Final results of the real-life observational VICTOR-6 study on metronomic chemotherapy in elderly metastatic breast cancer (MBC) patients.

Nowadays, treatment of metastatic breast cancer (MBC) has been enriched with novel therapeutical strategies. Metronomic chemotherapy (mCHT) is a continuous and frequent administration of chemotherapy at a lower dose and so whit less toxicity. Thus, this strategy could be attractive for elderly MBC patients. Aim of this analysis is to provide insights into mCHT's activity in a real-life setting of elderly MBC patients. Data of patients ≥ 75 years old included in VICTOR-6 study were analyzed. VICTOR-6 is a multicentre, Italian, retrospective study, which collected data on mCHT in MBC patients treated between 2011 and 2016. A total of 112 patients were included. At the beginning of mCHT, median age was 81 years (75-98) and in 33% of the patients mCHT was the first line choice. Overall Response Rate (ORR) and Disease Control Rate (DCR) were 27.9% and 79.3%, respectively. Median PFS ranged between 7.6 and 9.1 months, OS between 14.1 and 18.5 months. The most relevant toxicity was the hematological one (24.1%); severe toxicity (grade 3-4) ranged from 0.9% for skin toxicity up to 8% for hematologic one. This is a large study about mCHT in elderly MBC patients, providing insights to be further investigated in this subgroup of frail patients.

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.

Arc and forearc rifting in the Tyrrhenian subduction system.

The evolution of forearc and backarc domains is usually treated separately, as they are separated by a volcanic arc. We analyse their spatial and temporal relationships in the Tyrrhenian subduction system, using seismic profiles and numerical modelling. A volcanic arc, which included the Marsili volcano, was involved in arc-rifting during the Pliocene. This process led to the formation of an oceanic backarc basin (~ 1.8 Ma) to the west of the Marsili volcano. The eastern region corresponded to the forearc domain, floored by serpentinised mantle. Here, a new volcanic arc formed at ~ 1 Ma, marking the onset of the forearc-rifting. This work highlights that fluids and melts induce weakening of the volcanic arc region and drive the arc-rifting that led to the backarc basin formation. Later, the slab rollback causes the trench-ward migration of volcanism that led to the forearc- rifting under the control of fluids released from the downgoing plate.

The prognostic impact of tumor mutational burden (TMB) in the first-line management of advanced non-oncogene addicted non-small-cell lung cancer (NSCLC): a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The role of tumor mutational burden (TMB) is still debated for selecting advanced non-oncogene addicted non-small-cell lung cancer (NSCLC) patients who might benefit from immune checkpoint inhibitors (ICIs). Of note, TMB failed to predict a benefit in overall survival (OS) among such patients. MATERIALS AND METHODS: The purpose of this meta-analysis was to compare efficacy outcomes among first-line immune-oncology (IO) agents versus standard platinum-based chemotherapy (CT) within two subgroups (TMB-low and TMB-high on either tissue or blood). We collected hazard ratios (HRs) to evaluate the association for progression-free survival (PFS) and OS, with the relative 95% confidence intervals (CIs). Risk ratios (RRs) were used as an association measure for objective response rate (ORR). RESULTS: Eight different cohorts of five randomized controlled phase III studies (3848 patients) were analyzed. In TMB-high patients, IO agents were associated with improved ORR (RRs 1.37, 95% CI 1.13-1.66), PFS (HR 0.69, 95% CI 0.61-0.79) and OS (HR 0.67, 95% CI 0.59-0.77) when compared with CT, thus suggesting a possible predictive role of high TMB for IO regimens. In TMB-low patients, the IO strategy did not lead to any significant benefit in survival and activity, whereas the pooled results of both ORR and PFS were intriguingly associated with a statistical significance in favor of CT. CONCLUSIONS: This meta-analysis resulted in a proven benefit in OS in favor of IO agents in the TMB-high population. Although more prospective data are warranted, we postulated the hypothesis that monitoring TMB, in addition to the existing programmed death-ligand 1 (PD-L1) expression level, could represent the preferable option for future clinical research in the first-line management of advanced non-oncogene addicted NSCLC patients.

Struma ovarii complicating pregnancy. Case report and literature review.

