Encorafenib plus cetuximab with or without binimetinib in patients with BRAF V600E-mutated metastatic colorectal cancer: real-life data from an Italian multicenter experience.

BACKGROUND: Encorafenib plus cetuximab with or without binimetinib showed increased objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) compared with chemotherapy plus anti-EGFR in previously treated patients with BRAF V600E-mutated (mut) metastatic colorectal cancer (mCRC). Although no formal comparison was planned, addition of binimetinib to encorafenib plus cetuximab did not provide significant efficacy advantage. PATIENTS AND METHODS: This real-life study was aimed at evaluating safety, activity, and efficacy of encorafenib plus cetuximab with or without binimetinib in patients with BRAF V600E-mut mCRC treated at 21 Italian centers within a nominal use program launched in May 2019. RESULTS: Out of 133 patients included, 97 (73%) received encorafenib plus cetuximab (targeted doublet) and 36 (27%) the same therapy plus binimetinib (targeted triplet). Most patients had Eastern Cooperative Group Performance Status (ECOG-PS) of 0 or 1 (86%), right-sided primary tumor (69%), and synchronous disease (66%). Twenty (15%) tumors were DNA mismatch repair deficiency (dMMR)/microsatellite instability (MSI)-high. As many as 44 (34%) patients had received two or more prior lines of therapy, 122 (92%) were previously exposed to oxaliplatin, and 109 (82%) to anti-vascular endothelial growth factor (anti-VEGF). Most frequent adverse events were asthenia (62%) and anti-EGFR-related skin rash (52%). Any grade nausea (P = 0.03), vomiting (P = 0.04), and diarrhea (P = 0.07) were more frequent with the triplet therapy, while melanocytic nevi were less common (P = 0.06). Overall, ORR and disease control rate (DCR) were 23% and 69%, respectively, with numerically higher rates in the triplet group (ORR 31% versus 17%, P = 0.12; DCR 78% versus 65%, P = 0.23). Median PFS and OS were 4.5 and 7.2 months, respectively. Worse ECOG-PS, peritoneal metastases, and more than one prior treatment were independent poor prognostic factors for PFS and OS. Clonality of BRAF mutation measured as adjusted mutant allele fraction in tumor tissue was not associated with clinical outcome. CONCLUSIONS: Our real-life data are consistent with those from the BEACON trial in terms of safety, activity, and efficacy. Patients in good general condition and not heavily pretreated are those more likely to derive benefit from the targeted treatment.

Stroke care in young patients.

The aims of this study were (i) to evaluate the clinical features of a consecutive series of young patients with ischemic stroke and (ii) to assess the changes in the clinical management of these patients over the study period. All consecutive cases of young adults aged 16 to 44 years, with ischemic stroke, that were admitted between 2000 and 2005 in 10 Italian hospitals were included. We retrospectively identified 324 patients. One or more vascular risk factors were present in 71.5% of the patients. With respect to the diagnostic process, an increase in the frequency of cerebral noninvasive angiographic studies and a decrease in the use of digital subtraction angiography were observed (P < 0.001 and P = 0.03, resp.). Undetermined causes decreased over 5-year period of study (P < 0.001). The diagnosis of cardioembolism increased. Thrombolysis was performed for 7.7% of the patients. PFO closure (8%) was the most frequently employed surgical procedure. In conclusion, the clinical care that is given to young patients with ischemic stroke changed over the study period. In particular, we detected an evolution in the diagnostic process and a reduction in the number of undetermined cases.

Incidence and predictors of acute symptomatic seizures after stroke.

OBJECTIVE: To assess incidence and predictors of acute symptomatic seizures in a prospective cohort of patients with first stroke. METHODS: Patients with first stroke hospitalized in 31 Italian centers were recruited. Relevant demographic data, disease characteristics, and risk factors were collected. Acute symptomatic seizures (≤7 days) were recorded and correlated to age, gender, family history of epilepsy, and vascular risk factors. RESULTS: A total of 714 patients (315 women, 399 men; age 27-97 years) were enrolled. A total of 609 (85.3%) had cerebral infarction (32 cerebral infarction with hemorrhagic transformation [CIHT]) and 105 (14.7%) primary intracerebral hemorrhage (PIH). A total of 141 (19.7%) had a large lesion (>3 cm) and 296 (41.5%) cortical involvement. Twelve patients reported family history of seizures. Forty-five patients (6.3%) presented acute symptomatic seizures, 24 with cerebral infarction (4.2%), 4 with CIHT (12.5%), and 17 (16.2%) with PIH. In multivariate analysis, compared to cerebral infarction, PIH carried the highest risk (odds ratio [OR] 7.2; 95% confidence interval [CI] 3.5-14.9) followed by CIHT (OR 2.7; 95% CI 0.8-9.6). Cortical involvement was a risk factor for PIH (OR 6.0; 95% CI 1.8-20.8) and for CI (OR 3.1; 95% CI 1.3-7.8). Hyperlipidemia (OR 0.2; 95% CI 0.03-0.8) was a protective factor for IPH. CONCLUSION: The incidence of acute symptomatic seizures is the highest reported in patients with first stroke with prospective follow-up. Hemorrhagic stroke and cortical lesion were independent predictors of acute symptomatic seizures. Hyperlipidemia was a protective factor for hemorrhagic stroke.

