the purposes of screening, diagnosis, treatment, and prognosis. Prolonging the monitoring reduces the uncertainty in the estimation of circadian parameters; the current recommendation of BIOCOS requires monitoring for at least 7 days. The BIOCOS approach consists of a parametric and a non-parametric analysis of the data, in which the results from the individual subject are being compared with gender- and age-specified reference values in health.Chronobiological designs can offer important new information regarding the optimization of treatment by timing its administration as a function of circadian and other rhythms.New technological developments are needed to close the loop between the monitoring of blood pressure and the administration of antihypertensive drugs.

Synthesis and quality control of viral membrane proteins.

Viruses use the host cellular machinery to translate viral proteins. Similar to cellular proteins directed to the secretory pathway, viral (glyco)proteins are synthesized on polyribosomes and targeted to the endoplasmic reticulum (ER). For viruses that encode polyproteins, folding of the individual proteins of the precursor often is coordinated. Translocation and the start of folding coincide and are assisted by cellular folding factors present in the lumen of the ER. The protein concentration a newborn protein finds in this compartment is enormous (hundreds of mg/ml) and the action of molecular chaperones is essential to prevent aggregation. Viral envelope proteins also undergo the cellular quality control mechanisms, which ensure, with variable stringency, that only proteins with the correct structure will proceed through the secretory pathway. Proteins that are misfolded, or not yet folded, are retained in the ER until they reach the native conformation or until their retrotranslocation into the cytosol for degradation. Peculiar characteristic of viruses is their ability to interfere with the cellular machinery to ensure virus production and, moreover, to pass through the body unobserved by the host immune system. This section describes some mechanisms of genetic variation and viral immune evasion that involve the secretory pathway.

Advances in treatment of mesothelioma.

INTRODUCTION: Malignant pleural mesothelioma (MPM) is an uncommon, aggressive cancer, derived from pleural mesothelial cells, that has a close relationship to asbestos exposure. To date, MPM prognosis is poor and very few treatment options are available for both localized and advanced MPM. AREAS COVERED: The standard of care is still chemotherapy with platinum derivates and antifolate agents. In the last few years, several new agents have been studied on the basis of mesothelioma carcinogenesis and invasiveness mechanisms; however, the recent results are poor and few drugs have been tested in phase III trials because of toxicity or because they did not improve patient outcomes. The aim of this review is to focus on the current available treatment for MPM through the analysis of the results comes from the phase III trials and to discuss the future perspectives in the pathogenesis, diagnosis and treatment. EXPERT OPINION: Many compounds are currently under investigation in different subsets of patients. Interesting data have come from preliminary studies on immunotherapy, but randomized studies are needed to confirm the preliminary positive results of this new strategy. A better comprehension of MPM pathogenesis should be obtained to improve and develop new diagnostic tools and target therapies.

Circadian rhythm of maternal blood pressure and fetal growth.

This study aimed at examining any relation between the circadian variation in blood pressure (BP) in human pregnancy and fetal growth. A prospective study included 52 pregnant women monitored during the third trimester of pregnancy. There were 33 uncomplicated pregnancies with normal fetal growth (Group 1) and 19 pregnancies complicated by intrauterine growth retardation (IUGR), confirmed at birth (Group 2). Ten women (five in each group) had pregnancy-induced hypertension. All women were hospitalized and followed a similar daily routine. BP was recorded with an automatic wearable device. Measurements were obtained every 20 min for 24 +/- 1 h. BP profiles were analyzed by conventional statistical methods and by cosinor, involving the least squares fit of cosine curves with an anticipated period (24 h) to the data. BP parameters, fetal outcome, demographic and obstetric characteristics were compared between the two groups. Logistic regression and multivariate analyses were used to assess factors putatively associated with fetal outcome. The circadian amplitude of diastolic BP was found to be larger in normotensive women with IUGR. As gauged by odds ratios (OR), the circadian amplitude of diastolic BP (OR = 1.7, 95% CI: 1.1-2.8; P = 0.03) and hematocrit (OR = 1.4, 95% CI: 1.0-1.9; P = 0.04) were the only variables positively and independently associated with IUGR. In the presence of maternal hypertension, the circadian amplitude of systolic BP was negatively associated with IUGR (OR = 0.7, 95% CI: 0.5-1.0; P = 0.03). A larger circadian variation in diastolic BP, rather than a difference in the mean value of systolic or diastolic BP, was found to be statistically significantly associated with IUGR. This study adds another condition in which the circadian BP amplitude constitutes a harbinger of elevated risk, apart from an association with a shortened lifespan in the absence or presence of malignant hypertension and with an increased risk of stroke and nephropathy reported earlier.