A 19-year-old woman at 12th week of pregnancy was referred to our hospital with severe acute abdominal pain, nausea and vomiting. Patient's abdomen was untreatable. Routine examinations, except neutrophilic leukocytosis, were normal. Ultrasound imaging showed the presence of intrauterine pregnancy corresponding to amenorrhea and a right complex ovarian mass, with well defined margins without papillary projection, 14x12 cm in diameter. No free fluid was evident. Due to untreatable abdomen and suspecting torsion of the ovarian tumor the patient underwent laparotomy under general anesthesia. The pregnant uterus was normal. The right ovary had increased volume for a cystic-solid mass of the size of 14 cm with smooth surface and twisted on the vascular peduncle. A right adnexectomy was performed. Intraoperative frozen section was negative for malignancy and postoperative histological examination revealed a struma ovarii without atypia of the follicular cells. Postoperative course was normal. The patient was discharged after three days and she delivered at term a normal baby. Mostly struma ovarii represents an incidental finding during cesarean section, but in rare case it may be cause of complications such as torsion, rupture, hypertiroidism and rarely may be a malignant tumor. The AA describe literature data on struma ovarii diagnosed in pregnancy.

Spectrally resolved helium absorption from the extended atmosphere of a warm Neptune-mass exoplanet.

Stellar heating causes atmospheres of close-in exoplanets to expand and escape. These extended atmospheres are difficult to observe because their main spectral signature-neutral hydrogen at ultraviolet wavelengths-is strongly absorbed by interstellar medium. We report the detection of the near-infrared triplet of neutral helium in the transiting warm Neptune-mass exoplanet HAT-P-11b by using ground-based, high-resolution observations. The helium feature is repeatable over two independent transits, with an average absorption depth of 1.08 ± 0.05%. Interpreting absorption spectra with three-dimensional simulations of the planet's upper atmosphere suggests that it extends beyond 5 planetary radii, with a large-scale height and a helium mass loss rate of ≲3 × 105 grams per second. A net blue-shift of the absorption might be explained by high-altitude winds flowing at 3 kilometers per second from day to night-side.

Broadband near-infrared astronomical spectrometer calibration and on-sky validation with an electro-optic laser frequency comb.

The quest for extrasolar planets and their characterization as well as studies of fundamental physics on cosmological scales rely on capabilities of high-resolution astronomical spectroscopy. A central requirement is a precise wavelength calibration of astronomical spectrographs allowing for extraction of subtle wavelength shifts from the spectra of stars and quasars. Here, we present an all-fiber, 400 nm wide near-infrared frequency comb based on electro-optic modulation with 14.5 GHz comb line spacing. Tests on the high-resolution, near-infrared spectrometer GIANO-B show a photon-noise limited calibration precision of < 10 cms as required for Earth-like planet detection. Moreover, the presented comb provides detailed insight into particularities of the spectrograph such as detector inhomogeneities and differential spectrograph drifts. The system is validated in on-sky observations of a radial velocity standard star (HD221354) and telluric atmospheric absorption features. The advantages of the system include simplicity, robustness and turn-key operation, features that are valuable at the observation sites.

Scuba diving death: Always due to drowning? Two forensic cases and a review of the literature.

Scuba diving is an increasingly common recreational activity. We describe the physiopathology of barotrauma in two cases where death was caused by pulmonary barotrauma while diving. An inspection and autopsy were carried out in both cases. The autopsy data were supported by post-mortem radiological investigation. Histological and toxicological analyses were also carried out, and dive computer and tank manometer analysis performed. In both cases, the cause of death was attributable to arterial gas embolism, resulting from pulmonary barotrauma subsequent to pulmonary over-distension. The dive computer analysis and the tank manometer allowed us to understand what happened underwater. In our opinion, a multidisciplinary approach is crucial in order to clarify the cause of death. Some pathological conditions and risk factors should be considered before diving.

Regulation of miR-483-3p by the O-linked N-acetylglucosamine transferase links chemosensitivity to glucose metabolism in liver cancer cells.

The miR-483-3p is upregulated in several tumors, including liver tumors, where it inhibits TP53-dependent apoptosis by targeting the pro-apoptotic gene BBC3/PUMA. The transcriptional regulation of the miR-483-3p could be driven by the ß-catenin/USF1 complex, independently from its host gene IGF2, and we previously demonstrated that in HepG2 hepatoblastoma cells carrying wild-type TP53 the upregulation of the miR-483-3p overcomes the antitumoral effects of the tumor-suppressor miR-145-5p by a mechanism involving cellular glucose availability. Here we demonstrate that in HepG2 cells, the molecular link between glucose concentration and miR-483-3p expression entails the O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT), which stabilizes the transcriptional complex at the miR-483 promoter. HepG2 cells showed reduced miR-483-3p expression and increased susceptibility to 5-fluorouracil (5-FU)-induced apoptosis in presence of the inhibitor of glycolysis 2-deoxy-d-glucose (2-DG). However, in vivo experiments showed that HepG2 cells with higher miR-483-3p expression were selected during tumor progression regardless of 5-FU treatment. Furthermore, treatment with 2-DG alone did not significantly reduce HepG2 xenograft load in immunodeficient mice. In conclusion, we show that in HepG2 cells glucose uptake increases the expression of the oncogenic miR-483-3p through the OGT pathway. This suggests that depletion of the miR-483-3p may be a valuable therapeutic approach in liver cancer patients, but the use of inhibitors of glycolysis to achieve this purpose could accelerate the selection of resistant neoplastic cell clones.