[Drug use among workers: an update]. / Aggiornamenti in tema di abuso di sostanze stupefacenti e psicotrope.

We present data coming from two years of surveillance of drug use among workers, as provided for by the recent law. Urine samples have been collected either by our lab or by the firm; procedures and investigated substances followed the law. Self-reported information on job duties and history of drug use have also been collected. Between September 2008 and April 2010, n = 2745 workers (age 40.5 +/- 9.5, 98% men, 43% handling workers) were screened, for a total number of 3002 urine samples. Among the samples with creatinine > = 20 mg/dl (n = 2878), 46 were positive (1.6%); no temporal trends were detected. Cannabis e cocaine were the two most spread substances. Positivity was associated with young age and presence of another positive sample in the same firm. Furthermore, we present the results of the analysis (urine and hair samples) on 146 suspected drug abuser selected by the SERT Varese in the same time period.

Nanoscale reversible mass transport for archival memory.

We report on a simple electromechanical memory device in which an iron nanoparticle shuttle is controllably positioned within a hollow nanotube channel. The shuttle can be moved reversibly via an electrical write signal and can be positioned with nanoscale precision. The position of the shuttle can be read out directly via a blind resistance read measurement, allowing application as a nonvolatile memory element with potentially hundreds of memory states per device. The shuttle memory has application for archival storage, with information density as high as 10(12) bits/in(2), and thermodynamic stability in excess of one billion years.

Comparative HPLC and ELISA studies for CDT isoform characterization in subjects with alcohol related problems. Prospective application in workplace risk-prevention policy.

Serum carbohydrate-deficient transferrin (CDT) is the most specific marker of chronic alcohol abuse so far. The performance of commercial HPLC over the ELISA method for measurement of CDT was evaluated on a series of 105 serum samples obtained from subjects referred to the Toxicology Laboratory of Salvatore Maugeri Hospital for alcohol-related problems. Compared to ELISA, HPLC analysis was more valuable for determining alcohol-related patterns of CDT isoforms and quantifying serum levels of disialotransferrin that better reflect chronic heavy drinking. Other significant advantages of the HPLC method included reproducible separation and easier detection of glycoform types and genetic transferrin variants that are known to cause falsely high or low results in sera examined by immunoassay. Current scientific evidence indicates that disialotransferrin is the target analyte for CDT determination and HPLC the current CDT analysis reference method. Systematic studies for early assessment of excessive alcohol intake or abuse of alcoholic substances in workers are recommended by the Italian legislation in accordance with the European Alcohol Action Plan (EAAP) launched by the WHO Regional Committee for Europe. These studies are advisable given their potential role in preventing negative effects of alcohol abuse in workplace. A research strategy combining CDT and other laboratory markers with questionnaire and physician interview is recommended for examining subjects with alcohol related problems and the diagnosis of alcoholism. This approach can be applied for alcohol abuse in workplace surveillance.

Energy minimization and ac demagnetization in a nanomagnet array.

We study ac demagnetization in frustrated arrays of single-domain ferromagnetic islands, exhaustively resolving every (Ising-like) magnetic degree of freedom in the systems. Although the net moment of the arrays is brought near zero by a protocol with sufficiently small step size, the final magnetostatic energy of the demagnetized array continues to decrease for finer-stepped protocols and does not extrapolate to the ground-state energy. The resulting complex disordered magnetic state can be described by a maximum-entropy ensemble constrained to satisfy just nearest-neighbor correlations.

Unusual morphological features in a presumably Neolithic individual from Riparo della Rossa, Serra San Quirico (Ancona, Italy).