Circadian rhythm of ANP, aldosterone and PRA in normotensive IUGR.

OBJECTIVE: Atrial natriuretic peptide (ANP) increases are reported during normal pregnancy, but the relation to arterial pressure and the renin-angiotensin system is debatable. We assessed whether normotensive pregnancies with intrauterine growth retardation (IUGR) present an alteration of maternal ANP levels. DESIGN: A total of 11 pregnant women with IUGR, in the absence of any other maternal or fetal pathology, entered the study during the third trimester. They were compared with 12 healthy pregnant women of similar age and characteristics. We monitored all subjects for blood pressure (BP), ANP, aldosterone and plasma renin activity (PRA), under the same conditions for 24 h. All subjects were submitted to the same regimen of life; with homogeneous dark : light periods, salt intake and meal times. METHODS: BP was monitored at 20 min intervals for 24 h and blood tests performed at six time points during the 24 h. EDTA plasma samples were immediately centrifuged. Hormone assays were performed by radioimmunoassay. Koch's nonparametric two-way analysis of variance (ANOVA) was used to compare the hormone time-dependent profiles in the two groups. Circadian rhythms were assessed by cosinor analysis. RESULTS: The IUGR group was characterized by higher ANP values compared to normal pregnancy, (205 +/- 24 versus 146 +/- 21 pg/ml: P < 0.05) but not significant differences were shown for PRA, aldosterone and BP circadian rhythms. CONCLUSIONS: This study shows higher ANP values in human pregnancy complicated by IUGR, with presence of normal BP, aldosterone and PRA profiles.

Cardiac autonomic adjustments to normal human pregnancy: insight from spectral analysis of R-R interval and systolic arterial pressure variability.

OBJECTIVE: To assess the adaptation in autonomic control mechanisms that accompanies the marked haemodynamic changes, such as increases in cardiac size and output, that occur in the course of normal human pregnancy. DESIGN: We studied 14 healthy pregnant women (aged 30+/-1 years) before the 6th week (early stage) and within weeks 32-34 (late stage) of pregnancy, while they were at rest or in a state of active orthostatism (standing), which enhances sympathetic activity. METHODS: We used echocardiography to assess cardiac volumes and mass, and spectral analysis of the R-R interval and systolic arterial pressure variability to obtain indices of autonomic regulation of the circulation. This non-invasive methodology, recently validated with direct recordings of muscle sympathetic nerve activity, furnishes quantitative markers of sympathetic modulation of the sino-atrial node (low frequency component, LF in normalized units, nu), vagal modulation (high frequency component, HF in normalized units, nu) and the overall arterial pressure-heart rate baroreflex gain (alpha index). RESULTS: Late pregnancy was characterized by an increase in cardiac size and volumes and by a reduction of R-R interval, R-R interval variance and the alpha index, together with an increase in the LF/HF ratio (from 1.4+/-0.4 to 5.6+/-1.9). Changes in markers of autonomic modulation of the sino-atrial node normally induced by the standing position were blunted. CONCLUSIONS: The late stage of normal human pregnancy appears to be characterized by alterations in the autonomic control of the circulation and by attenuated responsiveness to active standing, possibly as a consequence of the accompanying increase in cardiac size.

Scanning electron microscopy of postovulatory human endometrium in spontaneous cycles and cycles stimulated by hormone treatment.

The ultrastructure of the luminal surface epithelium was compared in endometrial samples taken from 23 normally cycling women and from 22 patients submitted to ovarian stimulation with clomiphene citrate (100 mg/day for 5 days), human menopausal gonadotrophin (hMG) and human chorionic gonadotrophin (hCG). On day 2 after ovulation, only four out of nine specimens taken from the women in the hormone-treated group were identical to those of normally cycling women. On day 6 after ovulation, only two out of the 13 biopsy specimens from the treated group were the same as those from normally cycling women at that stage. Apical protrusions (pinopodes), typical for this period of the cycle, were missing in 11 of the 13 endometrial samples from the treated group. These observations suggest that the hormonal treatment applied to induce ovulation (clomiphene citrate, hMG and hCG) can modify the normal development of the prenidatory endometrium, and may thus have a negative effect on the rate of egg implantation.