Kikuchi-Fujimoto disease: a clinicopathologic update.

Kikuchi-Fujmoto disease (KFD), also known as "histiocytic necrotizing lymphadenitis", is a rare lymphadenitis of unknown origin, but with an excellent prognosis. It is more common in Asia, but isolated cases are also reported in America, Africa and Europe. The disease can have an acute or subacute course, usually develops in 1 to 3 weeks, with spontaneous resolution in 1-4 months. The main clinical sign is cervical lymphadenopathy, especially in the posterior cervical triangle with bulky and painful lymph nodes, usually affecting only one side; rare cases of generalized lymphadenopathy can be seen. This common clinical presentation can also be accompanied by nausea, vomiting, weight loss, weakness, headache and arthralgia. An extranodal extension of the disease, including involvement of skin, eye, and bone marrow localizations, has been rarely described. Most patients have leukopenia or neutropenia with a relative leukocytosis. At an ultrasound exploration of the affected lymph nodes, a hypoechoic aspect can be seen, with an external, thick and irregular hyperechoic ring. As there are no specific tests for KFD, the final diagnosis is histologically-based from lymph node excisional biopsy. Histological examination shows paracortical foci of coagulative necrosis containing karyorrhectic debris, which are surrounded by numerous CD68+/myeloperoxidase (MPO)+ histiocytes, CD68+/CD123+ plasmacytoid dendritic cells, and a minority of small- to large-sized CD8+lymphocytes and immunoblasts. Differential diagnosis mainly includes systemic lupus erithematous (SLE)-related lymphadenopathy and large cell lymphoma. The histological absence of neutrophils, plasmacells, as well as hematoxylin bodies, is a feature which argues against the diagnosis of SLE. In addition, the absence of auto-antibodies and anti-nuclear antibodies is useful in ruling out an autoimmune disorder. Early diagnosis of KFD is crucial to prevent the patients undergo extensive investigations related to suspected malignant lymphomas or other diseases.

Allele-specific loss and transcription of the miR-15a/16-1 cluster in chronic lymphocytic leukemia.

Deregulation of the miR-15a/16-1 cluster has a key role in the pathogenesis of chronic lymphocytic leukemia (CLL), a clinically heterogeneous disease with indolent and aggressive forms. The miR-15a/16-1 locus is located at 13q14, the most frequently deleted region in CLL. Starting from functional investigations of a rare SNP upstream the miR cluster, we identified a novel allele-specific mechanism that exploits a cryptic activator region to recruit the RNA polymerase III for miR-15a/16-1 transcription. This regulation of the miR-15a/16- locus is independent of the DLEU2 host gene, which is often transcribed monoallellically by RPII. We found that normally one allele of miR-15a/16-1 is transcribed by RNAPII, the other one by RNAPIII. In our subset of CLL patients harboring 13q14 deletions, exclusive RNA polymerase III (RPIII)-driven transcription of the miR-15a/16-1 was the consequence of loss of the RPII-regulated allele and correlated with high expression of the poor prognostic marker ZAP70 (P=0.019). Thus, our findings point to a novel biological process, characterized by double allele-specific transcriptional regulation of the miR-15a/16-1 locus by alternative mechanisms. Differential usage of these mechanisms may distinguish at onset aggressive from indolent forms of CLL. This provides a basis for the clinical heterogeneity of the CLL patients carrying 13q14 deletions.

An unusual case of multiple and bilateral ovarian dermoid cysts. Case report.