The present study describes human skeletal remains from Riparo della Rossa, a rock shelter in the Marche region (Central Italy). The remains consist of a cranial vault and a few non-articulated postcranial bones, possibly belonging to the same adult individual. As the cranial vault showed some morphological features that are unusual for a modern human (marked prominence of the supraorbital region, very prominent nasal bones and rather high thickness of the vault), an accurate anthropological analysis and quantification of the antiquity of the bones were required. The remains were dated with two different absolute dating methods, AMS (14)C and (235)U-(231)Pa non-destructive gamma-ray spectrometry (NDGRS), which produced discordant results: the uncalibrated (14)C dating produced 5690 +/- 80 BP for the cranial vault and 6110 +/- 80 BP for the clavicle; the NDGRS dating produced 10,000 +/- 3000 BP for the cranial vault. The sex discriminant morphological characters on the skull are not unequivocal, though the masculine ones appear more evident. The aims of the present paper are: to provide a morphological and metric description of the remains; to interpret their unusual morphological features; to attempt to attribute them to male or female sex and to one of the possible prehistoric cultural groups, according to dating results (Upper Palaeolithic, Mesolithic or Neolithic). The attribution was obtained by a Bayesian procedure taking into account the reliability of the combined information of morphological/metric features and absolute dating results. The results suggest that the Riparo della Rossa remains are best attributed to a male individual of the Neolithic age.

[Diagnostic agreement between two different analytic methods for in vitro measurement of specific IgE and comparison with clinical evaluation and in vivo test for ubiquitarian and professional allergens]. / Concordanza diagnostica tra due differenti metodi analitici per la determinazione in vitro di IgE specifiche e confronto con valutazione clinica e test in vivo per allergeni ubiquitari e professionali.

This study surveys the diagnostic agreement between two different analytic systems for the measurement of serum specific IgE (sLgE), Immulite 2000 (IML) and ImmunoCap (CAP), with clinic evaluation and in vivo test. Our sample is represented by 33 adults (27 females and 6 males), with suspect of immediate allergic disease and suspect of sensitization to at least one allergen of the study panel (18 allergens: inhalant, alimentary and professional). All patients have been subjected to Skin Prick Test (SPT) for all the studied allergens, therefore sIgE measurement with IML and CAP systems has been executed (twice for each method) only for the allergens which resulted positive to the diagnostic suspect and to SPT, and for an equal number of allergens chosen by bound randomisation. In vitro methods (IML and CAP), evaluated by K Cohen statistics, give good diagnostic agreement. In the same way, the diagnostic agreement of the used analytic systems both with clinical suspect and with in vivo test is satisfying, with higher K values for IML.

Artificial 'spin ice' in a geometrically frustrated lattice of nanoscale ferromagnetic islands.

Frustration, defined as a competition between interactions such that not all of them can be satisfied, is important in systems ranging from neural networks to structural glasses. Geometrical frustration, which arises from the topology of a well-ordered structure rather than from disorder, has recently become a topic of considerable interest. In particular, geometrical frustration among spins in magnetic materials can lead to exotic low-temperature states, including 'spin ice', in which the local moments mimic the frustration of hydrogen ion positions in frozen water. Here we report an artificial geometrically frustrated magnet based on an array of lithographically fabricated single-domain ferromagnetic islands. The islands are arranged such that the dipole interactions create a two-dimensional analogue to spin ice. Images of the magnetic moments of individual elements in this correlated system allow us to study the local accommodation of frustration. We see both ice-like short-range correlations and an absence of long-range correlations, behaviour which is strikingly similar to the low-temperature state of spin ice. These results demonstrate that artificial frustrated magnets can provide an uncharted arena in which the physics of frustration can be directly visualized.

Dizziness and vertigo: an epidemiological survey and patient management in the emergency room.

Dizziness and vertigo are frequent causes of presentation at the emergency room, with an incidence in the Vimercate district, Italy, close to 3.5%. The basic management of the "dizzy" patients in the emergency room includes a detailed history and an accurate physical/neurological examination, with the aim to identify "at risk" patients who require further diagnostic procedures and/or immediate admission to the hospital.

Strong superconductivity with local Jahn-Teller phonons in C60 solids.

We analyze fulleride superconductivity at experimental doping levels, treating the electron-electron and electron-phonon interactions on an equal footing, and demonstrate that the Jahn-Teller phonons create a local (intramolecular) pairing which is surprisingly resistant to the Coulomb repulsion, despite the weakness of retardation in these low-bandwidth systems. The requirement for coherence throughout the solid then yields a very strong doping dependence to T(c), one consistent with experiment and much stronger than expected from standard Eliashberg theory.

Thrombolysis for acute ischemic stroke: the patient's point of view.