OBJECTIVE: Multiple and bilateral ovarian dermoid cysts constitute a very unusual report. We report an rare case of a woman with three ovarian dermoid cyst, two localized in the same ovary, detected by US examination and removed by laparoscopy. CASE REPORT: A patient aged 29 years, para 0, gravida 0, was referred to our hospital with pain of the right adnexal region. Gynaecological examination showed an antiverted uterus with normal volume; on the right side a mobile mass approximately 7 cms in diameter was palpable, moreover the left ovary was normal. Ultrasound examination showed a normal uterus. The right ovary presented two complex masses of 7 and 3 cm in diameter, respectively; moreover, the left ovary showed a hyperechogenic complex mass of 3 cm in diameter. The ultrasound pattern was compatible with bilateral ovarian dermoid cysts. On laparoscopy abdominal cavity and uterus were normal, while the right ovary presented two masses and the left ovary a small mass which were enucleated and removed. The patient had an uncomplicated postoperative recovery and was discharged two day after laparoscopy. Pathologic examination confirmed the diagnosis of ovarian dermoid cysts. A one year follow-up showed no evidence of recurrence. CONCLUSION: The case reported shows that exceptionally multiple and bilateral dermoid cysts may be detected underlining the importance of an accurate preoperative diagnostic imaging. Some recurrence of ovarian dermoid cysts may be due to undiagnosed small dermoid cists during preoperative imaging and/or surgical exploration.

Surface analysis and osteoblasts response of a titanium oxi-carbide film deposited on titanium by ion plating plasma assisted (IPPA).

Titanium is the most widely used material in orthopaedic and dental implantoprosthesis due to its superior physical properties and enhanced biocompatibility due to the spontaneous formation of a passivating layer of titanium oxides which, however, does not form good chemical bonds with bone and tends to brake exposing bulk titanium to harsh body fluids releasing titanium particles which may prime an inflammation response and a fibrotic tissue production. In order to avoid these possible problems and to enhance the biocompatibility of titanium implants, modifications of titanium surfaces by many different materials as hydroxyapatite, titanium nitride, titanium oxide and titanium carbide have been proposed. The latter is shown to be an efficient protection for the titanium implant in the harsh conditions of biological tissues and, compared to untreated titanium, acting like an osteoblast stimulation factor increasing in vitro production of proteins involved in osteogenesis. These results were confirmed by in vivo experiments in rabbits: implants covered by the titanium carbide (TiC) layer were faster and better osseointegrated than untreated titanium implants. The TiC layer was deposited by a Pulsed Laser Deposition (PLD) device which allowed only one deposition per cycle, shown to be unsuitable for industrial applications. Therefore the main objective of the present work was to replace PLD process with an Ion Plating Plasma Assisted (IPPA) deposition process, which is suitable for industrial upgrading. By this technique, nanostructured TiOx-TiCy-C has been deposited on titanium after sandblasting with 120 micron zirconia spheres. XPS analyses revealed the presence of about 33% carbon (50% of which is present as free carbon), 39% oxygen and 28% titanium (37% of which is bound to carbon to form TiC and 63% is bound to oxygen to form non stoichiometric oxides). Surface mechanical response of as-deposited coatings has been performed by nanoindentation techniques. Focused Ion Beam micrographs showed bigger differences on the obtained nanostructure compared to the PLD coating structure; in vitro tests confirm for IPPA produced coatings an improvement in stimulating osteoblasts to produce mRNA's of proteins involved in the ossification process, this latter case they resulted to be faster and more efficient. The proposed treatement is expected to improve the good results obtained by PLD, in vivo as well.

A transiting giant planet with a temperature between 250 K and 430 K.

Of the over 400 known exoplanets, there are about 70 planets that transit their central star, a situation that permits the derivation of their basic parameters and facilitates investigations of their atmospheres. Some short-period planets, including the first terrestrial exoplanet (CoRoT-7b), have been discovered using a space mission designed to find smaller and more distant planets than can be seen from the ground. Here we report transit observations of CoRoT-9b, which orbits with a period of 95.274 days on a low eccentricity of 0.11 +/- 0.04 around a solar-like star. Its periastron distance of 0.36 astronomical units is by far the largest of all transiting planets, yielding a 'temperate' photospheric temperature estimated to be between 250 and 430 K. Unlike previously known transiting planets, the present size of CoRoT-9b should not have been affected by tidal heat dissipation processes. Indeed, the planet is found to be well described by standard evolution models with an inferred interior composition consistent with that of Jupiter and Saturn.

An orbital period of 0.94 days for the hot-Jupiter planet WASP-18b.

The 'hot Jupiters' that abound in lists of known extrasolar planets are thought to have formed far from their host stars, but migrate inwards through interactions with the proto-planetary disk from which they were born, or by an alternative mechanism such as planet-planet scattering. The hot Jupiters closest to their parent stars, at orbital distances of only approximately 0.02 astronomical units, have strong tidal interactions, and systems such as OGLE-TR-56 have been suggested as tests of tidal dissipation theory. Here we report the discovery of planet WASP-18b with an orbital period of 0.94 days and a mass of ten Jupiter masses (10 M(Jup)), resulting in a tidal interaction an order of magnitude stronger than that of planet OGLE-TR-56b. Under the assumption that the tidal-dissipation parameter Q of the host star is of the order of 10(6), as measured for Solar System bodies and binary stars and as often applied to extrasolar planets, WASP-18b will be spiralling inwards on a timescale less than a thousandth that of the lifetime of its host star. Therefore either WASP-18 is in a rare, exceptionally short-lived state, or the tidal dissipation in this system (and possibly other hot-Jupiter systems) must be much weaker than in the Solar System.

[Risk factors for fetal and neonatal brain injury]. / Fattori di rischio per il danno cerebrale fetale e neonatale.

Epidemiological studies have suggested a strong association of fetal and neonatal brain damage with fetal infections and free radical release. Intrauterine infection and hypoxia ischemia appear to share some characteristics, including high levels of cytokines and adhesion molecules. The relevance of the actions of cytokines to a variety of neurological disorders has opened a potentially fruitful area of research and therapeutic development.

[Fetal malformations diagnosed using ultrasonography during tri-test. A retrospective study of 1633 fetuses]. / Malformazioni fetali diagnosticate all'esame ultrasuonografico durante l'esecuzione del tri-test. Studio retrospettivo su 1,633 feti.

BACKGROUND: To find out which fetal malformations are diagnosed during the tri-test. METHODS: A total of 1633 pregnant women were enrolled in the study and underwent biochemical screening for Down s syndrome and DTN at the Outpatient Clinic for Prenatal Diagnosis of Santo Bambino Hospital in Catania between January 1997 and December 1998. Scans were performed using a TA route in all cases and mainly during the 16th week. RESULTS: 21 abnormal fetuses were diagnosed, equal to 1 out of 77 fetuses (3 cases of isolated DTN; 1 case of cyst in the posterior cranial fossa associated with complex heart malformation; 6 cases of cyst of the choroid plexus; 2 cases of bone dysplasia; 2 cases of cardiopathy; 4 cases of non-immunological fetal hydrops; 1 case of hygroma). In 8 out of 21 abnormal fetuses the tri-test was positive for DNT and SD or atypical. One case of trisomy 18 and 1 case of mosaicism were diagnosed. CONCLUSIONS: A fetal abnormality was diagnosed in one out of 77 fetuses. This finding, although it underestimates the real frequency of these anomalies (retrospective study, selected sample, non optimal period for the diagnosis of fetal malformations, non-systematic study of 4 chambers), once again underlines the importance of a careful morphological evaluation in eyery scan carried out. In our study some malformations were not diagnosed previously because this was the first scan (1 case of anencephaly), or because the abnormality was presumably not present in earlier tests (bone dysplasia at early stage of pregnancy) or because the earlier test was inadequate (2 DTN tested after the 12th week). In some cases it is also possible to diagnose images, such as transient hygromas which indicate a group of patients with a risk of chromosome pathology. Since they are transient, these lesions are only found if the test is performed at a period of pregnancy before the optimal moment for the tri-test. In personal experience the execution of biochemical screening for Down s syndrome and DTN should always be associated with a scan not only to date the pregnancy, but also because it is not infrequent to diagnose malformations.

The Spectroscopic Orbit of the Planetary Companion Transiting HD 209458.

We report a spectroscopic orbit with period P=3.52433+/-0.00027 days for the planetary companion that transits the solar-type star HD 209458. For the metallicity, mass, and radius of the star, we derive [Fe/H&sqbr0;=0.00+/-0.02, M*=1.1+/-0.1 M middle dot in circle, and R*=1.2+/-0.1 R middle dot in circle. This is based on a new analysis of the iron lines in our HIRES template spectrum and also on the absolute magnitude, effective temperature, and color of the star, and it uses isochrones from four different sets of stellar evolution models. Using these values for the stellar parameters, we reanalyze the transit data and derive an orbital inclination of i=86&fdg;1+/-1&fdg;6. For the planet, we derive a mass of Mp=0.69+/-0.05 MJup, a radius of Rp=1.40+/-0.17 RJup, and a density of rho=0.31+/-0.07 g cm-3.