BACKGROUND: The use of thrombolytic therapy for acute ischemic stroke is still controversial. A major problem is balancing the improvement in functional ability against the risk of early death from cerebral hemorrhage. Our aim was to assess whether patients who have had a stroke, and their proxies, would give consent to thrombolysis if this therapy were introduced into clinical practice for acute ischemic stroke in Italy. METHODS: A 10-item questionnaire was administered by personnel not directly involved in the care of patients in 12 Italian hospitals. Interviews were carried out with at least 10 consecutive stroke inpatients per center in the postacute phase and to their proxies. RESULTS: There were 685 responders (377 female), median age 58 years (range 18-98); 332 were patients and 353 proxies. Responders were representative of the Italian population as a whole as regards mean age and sex, education and marital status; 59% of responders (95% confidence interval 55-62%) would agree to thrombolysis in the case of stroke. There was more uncertainty among proxies than patients, especially when the decision had to be taken for a relative (41 vs. 17% could not decide, p < 0.001). The preference for thrombolysis was higher among more educated people (p = 0.001) and was not influenced by sex, age and marital status. Overall, 81% of responders would prefer to risk dying rather than remain severely disabled. CONCLUSION: Thrombolytic therapy is feasible in Italy as there is ample willingness to trade off a better functional outcome with a higher risk of death. Education is the main sociodemographic determinant of independent decision-making, as only those with an adequate cultural level are able to discriminate between one treatment option and another. The proxy's uncertainty about how to interpret a patient's preference regarding consent to thrombolytic therapy should be tackled, since proxies play a key role in making patients' preferences known in case of incompetence after an acute stroke.

Smallest nanotube: breaking the symmetry of sp(3) bonds in tubular geometries.

We describe how sp(2) carbon, threefold coordinated by other carbons, can be replaced by sp(3) carbon, also threefold carbon coordinated, to produce extremely small-diameter ( approximately 0.4 nm) carbon nanowires with only minimal bond-angle distortion. Under a naming convention analogous to that for ordinary carbon nanotubes, the smallest sp(3) tubes have wrapping indices (3,0) and (2,2). These systems have large band gaps and a stiffness larger even than that of traditional sp(2)-bonded carbon nanotubes. They therefore form the stiffest one-dimensional systems known.

Stochastic heterostructures and diodium in B/N-doped carbon nanotubes.

Carbon nanotubes are one dimensional and very narrow. These obvious facts imply that, under doping with boron and nitrogen, microscopic doping inhomogeneity is much more important than for bulk semiconductors. We consider the possibility of exploiting such fluctuations to create interesting devices. Using the self-consistent tight-binding technique, we study heavily doped highly compensated nanotubes, revealing the spontaneous formation of structures resembling chains of random quantum dots, or nanoscale diodelike elements in series. We also consider truly isolated impurities, revealing simple scaling properties of bound state sizes and energies.

Helium in one-dimensional nanopores: free dispersion, localization, and commensurate/incommensurate transitions with nonrigid orbitals.

The single-particle states of helium within a bundle of carbon nanotubes can range from nearly free-particle dispersion to localization, even within a single bundle. At intermediate effective masses, the corrugation in the external potential can be comparable to the intrasite He-He hard-core interaction. This results in a commensurate/incommensurate transition, where the mobility of the doubly occupied domain-wall solitons at high density greatly exceeds the corresponding hole mobility below the transition.

Computational design of direct-bandgap semiconductors that lattice-match silicon.

Crystalline silicon is an indirect-bandgap semiconductor, making it an inefficient emitter of light. The successful integration of silicon-based electronics with optical components will therefore require optically active (for example, direct-bandgap) materials that can be grown on silicon with high-quality interfaces. For well ordered materials, this effectively translates into the requirement that such materials lattice-match silicon: lattice mismatch generally causes cracks and poor interface properties once the mismatched overlayer exceeds a very thin critical thickness. But no direct-bandgap semiconductor has yet been produced that can lattice-match silicon, and previously suggested structures pose formidable challenges for synthesis. Much recent work has therefore focused on introducing compliant transition layers between the mismatched components. Here we propose a more direct solution to integrating silicon electronics with optical components. We have computationally designed two hypothetical direct-bandgap semiconductor alloys, the synthesis of which should be possible through the deposition of specific group-IV precursor molecules and which lattice-match silicon to 0.5-1% along lattice planes with low Miller indices. The calculated bandgaps (and hence the frequency of emitted light) lie in the window of minimal absorption in current optical fibres.

Tuning Fermi-surface properties through quantum confinement in metallic metalattices: new metals from old atoms.

We describe a new class of nanoscale structured metals wherein the effects of quantum confinement are combined with dispersive metallic electronic states to induce modifications to the fundamental low-energy microscopic properties of a three-dimensional metal: the density of states, the distribution of Fermi velocities, and the collective electronic response.